EP3003446A1

EP3003446A1 - Controlling arterial blood gas concentration

Info

Publication number: EP3003446A1
Application number: EP14806925.5A
Authority: EP
Inventors: Michael Klein; Joseph Fisher
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-06-05
Filing date: 2014-06-03
Publication date: 2016-04-13
Also published as: WO2014194401A1; EP3003446A4; CA2914406A1

Abstract

A system for controlling an amount of at least one gas X in a subject's lung to target at least one end tidal partial pressure of at least one gas X (PetX^T), the system uses a control system for controlling the gas delivery device, wherein the control system implements a sequential gas delivery system and a feedback algorithm which compares a PetX^T for a respective breath [i] of variable size and preferably a respective current PetX value measured by a measurement system, to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

Description

TITLE: CONTROLLING ARTERIAL BLOOD GAS CONCENTRATION

This PCT application, filed June 3, 2014 claims priority from U.S. Provisional Patent Application No.: 61/831 ,492 filed July 5, 2013 entitled "CONTROLLING ARTERIAL BLOOD GAS CONCENTRATION", the entirety of which is hereby incorporated by reference.

Field of the Invention

The present invention relates to a system, method and apparatus for controlling arterial blood gas concentrations of one or more gases.

Background of the Invention

Techniques for controlling end-tidal partial pressures of carbon dioxide, oxygen and other gases are gaining increasing importance for a variety of research, diagnostic and medicinal purposes. Methods for controlling end tidal pressures of gases have gained particular importance as a means for manipulating arterial levels of carbon dioxide (and also oxygen), for example to provide a controlled vasoactive stimulus to enable the measurement of cerebrovascular reactivity (CVR) e.g. by MRI.

Conventional methods of manipulating arterial carbon dioxide levels such as breath holding, hyperventilation and inhalation of fixed concentration of carbon dioxide balanced with medical air or oxygen are deficient in their ability to rapidly and accurately attain targeted arterial carbon dioxide partial pressures for the purposes of routinely measuring vascular reactivity in a rapid and reliable manner.

The end-tidal partial pressures of gases are determined by the gases inspired into the lungs, the mixed venous partial pressures of gases in the pulmonary circulation, and the exchange of gases between the alveolar space and the blood in transit through the pulmonary capillaries. Changes in the end-tidal partial pressures of gases are reflected in the pulmonary end-capillary partial pressures of gases, which in turn flow into the arterial circulation. The gases in the mixed-venous blood are determined by the arterial inflow of gases to the tissues and the exchange of gases between the tissue stores and the blood, while the blood is in transit through the tissue capillary beds. In the simplest approaches, manipulation of the end-tidal partial pressures of gases has been attempted with fixed changes to the composition of the inspired gas. However, without any additional intervention, the end-tidal partial pressures of gases vary slowly and irregularly as exchange occurs at the lungs and tissues. Furthermore, the ventilatory response to perturbations in the end-tidal partial pressures of gases is generally unpredictable and potentially unstable. Often, the ventilatory response acts to restore the condition of the blood to homeostatic norms. Therefore, any changes in the end-tidal partial pressures of gases are immediately challenged by a disruptive response in the alveolar ventilation. Consequently, fixed changes in the inspired gas composition provoke only slow, irregular, and transient changes in blood gas partial pressures.

In more complex approaches, manipulation of the end-tidal partial pressures of gases has been attempted with negative feedback control. This approach continuously varies the composition of the inspired gas so as to minimize error between measured and desired end-tidal partial pressures of gases. Technically, such systems suffer from the same limitations as all negative feedback control systems - an inherent trade-off between response time and stability. For example, to generate a transition (e.g. a 10 mm. Hg increase) in PetC02 for imaging vascular reactivity of the heart (e.g. by MRI) rapid transition times can be commercially vital but augmenting transition time cannot be done at the expense of stability. Stability may also be affected by irregular breathing in response to exercise, in response to positioning of a subject on a medical examination table or as a result of stresses arising during the course of a diagnostic procedure in which control of blood gas concentration is used as a stimulus. Notably, elevating the partial pressure of C0₂ (and to some extent oxygen) causes hyperventilation which in turn affects stability.

Consequently, there is a need to overcome previous limitations in end-tidal gas control, allowing for more precise and rapid execution of end tidal gas targeting sequences in a wide range of subjects and environments. Summary of the Invention

The present invention is particularly directed to targeting a partial pressure of at least one gas X (PetX^T) in a mammal's arterial blood in circumstances in which the subject's tidal volume is of variable size from breath to breath such that the amount of a gas of requisite composition to attain the target arterial partial pressure of gas X that will prove to be inhaled by the subject in any respective breath is not predictable in advance, for example in most circumstances where the subject is not breathing on a ventilator that is controlling the subject's tidal volume. Accordingly such tidal volumes may be of variable size from breath to breath, as in the common case of a

spontaneously breathing subject.

For present purposes a surrogate measure of the subject's arterial partial pressure of gas X in the form of the subject's end tidal partial pressure of gas X (PETX) is deemed to be a sufficiently closely approximation of the arterial value inasmuch as the end tidal expired gas is a gas of composition which has substantially equilibrated with blood leaving the lung and entering the systemic circulation.

Erratic breathing is not uncommon in subjects compelled to breath via a gas delivery device, as discussed below. The present inventors have developed a new method and apparatus for more rapidly and accurately targeting and maintaining an end tidal partial pressure of a gas X in a subject's lung in circumstances in which tidal volume from breath to breath is unpredictable and potentially highly erratic. Accordingly, it is now possible to more effectively target a partial pressure of at least one gas X in a spontaneously breathing subject's arterial blood across the range of scenarios and varied subject responses which potentially encompass highly erratic breathing.

Breath size is considered to be variable if it varies unpredictably, for example, for purposes herein in a manner or to an extent which cannot, in the existing circumstances, be described as insignificant. Methods of mechanical ventilation, for example, that do not control breath size are amenable to such an advantageous method of targeting. The present invention is corroborated by the discovery, in human clinical testing, that a target end tidal concentration of a gas X can be attained and maintained in a spontaneously breathing subject using a negative feedback algorithm despite substantial unpredictable changes in the subject's minute ventilation. This clinical study demonstrates that the inherent trade-off between response time and stability in targeting a particular end tidal concentration of a gas X, using negative feedback control, can be substantially mitigated using sequential gas delivery (SGD) in subjects responding variously to test conditions, the foregoing despite a given subject's changing response to the type of gas being delivered (e.g. where gas X is carbon dioxide subjects will tend to hyperventilate to greater or lesser extents) or the possible amplitude or such change having regard the nature of the diagnostic or therapeutic protocol. For example, the stress of breathing through an apparatus and/or the stress associated with being confined or otherwise discomforted in an imaging device (not measured in this study) and/or the stress or pain associated with receiving therapy(not measured in this study). Indeed, this advantage has been determined to be appreciable despite highly erratic breathing and even when a prospective or feed-forward model is used as an aid to reduce the variability achievable with negative feedback alone in attaining the target end tidal partial pressure of gas X.

The study data presented herein shows that fluctuation from a targeted end tidal PC0₂ was significantly less using SGD than without using SGD under conditions in which breath size of subject was substantially varied in a series of breaths over time.

Accordingly, in respective aspects, the invention is directed to one of a method, system, computer program product, IC chip (e.g. a programmable chip) and apparatus for targeting a partial pressure of at least one gas X (PetX^T) in a spontaneously breathing mammal's (subject's) arterial blood (optionally using end tidal values as preferred non-invasive surrogate measures of the actual arterial values) as well as to a method of controlling a gas delivery device (for respiratory gas delivery) such as a gas blender. It should be appreciated that the same end tidal partial pressure of gas X may be targeted for a series of successive breaths. Therefore, the term "targeting" or "for attaining" or "to attain" or "attainable" (terms used interchangeably) implies that a some particular value for PetX^T will be targeted, optionally on a breath by breath basis, whether or not the target for a respective breath [i] is the same or different, higher or lower. Therefore the term "to attain" or "target" and related terms encompass an often important goal maintaining a particular target end tidal partial pressure of gas X from breath to breath or interval to interval. It should also be appreciated that logistically attainable target partial pressures for several gases may in principle be targeted independently of one another. A predictive algorithm can be employed to discern logistically attainable targets which are relatively extreme; non-extreme values for logistically attainable target partial pressures for one or more gases will be known to persons skilled in the art as a matter of experience with the subject matter of the invention.

Those skilled in the art will also appreciate that increasing a target end tidal partial pressure of a gas X may require delivery of a gas containing a computed amount or concentration of gas X and that the control system may direct reduction in the concentration of a gas X to obtain a lower partial pressure of gas X by sending a signal to the flow controller to deliver a gas containing a low concentration or 0% of gas X for one or more breaths. This should be appreciated as well in the particular context in which gas X is a gas produced or consumed by the body (e.g carbon dioxide, oxygen, an anesthetic etc). It should also be appreciated that a spontaneously breathing subject may be asked to hyperventilate or hypoventilate "to attain" (i.e. "with the goal of attaining") a reduced partial pressure of a gas X more quickly or slowly and that a subject's spontaneous ventilation may be assisted mechanically in a manner known to those skilled in the art, particularly in a manner or to an extent that breath size for the duration in question is variable and unpredictable.

According to one aspect, the invention is directed to a method for targeting at least one partial pressure of at least one gas X (PetX^T) in a subject, optionally in a spontaneously breathing mammars blood, comprising, with respect to a series of respective breaths {i]:

(A) making available to a subject a first gas in the first part of a respective breath [i] and a neutral second gas (e.g. a gas having a partial pressure of gas X which equals the measured end tidal concentration of gas X in an immediately preceding breath or equals PetX^T targeted in the current respective breath [i]), in the second part of a respective breath [ij, wherein the amount of neutral gas received in a respective breath [i] at least equals or preferably exceeds the dead space volume of the subject's lung; and

(B) using a feedback control algorithm to:

(i) obtain, on a breath by breath basis, a measured value corresponding, at least approximately, to the arterial partial pressure of gas X after gas exchange in a previous breath (preferably breath [i-1]);

(ii) based on the measured value, compute an error signal with respect to PetX^T for the respective breath [i]; and

(iii) generate a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in the first gas to target PetX^T for the respective breath [i].

Optionally, the method is employed to conduct clinical testing in a mammal.

Optionally, the method is directed to enhancing a non-therapeutic diagnostic procedure, optionally an imaging procedure, the imaging procedure optionally exploiting a high resolution imaging modality, for example an Rl-based imaging modality.

Optionally, the method is employed in a therapeutic procedure.

Optionally, the method is employed to control a gas delivery device in the form of a gas blender adapted for delivering a respiratory gas to a mammal. The gas delivery device optionally comprises a measurement system for measuring the concentration of gas X in a subject's end tidal exhaled breath (arterial blood gases can also be measured directly in blood but such methods, although encompassed herein, are typically invasive) and a flow controller for controlling a gas delivery the concentration of gas X in a gas inhaled by the subject in a respective breath

['J.

Optionally, the amount of gas X required to be inspired by the subject the first portion of a respective breath [i] to target the PetX^T for a respective interval or breath is also determined prospectively based on a predictive algorithm. Optionally, the feedback control signal is added to the control signal generated as a result of the prospective determination.

Optionally, the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively, on a breath by breath basis.

The invention encompasses any robust feedback control algorithm known to those skilled in the art. Optionally, the feedback control signal is generated using a feedback control algorithm selected from a group comprising a PD, a PI and a PID control algorithm.

Optionally, the predictive algorithm (an example of which is more fully described with reference to Section C hereinbelow) is executed by: a. obtaining input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i]

(CMVXIH); b. obtaining input of a logistically attainable end tidal partial pressure of gas X (PetX[i]^T) for a respective breath [i]; c. obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX.I], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

Optionally, the mass balance equation is computed based on a tidal model of the lung.

Optionally, the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes comprising or corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

Optionally, a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [ij.

Optionally, the mass balance equation is solved for F|X.

Optionally, the predictive algorithm obtains inputs required to compute an F|X to target PetX[i]^T for a respective breath [i], wherein F|X is computed prospectively using a mass balance equation which comprises terms corresponding to optionally all the terms in:

eq. 1

It may be appreciated (as more fully discussed below) that some of these terms might be considered by those practicing the invention to exert minor effects on the targeting outcome, depending on which term and the circumstances including the degree to which accuracy is required, whether a smaller or large target change in arterial partial pressure of gas X is sought, the identity of gas X and it's importance in the testing procedure, whether a particular target is being maintained (at one extreme) and whether a rapid transition to one or several new targets, in rapid succession, is being sought (at the other extreme) as well as other factors affecting how well the hardware and negative feedback system function is a given situation. Accordingly, the invention contemplates that accounting only for an application or situation specific subset of the terms in the equations will still provide a useful predictive model for attaining one or more target end tidal concentration of gas X.

The invention is also directed to a computer program product and an IC chip for targeting at least one partial pressure of at least one gas X (PetX^T) in a subject, optionally in a spontaneously breathing mammal's blood, comprising, with respect to a series of respective breaths [i], machine readable code for:

(A) making available to a subject a first gas in the first part of a respective breath [i] and one of a neutral second gas and a gas having a partial pressure of gas X which equals PetX^T targeted in the respective breath [i], in the second part of a respective breath [i], wherein the amount of neutral gas (i.e. neutral with respect to the previous breath or the current breath, as explained below) received in a respective breath [i] at least equals or preferably exceeds the dead space volume of the subject's lung; and

(B) using a feedback control algorithm to:

(ii) based on the measured value, compute an error signal with respect to PetX^T for the respective breath [i]; and (iii) generate a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in the first gas to target PetX^T for the respective breath [i].

Optionally, a method, computer program product, IC chip, system or apparatus of the invention are employed as enhanced research tools.

In an apparatus, for example a gas delivery device including a measurement system, the control system of the apparatus is typically implemented by a computer, the computer typically configured to provide output signals to one or more rapid flow controllers based on input from the measurement system.

Optionally, the gas delivery device is a gas blender and the measurement system includes at least one flow sensor positioned to measure flow of an inspiratory gas stream to a subject and wherein the gas blender is controlled to add a variable amount of a gas containing a gas X to the inspiratory gas stream based on measurements obtained from the flow sensor to deliver an amount of gas X required to be inspired by the subject to target the PetX^T for a respective interval.

The breathing circuit may a physical SGD circuit in which the subject inhales neutral gas in the second part of a respective breath [i] in the form of gas exhaled by the subject's in a previous breath or alternatively an SGD circuit may be constituted by a virtual SGD circuit which may employ a conventional breathing circuit.

For the purposes of the present invention, the term neutral gas includes gas having a partial pressure of gas X which is the same at the partial pressure of gas X at the end of a previous breath, preferably the immediately preceding breath. An alternative to delivering this neutral gas from a previous breath as the second gas (the gas delivered for the remainder of a respective breath [i]) is delivering a gas having the targeted end tidal partial pressure of gas X for the respective breath [i] in question which is "neutral" with respect the current breath in contrast to the previous breath. Optionally, the method is employed to control a gas delivery device e.g. in the form of a gas blender adapted for delivering a respiratory gas to a mammal, the steps of this method optionally including: a) measuring for a respective breath [i] the concentration of the at least one gas X in a subject's expired gas in a previous breath; b) making available to a subject, for inspiration in a respective breath [i], a first gas and a second gas which is one of a neutral gas and a gas having a partial pressure of gas X which equals PetX^T targeted in the respective breath [i], such that when the subject's minute ventilation exceeds the fresh gas available for a breath, the second gas is delivered for the remainder of the breath; c) computing an error signal based on PetX^T for the respective breath [i] and a measured value of the concentration of gas X in the subject's end tidal expired gas for the previous breath [i-1]; d) generating a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in first gas to target PetX^T for the respective breath [i].

Irrespective of whether the breathing circuit is a physical sequential gas delivery circuit or a virtual sequential gas delivery circuit, ensuring that the subject (mammal) gets a volume of neutral gas which substantially equals and preferably exceeds its dead space volume (since breath sizes varies it is better to exceed the dead space volume by a safe margin) better ensures that the entirety of the first gas participates in gas exchange. This is optionally accomplished by setting the flow of the first gas into the breathing circuit to be equal to or less (preferably) than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation, so that the entire volume of the first gas controls enters the alveolar space and participates in gas exchange. The term sequential gas delivery and by extension circuits adapted or used for this purpose are defined below in Section C under a separate heading and in connection with Section B which explains virtual sequential gas delivery.

In one aspect, the invention is directed to a method for targeting an end tidal partial pressure of a gas X (PetX^T) in a respective breath [i], comprising, with respect to a respective breath [i]: a) measuring at least at the end of at least one previous breath, the concentration of the at least one gas X in a subject's expired gas to obtain a measured value of the concentration of gas X in the subject's end tidal expired gas in the previous breath, preferably the previous breath is the immediately preceding breath [i-1]; b) setting the flow of the first gas into the breathing circuit to be equal to or less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation; c) making available to a subject, for inspiration a first gas and a second gas, such that when the subject's minute ventilation exceeds the fresh gas available for a breath, the second gas is delivered for the remainder of the breath; wherein the first gas has a partial pressure of a gas X (PX) computed using a feedback algorithm which compares a PetX^T for a respective breath [i] and the measured value of the concentration of gas X in the subject's end tidal expired gas to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in first gas to target PetX^T for the respective breath [i];and wherein the second gas is one of a neutral gas (optionally a gas which has a (PX) approximating the PX in the subject's arterial blood after the immediately preceding breath) and the PetX^T for the current respective breath [i]).

Optionally the method employs a sequential gas delivery breathing circuit. Optionally, the method employs a virtual sequential gas algorithm as hereinafter described.

Optionally, the gas X is carbon dioxide.

Optionally, the imaging procedure measures a vascular response to vasoactive amount of carbon dioxide, optionally a vasodilatory amount of carbon dioxide.

Optionally, the partial pressures of a plurality of gases are controlled; optionally a plurality of gases comprising at least one of carbon dioxide and oxygen.

In another aspect, the invention is directed to a method for enhancing a non- therapeutic diagnostic imaging procedure in a subject wherein the method involves targeting at least one end tidal partial pressure of a gas X (PetX^T) in a respective breath [i], optionally to produce a vasoactive response, comprising, with respect to a respective breath [i]: a) measuring at least at the end of at least one previous breath, the concentration of the at least one gas X in a subject's expired gas to obtain a measured value of the concentration of gas X in the subject's end tidal expired gas in the previous breath, preferably the previous breath is the immediately preceding breath b) setting the flow of the first gas into the breathing circuit to be equal to or less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation; c) making available to a subject, for inspiration a first gas and a second gas, such that when the subject's minute ventilation exceeds the fresh gas available for a breath, the second gas is delivered for the remainder of the breath; wherein the first gas has a partial pressure of a gas X (PX) computed using a feedback algorithm which compares a PetX^T for a respective breath [i] and the measured value of the concentration of gas X in the subject's end tidal expired gas to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in first gas to target PetX^T for the respective breath [i]; and wherein the second gas is one of a neutral gas (optionally a gas which has a (PX) approximating the PX in the subject's arterial blood after the immediately preceding breath) and the PetX^T for the current respective breath [i]^'.

Preferably, PetX^T is targeted in each of a series successive breaths i, i+1...i+n preceding the capture of a respective image and optionally for the duration in which the respective image is captured.

In yet another aspect, the invention is directed to a method for controlling a gas delivery device to target an end tidal partial pressure of a gas X (PetX^T) in a respective breath [i], the gas delivery device operatively connected to a breathing circuit, the method comprising, with respect to a respective breath [i]: a) measuring at least at the end of at least one previous breath, the concentration of the at least one gas X in a subject's expired gas to obtain a measured value of the concentration of gas X in the subject's end tidal expired gas in the previous breath, preferably the previous breath is the immediately preceding breath [i-1]; b) setting the flow of the first gas into the breathing circuit to be equal to or less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation; c) making available to a subject, for inspiration a first gas and a second gas, such that when the subject's minute ventilation exceeds the fresh gas available for a breath, the second gas is delivered for the remainder of the breath; wherein the first gas has a partial pressure of a gas X (PX) computed using a feedback algorithm which compares a PetX^T for a respective breath [i] and the measured value of the concentration of gas X in the subject's end tidal expired gas to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in first gas to target PetX^T for the respective breath [i]; and wherein the second gas is one of a neutral gas, optionally a gas which has a (PX) approximating the PX in the subject's arterial blood after the immediately preceding breath, and the PetX^T for the current respective breath [i].

According to yet another aspect, the invention is directed to an apparatus for attaining a target partial pressure of at least one gas X (PetX^T) in a spontaneously breathing mammal's blood, comprising:

(1) a gas delivery device configured for connection to a breathing circuit;

(2) a control system;

(3) a measurement system configured to obtain a value which represents an approximation of the partial pressure of the at least one gas X in the subject's arterial blood after gas exchange in a previous breath, optionally the concentration of the at least one gas X in a subject's end tidal expired gas after gas exchange in breath [i-1]; wherein the control system is configured, with respect to a series of respective breaths

(A) to make available to a subject a first gas in the first part of a respective breath [i] and a neutral second gas in the second part of a respective breath [i], such that the amount of neutral gas received in a respective breath [Ί] at least equals and preferably exceeds the dead space volume;

(B) to use a feedback control algorithm to:

(i) obtain, on a breath by breath basis, the measured value corresponding, at least approximately, to the arterial partial pressure of gas X after gas exchange in a previous breath (preferably breath [i-1]);

The invention is also directed to an apparatus for targeting an end tidal partial pressure of a gas X (PetX^T), optionally in a spontaneously breathing mammal, comprising:

(1) a gas delivery device configured for connection to a breathing circuit;

(2) a measurement system configured for measuring the concentration of the at least one gas X in a subject's end tidal expired gas;

(3) a control system for controlling the gas delivery device, wherein the control system is configured to target a PetX^T for a series of respective inspiratory cycles of potentially variable length, the control system including a processor configured, for a respective breath [i]:

A. to obtain input of at least one logistically attainable PetX^T value;

B. to obtain input from the measurement system of at least one measured value corresponding to the subject's current arterial blood concentration of gas X (e.g. PaC0₂), optionally the end tidal partial of gas X (PetX) attained as a result of gas exchange in a previous breath, preferably the immediately preceding respective breath [i-1];

C. to determine of an amount of gas X required to be inspired by the subject in at least a first portion of an inspiratory cycle of a respective breath [i] to target the PetX^T for a respective interval, the gas delivery device configured to set a volume of the first portion of the inspiratory cycle in a respective breath [i] to be equal to or preferably less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation;

D. to control the amount of gas X in a volume of gas delivered to the subject in a first portion of the inspiratory cycle of a respective breath [i] and in a second remaining portion of that inspiratory cycle, to target the PetX^T via breath [i], at least one of the breathing circuit and the control system configured to be able to provide to a subject, for inspiration:

(a) a gas of a first composition determined by the processor for the first portion of the inspiratory cycle of a respective breath[i]; and

(b) when the subject's ventilation in a respective breath [ij exceeds the gas of first composition available for a breath, a gas of second composition having a partial pressure of gas X (PX) selected from one of a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i- ], and a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i]; and wherein the control system implements a feedback algorithm which compares a PetX^T for a respective breath [i] and optionally the value measured for the respective breath [i] from a previous breath.

According to another aspect, the invention is directed to a system for controlling an amount of at least one gas X in a mammal's lung, optionally a human subject, to target at least one end tidal partial pressure of at least one gas X (PetX¹), the system comprising:

(1) a measurement system preferably configured for measuring the concentration of the at least one gas X in a subject's end tidal expired gas;

(2) a control system for controlling a gas delivery device, optionally a gas blender, wherein the control system is configured to target and maintain a PetX^T for a series of respective inspiratory cycles of variable length, the control system including a processor configured, for a respective breath [i]:

A. to obtain input of at least one logistically attainable PetX^T value; B. to obtain input from the measurement system of at least one measured value corresponding to the subject's current arterial blood concentration of gas X (e.g. PaCC<2), optionally the end tidal partial of gas X (PetX) attained as a result of gas exchange in the immediately preceding respective breath

C. to determine of an amount of gas X required to be inspired by the subject in at least a first portion of an inspiratory cycle of a respective breath [i] to target the PetX^T for a respective interval;

D. to set a volume of the first portion of the inspiratory cycle in a respective breath [i] to be less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation;

E. to control the amount of gas X in a volume of gas delivered to the subject in a first portion of the inspiratory cycle of a respective breath [i] and in a second remaining portion of that inspiratory cycle, to target the PetX^T via breath ti], at least one of the breathing circuit and the control system configured to be able to provide to a subject, for inspiration:

(a) a gas of a first composition determined by the processor, during the first portion of the inspiratory cycle of a respective breath[i]; and

(b) when the subject's ventilation in a respective breath [i] exceeds the gas of first composition available for a breath, a gas of second composition having a partial pressure of gas X (PX) selected from one of a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i-1], and a PetX^T targeted in the respective breath [i] (i.e. the gas of second composition is provided for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i]); and wherein the control system implements a feedback algorithm which compares a PetX^T for a respective breath [i] and preferably a respective current measured PetX value to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

The system optionally comprises a gas delivery device. Alternatively, the system is embodied in a separate computer, optionally a portable computer that is connected to a gas delivery device, optionally a gas blender.

In one embodiment, the control system is configured to target a PetX^T for a plurality of respective intervals. Optionally, each respective interval is a single breath.

According to one aspect, the invention is directed to a system for controlling an amount of at least one gas X in a subject's lung to target at least one end tidal partial pressure of at least one gas X (PetX¹), the system comprising:

(1) a gas delivery device configured for connection to a breathing circuit, the breathing circuit of the type connectable a patient airway interface;

(2) a measurement system for measuring the concentration of the at least one gas X in a subject's end tidal expired gas;

(3) a control system for controlling the gas delivery device, wherein the control system is configured to target at least one PetX^T for at least one in a series of respective intervals, the respective intervals at least defined by a series of respective inspiratory cycles of variable size, the control system including a processor configured to, for a respective breath [i]:

A. obtain input of at least one logistically attainable PetX^T value for the respective interval;

B. obtain input from the measurement system of at least one measured PetX value attained as a result of gas exchange in a previous interval, preferably in an immediately preceding respective breath [i-1]; 2014/000473

C. determine of an amount of gas X required to be inspired by the subject in at least a first portion of an inspiratory cycle of a respective breath [i] to target the PetX^T for a respective interval, the gas delivery device configurable to set a volume of the first portion of the inspiratory cycle in a respective breath [i] to be equal to or preferably less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation;

D. Control the amount of gas X in a volume of gas delivered to the subject in a first portion of the inspiratory cycle of a respective breath [ij and in a second remaining portion of that inspiratory cycle, to target the PetX^T for the interval, the breathing circuit or the control system configured to make available to a subject, for inspiration:

(a) a gas of a first composition determined by the processor for the first portion of the inspiratory cycle of a respective breathfi]; and

(b) when the subject's ventilation in a respective breath [i] exceeds the gas of first composition available for a breath, a gas of second composition having a partial pressure of gas X (PX) selected from a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath or a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i]; and wherein the control system implements a feedback algorithm which compares a PetX^T for a respective breath [i] and preferably a respective current measured PetX value to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

In one embodiment, the control system is configured to target a PetX¹ for a plurality of respective intervals. Optionally, each respective interval is a single breath. In the context of the using feedback to improve an predictive model, the term "target" means to set as a goal "approximating" a particular end tidal value of gas X that is preferably at least as accurate as that which could be obtained by prospective modelling alone as defined below under the heading "Prospective Model For End Tidal Targeting, Targeting Sequences and Various Applications of End Tidal Targeting Systems and Algorithms". Although a prospective model is not required for operation of the invention, the attainment of the target using feedback and a sequential gas delivery approach is optionally capable of producing the results obtained in Example 1 below, however it will be appreciated that the accuracy demands of the particular application may well provide for latitude in targeting accuracy.

Optionally, the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively based on a predictive or feed forward algorithm, and a feedback control signal is added to the control signal generated as a result of the prospective determination in any applicable manner known to those skilled in the art.

With respect to the description of the prospective algorithm described in Section C below, it will be appreciated that reference to "controlling" the amount in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation, represents a partial accomplishment of the objective of using feedback to adjust the output of the predictive model. Thus "controlling" as described in Section C is to be understood for purposes of the present invention as "controlling in part or in tandem with negative feedback". The predictive algorithm is optionally tuned as herein defined in Section C.

Optionally, the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively on a breath by breath basis based on a tidal model of the lung (as described herein in Section C).

Optionally, the feedback control signal is generated using a feedback control algorithm selected from a group comprising a PD, a PI and a PID control algorithm. Optionally, the gas delivery device is a real-time gas blender.

Optionally, the breathing circuit includes a patient airway interface, a distally located one way inspiratory valve and a distally located one way expiratory valve. Optionally, the measurement system includes a gas X analyzer positioned to measure the gas X concentration exiting the one expiratory valve.

Each of the individual features described herein and each member feature of groups of features described collectively for convenience below or above, whether described individually or as members features of a group of features, is to be considered as described individually with respect to each of the broadest and narrower aspects of the invention described in this summary of invention.

Brief Description of the Drawings

Particular embodiments of the invention will now be described with reference to the drawings, of which:

Figure 1 is a diagrammatic representation of one prior art dynamic end tidal forcing system .

Figure 2 is a diagrammatic representation of a modified, prior art dynamic end tidal forcing system in which an inspiratory reservoir receives inspiratory gas intended for inspiration by a subject.

Figure 3a is a diagrammatic representation of components a subject's expired gas that would affect the results of a capnograph that would be obtained using a prior art dynamic end tidal forcing system.

Figure 3b is a diagrammatic representation of results that would be obtained from a capnograph when using a prior art or modified prior art dynamic end tidal forcing system. These results correspond to measured PetX values sampled from a location proximal to the patient airway interface (see positioning of gas analyzer in Figures 1 and 2). Figure 4 is a schematic diagram showing one embodiment of a system for implementing a targeting sequence to control a subject's end tidal concentration of a gas X according to the invention.

Figure 5 is a schematic diagram showing another embodiment of a system for implementing a targeting sequence to control a subject's end tidal concentration of a gas X according to the invention.

Figure 6a is a diagrammatic representation of a model of a lung for illustrating the dead space and gas exchange portions of the lung pertinent to using a system according to the invention according to an embodiment of the invention depicted in Figure 4 or 5. This model of the lung is further described with reference to Figure 10 described below.

Figure 6b is a graph of end tidal readings derived from the output of a capnograph that would be obtained using a system according to the invention referred to in Figure 4 or 5. These results correspond to measured PetX values sampled from the expiratory limb after exhaled gas passes through a one way expiratory valve.

Figure 6c is alternative configuration of the portion of the circuit shown in Figures 4 and 5 that is proximal to and includes one way inspiratory and expiratory valves; the alternative configuration obviating the need for these valves.

Figure 7 presents tabulated results of Example 1 using one embodiment of a system according to the invention, the system used for implementing a targeting sequence to control a subject's end tidal concentration of C0₂ according to the invention.

Figures 8a to 8f are graphs generated for Example 1 (for which the data is summarized in Figure 7) organized to plot end tidal readings and minute volumes with respect to time. The graphs show the progression over time of three respective subjects' targeted and actual end tidal PC0₂s , as well as variations in their breath size quantified in terms of minute ventilation in L/min (plotted with respect to time on the y axis). End tidal gas X readings are shown corresponding to minute ventilation values on dual X-axes.

Figure 8g reproduces a targeting sequence including a time line of the target end tidal PCO2 values sought to be approximated using the invention. Figure 9 is a schematic diagram showing yet another embodiment of a system for implementing a targeting sequence to control a subject's end tidal concentration of a gas X according to the invention. This system illustrates the use of a physical sequential gas delivery circuit and may be implemented with or without a prospective targeting algorithm in aid.

Figures 10-14 relate to features of the invention described above that are particularly related to a system for virtual gas delivery, and in particular, a virtual sequential gas delivery (VSGD) system. Immediately below, in the figure descriptions, and in the related description under the heading "Virtual Sequential Gas Delivery" reference to the invention is to virtual gas delivery and reference numerals appearing in Figures 10-14 are tied only to the description under this heading.

Figure 10 is a schematic representation of a lung illustrating how sequentially delivered components of a respiratory gas may contribute differentially to gas exchange with the pulmonary circulation.

Figure 11 is a schematic representation of one example of a reference breathing circuit.

Figure 12 is a schematic representation of another example of a reference breathing circuit- Figure 13 is a schematic representation of one embodiment of a respiratory gas delivery system according to the invention.

Figure 14 is a schematic representation of another embodiment of a respiratory gas delivery system according to the invention.

Figures 15-25 relate to features of the invention described above that are particularly related to a prospective model of end tidal targeting of one or more gases, and in particular, a tidal model for this purpose. Immediately below, in the figure descriptions, and in the related description under the heading "Prospective Model For End Tidal Targeting, Targeting Sequences and Various Applications of End Tidal Targeting Algorithms". Reference to the invention is to the inventions as defined in the summary of invention organized under this heading and reference numerals appearing in Figures 15-24 are tied only to the description under this heading and to the invention defined in claims paragraphs 1B to 79B andIC to 89C which define an embodiment of a prospective model that may be used in connection with the subject matter of the instant invention.

Figure 15 is a schematic overview of the movement of blood and the exchange of gases throughout the entire system.

Figure 16 is a detailed schematic representation of the movement of blood and the exchange of gases at the tissues.

Figure 17 is a detailed schematic representation of the movement of blood and the exchange of gases at the lungs when sequential rebreathing is not employed.

Figure 18 is a detailed schematic representation of the movement of blood and the exchange of gases at the lungs when sequential rebreathing is employed.

Figure 19 is a schematic diagram of one embodiment of an apparatus according to the invention that can be used to implement an embodiment of a method according to the invention.

Figure 20 is a graphic representation of a tuning sequence and observed errors that can be used to tune model parameters.

Figure 21 is a Table of abbreviations (Table 1) used in the description under the heading: "Prospective Model For End Tidal Targeting, Targeting Sequences and Various Applicationsof End Tidal Targeting Algorithms"

Figures 22a and 22b are graphical representations of changes in target end tidal values of C02 and response - mid-cerebral artery blood flow velocity, for a slow responder and a fast responder as revealed by a ramp sequence.

Figure 23 is a graphical representation of blood flow responses to PCO2 predicted for the model of a brain vascular territory with a partially-stenosed vessel branch and a healthy branch in parallel as revealed by a ramp sequence. Figure 24 is a graphical representation of a bold signal response to PC0₂ as revealed by a ramp sequence and corresponding CVR maps for an axial slice at different PetC0₂ ranges for a patient with moya moya disease.

Figure 25 discloses end tidal targets and results of targeting obtained using the prospective model and represents a partial raw data set - for 6 of the subjects.

Section A: Detailed Description of Preferred Embodiments of Present Invention

The expressions "for attaining" or "to attain" are used to express the goal of a targeting algorithm and are used synonymously with the term "targeting". Use herein of this phraseology with reference to PetX[i]^T should be understood to be most meaningful in a particular context for which the invention is used, for example having regard to the precision of the technology used for measuring the results and delivering the gas. Additionally, for gases such as oxygen and carbon dioxide relevant context includes the extent to which a particular PetX{i]^T departs from normal partial pressures of these gases since homeostatic mechanisms are in play to temper change. For the sake of example only, assuming a measurement error of +/- 2 mm. of Hg, in the case of C0₂, for a PetX[i]^T between 30 and 50 mmHg, a measured PetC0₂ value that is within 1 to 3 mm. of Hg of PetX[i]^T can be considered to be a goal ("targeted") and also actually achieved with relative precision.

For present purposes, a mass balance equation is understood to be a mathematical relationship that applies the law of conservation of mass (i.e. the amount of at least one gas X) to the analysis of movement of at least one gas X, in and out of the lung, for the purpose of prospectively targeting an end tidal partial pressure of gas X. Optionally, where an end tidal partial pressure of gas X is sought to be changed from a baseline steady state value or controlled for a sequence of respective breaths [i] the mass balance equation will account for the transfer of a mass of gas X between a subject's lung and pulmonary circulation (i.e. the mixed venous blood entering the pulmonary capillaries (CMVX[I])); SO that this key source of flux affecting the end tidal partial pressure of gas X in the breath(s) of interest, is accounted for. 00473

The term "high resolution" when used with reference to imaging modality or device refers to an imaging modality enjoying a spatial resolution of 1 cubic centimeter or smaller. The term includes MRI imaging modalities (for example BOLD, T2^*, ASL) and other imaging modalities well known as being useful to quantify surrogate measures of blood flow (CT, SPECT, PET).

A "gas blender" means a device that combines one or more stored (optionally stored under pressure or delivered by a pump) gases in a pre-defined or selectable proportion for delivery a selectable rate of flow, preferably under computer control. For example one or more stored gases may be combined with pumped room air or a combination of pure or blended (each blended gas may have at least 10% oxygen for safety) gases respectively contain one of carbon dioxide, oxygen and nitrogen as the sole or predominant component. Optionally, the selectable proportion is controlled automatically using an input device, optionally by variably controlling the flow of each stored gas (pure or pre-blended) separately, preferably using rapid flow controllers, to enable various concentrations or partial pressures of a gas X to be selected at will within a pre-defined narrow or broad range. For example, the gas blender may be a high flow blender which blows gas past the mouth (i.e. in which gas that is not inspired is vented to the room) or the gas blender may be adapted to conserve gas by delivering gas in volumes that closely match the patient's volume requirements of a breath.

Optionally, the respiratory gas delivery apparatus contains the basic structural or specialized algorithmic features described in WO/2012/139204.

The term "real time gas blender" means, with reference to instant invention, a gas blending apparatus that introduces a variable amount of at least one gas X (e.g. carbon dioxide, oxygen, nitric oxide or other medically active gases) into a principal inspiratory gas stream (e.g. consisting of air or oxygen enriched air) to make available to a subject, for inspiration, a combined gas stream having a selected concentration of gas X. Control of gas X flow into the principal gas stream is, in principle, based on continuously determining the rate of flow of the principal inspiratory gas flow and adding amounts of gas X accordingly. Such a blender may employ a flow based algorithm, for example as described in US Patent No. 5,558,083, or may more advantageously employ a volume- baaed control system as described in our co-pending published PCT application WO/2012/139204.

The term "computer" is used broadly to refer to any device (constituted by one or any suitable combination of components) which may be used in conjunction with discrete electronic components and/or parts e.g. valves to perform the functions contemplated herein, including computing and obtaining input signals and providing output signals, and optionally storing data for computation, for example inputs/outputs to and from electronic components and application specific device components as contemplated herein. As contemplated herein a signal processor or processing device in the form of a computer may use machine readable instructions or dedicated circuits to perform the functions contemplated herein including without limitation by way of digital and/or analog signal processing capabilities, for example a CPU, for example a dedicated microprocessor embodied in an IC chip which may be integrated with other components, for example in the form of a microcontroller. Key inputs may include input signals from - a pressure transducer, a gas analyzer, any type of input device for inputting parameters or values (for example, a knob, dial, keyboard, keypad, mouse, touch screen etc.), input from a computer readable memory etc. Key outputs may include output to a flow controller (e.g. PI control or PID control etc.). The term "processor" and "computer" are used interchangeably.

The term "dynamic end tidal forcing" refers to a negative feedback control system that continuously measures an end tidal value of a gas of interest and compares that value to one or more target values to control the composition of a gas delivered to a subject in an attempt to match one or more target end tidal values.

The term "high flow" used to describe a gas blender means that the gas blender is able to blend component gases of an inspiratory gas to a required concentration of at least one gas X for inspiration in amounts sufficient to continuously supply a volume of gas that supports the full inspiratory volume requirements of a subject under various physiological conditions which means that the output of the gas blender might need to be high well above a subject's minute ventilation. For example, in one exemplary study (Wise RG, et al. Dynamic forcing of end-tidal carbon dioxide and oxygen applied to functional magnetic resonance imaging. J Cereb Blood Flow Metab. 2007 Aug; 27 (8): 1521-32) the total gas delivery rate to the breathing system was maintained at 70 liters per minute (LPM) to avoid rebreathing of expired gases and to minimize the delay in supplying updated gas mixtures to the subject.

Various applications of the invention defined in the Summary of Invention above are presented throughout the disclosure herein and some are listed in the pubmed cross- referenced references 1 to 16 at the conclusion of the disclosure.

The demands of a diagnostic application may be ascertained empirically or from the literature. For example, a measure of short response times of brain blood vessels to hypercapnic stimulus can be determined to require a square wave change in the stimulus such as a change of 10 mmHg PETC0₂ from one breath to the next. Another example is when measuring response of BOLD signal with MRI to changes in partial pressure of C0₂ in the blood, the changes needed may be determined to be abrupt as the BOLD signal has considerable random drift over time.

For measuring heart vascular reactivity, the inventors have demonstrated that attaining target end tidal concentrations to within 1 to 3 mm of Hg of the targets, preferably to within 1 to 2 mm of Hg of the targets, using an apparatus, computer program product, or IC chip and method according to the invention enables the invention to be used for cardiac stress testing (see WO2012/1151583). Therefore, according to one aspect, the invention is directed to the use of apparatus, computer program product, IC chip and/or method according to the invention for cardiac stress testing.

The invention is also adapted for use as a controlled stimulus, for example to calibrate a BOLD signal (Mark CI et al. Improved fMRI calibration: Precisely controlled hyperoxic versus hypercapnic stimuli (2011) Neurolmage 54 1102-1111); Driver ID. et al. Calibrated BOLD using direct measurement of changes in venous oxygenation (2012) Neurolmage 63(3) 2278-87) or as an adjunct or preliminary step in diagnosing abnormal cerebrovascular reactivity. For example, determining the presence of abnormally reduced vascular reactivity using an apparatus, computer program product, IC chip and/or method according to the invention is useful for predicting susceptibility to stroke (Silvestrini, M. et al. Impaired Cerebrovascular Reactivity and Risk of Stroke in Patients With Asymptomatic Carotid Artery Stenosis JAMA (2000) 283(16) 2179; Han J.S. et al. Impact of Extracranial Intracranial Bypass on Cerebrovascular Reactivity and Clinical Outcome in Patients With Symptomatic Moyamoya Vasculopathy, Stroke (2011) 42:3047-3054)or dementia (Balucani, C. et al. Cerebral Hemodynamics and Cognitive Performance in Bilateral Asymptomatic Carotid Stenosis Neurology (2012) Oct 23; 79(17) 1788-95) and diagnosing or assessing cerebrovascular disease (Mutch WAC et al. Approaches to Brain Stress Testing: BOLD Magnetic Resonance imaging with Computer-Controlled Delivery of Carbon Dioxide (2012) PLoS ONE 7(11) e47443).

The invention is similarly adapted for diagnosing or assessing idiopathic intracranial hypertension (IIH) or idiopathic normal pressure hydrocephalus (Chang, Chia-Cheng et al. A prospective study of cerebral blood flow and cerebrovascular reactivity to acetazolamide inpatients with idiopathic normal-pressure hydrocephalus (2009) J Neurosurg 111:610-617), traumatic brain injury (Dicheskul ML and Kulikov VP Arterial and Venous Brain Reactivity in the Acute Period of Cerebral Concussion 2011 Neuroscience and Behavioural Physiology 41(1) 64),liver fibrosis or liver disease in which liver fibrosis is a feature (Jin, N. et al. Carbogen Gas-Challenge BOLD MR Imaging in a Rat Model of Diethylnitrosamine-induced Liver Fibrosis Jan 2010 Radiology 254(1)129-137) and conditions manifesting abnormal kidney vascular reactivity, for example renal denervation in transplant subjects (Sharkey et. al., Acute effects of hypoxaemia, hyperoxaemia and hypercapnia on renal blood flow in normal and renal transplant subjects, Eur Respir J 1998; 12: 653-657.

As seen in Figure 1 , a prior art dynamic end tidal forcing system employs a high flow blender 105 to blend gases stored under pressure in tanks 110 and 120 e.g. an air tank 110 and a gas X tank 120 e.g. a CO^ tank. A breathing circuit comprising a conduit 115 leads from the high flow blender 105 to a patient 150 outfitted with an airway interface such as a mask (not shown). Conduit 115 is connected to the patient airway interface through a one way inspiratory valve 125, a flow meter 130 and a gas analyzer 135 e.g. a C0₂ sensor. A subject exhales through the gas analyzer and through one way expiratory valve 140. Input of one or more target end tidal values of gas X 230 is received by a feedback controller 145 which also receives input from flow meter 130. The feedback controller 145, which may be embodied in a microprocessor or an external processor (e.g. a PC) receives output 210 from the gas X analyzer 135 and the difference between the gas analyzer output 210 and the current target end tidal value is used to provide an output signal 200 to a rapid flow controller in a high flow gas blender 105 to output an inspired concentration of gas X (F[X) required to attain the target end tidal concentration of gas X based on the feedback algorithm. The sole source of inspiratory gas is the output from the gas blender 105, so that total output from the gas blender 105 must at all times be greater than the subject's peak inspiratory flow rate. Gas not inspired is exhausted through the expiratory valve 140.

Figure 2 shows a variation of the system depicted in Figure 1 in which a gas blender 305 is connected to an inspiratory reservoir 160 (see Koehle MS. et al. Performance of a compact end-tidal forcing system, Respir. Physiol. Neurobiol. 2009 Jun 30; 167(2): 155-61). Accumulation of gas in the reservoir during expiration lessens the rate of flow needed to meet a subject^'s inspiratory requirements. This system wastes less gas than the blow-by-the-mouth method described with reference to Figure 1 (Wise et al. 2007).

For use of a physical sequential gas delivery circuit, the flow of gas of first composition is selected so that the subject empties the gas reservoir (e.g. bag) the gas of first composition. A breath in which this per chance does not occur is ignored.

However, it will also be appreciated that a particular gas composition formulated for delivery in respective breath, as determined by a dynamic feedback system, will in each breath be mixed with uncertain amount of gas remaining in the inspiratory reservoir and tubing from a previous breath, which introduces a source of instability into the system.

Notably, in the modified system depicted in Figure 2, the gas analyzer 135 could perhaps be placed in the expiratory limb provided that the inspiratory reservoir never overflows. The gas analyzer does not see inspiratory concentrations of gas X within a common line leading to the patient airway interface as described with reference to Figure 1. However, as described in more detail with reference to Figure 3, relative to the system and apparatus of the invention, greater inaccuracies may be introduced into the system as a result of errors in end tidal picking.

As seen in Figure 3b, depicting a theoretical capnograph tracing corresponding to two consecutive inspiratory cycles demarcated by dashed lines 545, expiratory gas initially exhaled by the patient consists of the lighter shaded area gas 510 remaining in the dead space 500 after an inspiratory cycle, as seen in model of the lung 515 in Figure 3a. This gas has essentially the concentration of gas X (e.g. CO_z) last inspired by the subject in the immediately preceding inspiratory cycle. This gas remains in and is first expired from the dead space 500. The last expired or end tidal gas 520 has the concentration of gas X in the alveoli 525 following gas exchange in a particular respective inspiratory cycle. Dashed line 546 demarcates the transition between expiration of the dead space gas 510(lighter shade of gray) and the alveolar gas 520 (darker shade or gray) evidencing the beginning of a rise in the subject's PC0₂. It will be appreciated that end tidal picking errors may reflect PCO2 values of the dead space gas 510.

The system of the present invention will now be described by way of contrast.

An embodiment of a system, method and apparatus for implementing the invention is shown schematically in consecutive embodiments described with reference to Figures 4, 5 and 9.

As seen in Figure 4, a control system including a feedback controller 146, optionally implemented by a processor, for example a microcontroller, obtains input 230 comprising at least one of a series of PetX[i]^T values, the series comprising at least one such value per breath or time period, or per series of breaths or time periods, namely one or more breath or time interval associated PetX[i]^T values e.g. relative increments and/or PetX[i]^T decrements, which may be stored, or input 230 via using any suitable input device. Optionally, at least one target for a first series of breaths will be obtained, for example, where gas X is CO2, PC0₂ values for each of a first series of breaths (e.g. 40 mm Hg) and then optionally at least one PC0₂ target for an ensuing series of breaths e.g. 50 mm of Hg, optionally followed by at least one PCO2 target for a series of final breaths in the collective series (e.g. 50). Optionally, the series may define a ramp sequence as described herein.

A feedback controller 146 may use any suitable control algorithm known to control- system programmers and may optionally be selected from a group comprising a PD, a PI and a PID control algorithm. The feedback algorithm compares 122 input end tidal target values 230 with output from the gas analyzer 135 (which is processed through an end tidal gas concentration picking algorithm to pick end tidal concentration values- not shown in order to simplify the illustration), for example on a breath by breath basis, and the feedback controller then sends control signals 200 to the gas blender, for example a real-time gas blender 108 to implement the feedback control system. The real time gas blender obtains a measure of flow 133 of a primary inspiratory gas 151 (e.g. air) via flow sensor 130 and adds a variable amount of gas X from tank 120 to this gas stream via conduit 18 to compose a gas of a composition which the feedback control algorithm has determined effective to attain the end tidal partial pressure of gas X input for the breath/interval. An exemplary volumetric real time gas blender is described in our published PCT application WO 2012/139204. A different flow-based real time blending algorithm is described in US Patent No. 5,558,083.

The control system also implements sequential gas delivery (SGD) either in conjunction with using a physical circuit SGD circuit, as described with reference to Figure 9, or using a virtual sequential gas delivery algorithm which does not require a physical SGD circuit, as described herein.

For example, input of flow sensor readings 133 and feedback controller signals 200 to the real time gas blender 108 may be used to add C02 to inspiratory gas stream 151 via conduit 118 from gas stored under pressure in C0₂tank 120.

Optionally, as seen in Figure 5, the control system may also use a prospective model or predictive algorithm102. For example, signals generated by the feedback controller 146 and as output of the prospective model 102 are added 124, such that the output of the prospective model (e.g. a computationally derived amount of at least one gas X required to be inspired by the subject in an inspired gas to target at least one PetX[i]^T value for a respective interval) is adjusted, for example, on a breath by breath basis, by the feedback controller 146. One predictive model is based on a tidal model of the lung described in detail herein. Another (flow based) is described in Robbins PA, et al., A prediction-correction scheme for forcing alveolar gases along certain time courses. J. Appl. Physiol. 1982 May; 52(5):1353-7, for example using mass balance equations described in this 1982 paper.

The feedback controller 146, is depicted in Figure 5 as determining the difference 122 (the error) between actual end tidal values of gas X obtained from the gas analyzer 135 (direct output of the gas analyzer is processed through an end tidal gas concentration picking algorithm to pick end tidal concentration values- not shown for simplicity) and the respective PetX[i]^T input target values input 230. Patient data 106 informs the prospective model 102 (see Section C below) to enable a processor to output a computationally derived (predicted) F|X value required to target a particular PetX[i]^T value as described in detail herein.

As seen in Figure 9, a breathing circuit may comprise a conduit 15 which delivers gas to an inspiratory reservoir 109 and sequential gas delivery circuit 101 which is operatively associated (this association, generally described below, depicted for ease of illustration with solid arrows 104) with a gas analyzer 135 for detecting gas X concentration in a subject's exhaled gas and a pressure transducer 136 which may be used to assist end tidal picking using an end tidal picking algorithm 138. Gas conduit 115 leads from a real time gas blender 108 towards a spontaneously breathing subject 150 donning a patient airway interface such as a mask (not shown). Located along the circuit between inspiratory reservoir 109 and the patient airway interface, preferably proximal to the patient airway interface, is a one way inspiratory valve (not shown), and a gas analyzer 135 (e.g. a C0₂ or O2 sensor) which provides output of at least gas X concentrations of gas exhaled by a subject. The circuit is optionally configured so that the subject exhales through the one way expiratory valve (not shown) and then past the gas analyzer 135. Optionally, the sequential gas delivery circuit is operatively connected to a pressure transducer 136, the output of which assists in end tidal picking via an end tidal picking algorithm 138. Input 230 of one or more target end tidal values of gas X is received by a feedback controller 146. The feedback controller 146, which may be embodied in a microprocessor or an external processor (e.g. a PC) receives output 210 from the gas X analyzer 135 (that has been processed through the end tidal picking algorithm 138) and the difference between the gas analyzer output 2 0 and the current target end tidal value is optionally 'added' to a signal derived from a predictive algorithm 102 (informed by subject parameters 106) which outputs a prospective determination of a predicted inspired concentration of gas X . This in turn is used to provide an output signal 200 to a rapid flow controller in gas blender 108 so as to output an inspired concentration of gas X (F|X) required to attain the target end tidal concentration of gas X based on the feedback algorithm. The physical SGD circuit 101 may comprise one way inspiratory and expiratory valves (not shown) and a third valve (not shown) that enables a subject to draw on a source of gas, optionally a reservoir containing primarily expired end tidal gas expired in an immediately preceding breath or a gas of equivalent composition supplied to the patient upon depletion of the inspiratory reservoir 109 in any respective breath. SGD breathing circuits are exemplified in Figures 11 and 12 and in pending published US application 2007/006534 (also published under No. WO/2004/073779). In the context of the instant invention, when implemented with a specially adapted SGD circuit, the control system is used to control the rate of flow and configured to make available to a subject, for inspiration:

(a) a first inspired gas of a first composition determined by the processor for the first portion of the inspiratory cycle of a respective breath[i]; and

(b) when the subject's ventilation in a respective breath [i] exceeds the first inspired gas of first composition available for a breath, a second inspired gas of second composition having a partial pressure of gas X (PX) selected from a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i-1], or a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i]. Some embodiments of the physical SGD circuits exemplified in WO/2004/073779 employ a set of three passive valves including one way inspiratory and expiratory valves and a valve associated with a by-pass conduit. Alternatively active valves may be employed.

In summary, a physical sequential gas delivery circuit is commonly a breathing circuit for use with a first gas (FG) and a second gas (SG), the circuit optionally comprising an inspiratory limb, an expiratory limb, an FG reservoir and a flow control system for sequentially delivering to a patient on inspiration, in a given breath [i], first the FG, preferably substantially free of SG, and, when the FG reservoir is emptied, SG, preferably substantially free of FG, for a balance of inspiration, wherein the inspiratory limb is operatively connected to the FG reservoir, and wherein the flow control system includes at least one first valve operatively associated with the expiratory limb for preventing inhalation of SG during delivery of the FG and at least one second valve operatively associated with the inspiratory limb to prevent inhalation of FG during delivery of the SG. The first and second valves may be passive (open responsive to pressure in the circuit) and may operate in tandem using interconnected valve closure members such that when one is open the other is closed and vice versa. In some embodiments, such a circuit may employ two active valves, one on the inspiratory side and one on the expiratory side. Alternatively, the circuit may employ an active valve or passive valve on the inspiratory side and two passive valves on the expiratory including a one way expiratory valve and another valve associated with a by-pass limb through which SG can be drawn to by-pass the one way expiratory valve.

A virtual SGD circuit may use one way inspiratory and expiratory valves as exemplified in Figures 4 and 5, but it should be noted that the inspiratory valve 125 (Fig 4, Fig 5) and expiratory valve 140 (Fig 4, Fig 5) are not required to modulate the inspiratory gas. As an alternative shown in Figure 6c, the patient may inspire a primary inspiratory gas 151 through a flow sensor 135 and gas analyzer 145 arranged in a single conduit 100, where the flow sensor 135 is part of a real-time gas blender (not shown) which is configured to add a gas X to a primary inspiratory gas 151 via a second conduit (not shown, 118 Fig 4 and Fig 5) connected to a port 110 to attain a desired amount of X in the inspiratory stream.

In one embodiment X is CO2.

In another embodiment, the control system independently controls PetX[i]^T for two or three gases e.g. C0₂ and O2.

As seen in Figure 6A, which diagrammatically depicts a subject's dead space 500 and alveolar 515 lung volumes, the respective gas compositions 510 and 520 of these volumes are similar when breathing on a sequential gas delivery circuit 101 (see Figure 9) as a result of the subject inhaling an end tidal gas coming from the alveoli 520 at the end of an immediately preceding breath as opposed to the tail end of the gas composition tailored to the first portion a respective breath [i] in the previous breath which would otherwise occupy the dead space 500 (in the absence of an SGD circuit 101). Figure 6b graphs end tidal PCO2 readings (Y scale) derived from a capnograph (broken lines 545 demarcate transitions between exhalation cycles) illustrating the transition (demarcated by broken line 546) between values related to exhalation of dead space gas 535 and alveolar gas 540. These values are not that marked different so that an error in end tidal picking - values 530 - will not radically alter the end tidal value.

Section A: Example 1 - Present Invention

The system was used to control PetC02 in spontaneously breathing subjects described in the following table. This table is also reproduced for ease of reference Figure 8g.

E Natural 55 0.5

F Alternating between 55 1

hyperventilation and

natural breathing each

breath

G Natural 60 5

H Natural Alternating between 55 2

and 60 every 0.5 min

Three subjects were tested according to the above protocol. Hyperventilation implies that the subject was coached to double their minute ventilation; during natural breathing the subject was allowed to breathe as they felt comfortable. The test on the third subject without SGD had to be terminated early in stage G because of destabilization of the feedback system caused by a highly irregular natural breathing pattern. For each test, the error was calculated as the difference between the measured PetC02 and target PetC02, and the root mean square (RMS), standard deviation (SD), minimum (MIN), and maximum (MAX) error was computed.

The results are summarized in the Figure 7 and Figures 8a-8f. As seen in Figure 7 and Figures 8a to 8f a method and apparatus according to invention - implementing SGD - enabled the target end tidal values in each segment of the test to be approximated with reduced variability. Additionally, it is apparent that the difference between the target end tidal values and the actual values attained were higher without SGD that with SGD.

Section B: Description of Virtual Sequential Gas Delivery (VSGD) Invention

Virtual sequential gas delivery or virtual SGD (VSGD) is disclosed in our copending PCT application no. PCT/CA2013/000266 filed March 19, 2013 and published under No. WO/2013/138910, the content of which is hereby incorporated by reference.

In many clinical and research situations, a subject is required to breathe through a breathing circuit. These circuits are normally designed to deliver different compositions of gases at different points throughout the breath cycle. In many cases, the breathing circuits are designed to minimize the use of an expensive component gas of the breathing mixture. These circuits, however, are normally designed with, and constructed from, components such as tubing, reservoir bags, and valves. These components are expensive, bulky, and prone to failure.

For example, the Hi-Ox 80 (CareFusion) breathing circuit is a breathing circuit designed to provide high inspired fractions of oxygen while minimizing the flow rate of oxygen to the patient. In this circuit, a constant flow rate of oxygen is provided to the circuit, the oxygen accumulating in a reservoir. The patient inspires through two one-way valves in parallel. The inlet side of the oxygen one-way valve is connected to the oxygen reservoir, while the inlet side of the air one-way valve is open to the atmosphere. The oxygen-supply one-way valve has negligible cracking pressure and so opens for any inspiratory effort. The air-supply one-way valve has a small cracking pressure which causes it to open only when a negative pressure is generated in the breathing circuit. In this way, during a typical inspiration, the patient inspires oxygen from the oxygen reservoir first. When the reservoir is empty, continued inspiration generates a negative pressure in the circuit thereby opening the air-supply one-way valve. Therefore, the balance of the breath is drawn from ambient air. Expiration is directed to the ambient atmosphere through a third expiratory one-way valve.

While this circuit is effective, it has a number of limitations. Firstly, the mechanical components are prone to failure. Failure of the one-way valves, such as a failure of the oxygen-supply one-way valve to open, may cause the subject to breath only ambient atmospheric air. Failure of the air-supply one-way valve to open will limit the subject's minute ventilation to the flow rate of oxygen to the circuit. On the other hand, if the oxygen-supply one-way valve does not effectively prevent back flow, the subject may expire into, and rebreathe from, the oxygen reservoir. Secondly, in addition to potential failures, the one-way valves increase the resistance to flow in the breathing circuit thereby increasing the work of breathing. This is uncomfortable for most patients, and may be a significant limitation to use in elderly patients or those with pulmonary disease. Thirdly, the size of the manifold which houses all the valves together with the reservoir can be quite large and cumbersome for some situations. For example, in an emergency medical resuscitation situation where access is required to the subject's chest, the oxygen reservoir may be in the way. Here, the physicians must remove the breathing circuit to access the chest.

According to one aspect, the VSGD invention is directed to a respiratory gas delivery system adapted to deliver an inspiratory gas of variable composition comprising:

A. a gas delivery apparatus operativeiy connected to a processor;

B. a flow sensor adapted to monitor in real time the rate of inspiration of a gas; wherein, for a plurality of respective inspiratory cycles (ft to [i]„ and a plurality of time points [t]i to [t]_n, over the course of a respective inspiratory cycle [i], the processor is configured to:

(a) use output from the flow sensor to monitor the cumulative volume of gas inspired in the respective inspiratory cycle at any given time point [t]i to [t]_n:

(b) execute an algorithm to determine a desired composition of the inspired gas based on whether or not at least one threshold cumulative volume of a desired gas composition has been inspired in the respective inspiratory cycle, the desired composition including a composition selected from a first composition selected for delivery for a first portion of a breath and at least one alternate nth composition; and

(c) generate a control signal effective to signal the gas delivery apparatus to deliver the first composition in the first part of breath and the nth composition during the course of a breath based on whether or not the at least one threshold cumulative volume has been reached.

Optionally, the first composition corresponding to a first portion of a breath is determined using at least one first criterion and the at least one alternate nth composition is determined using at least one different criterion. Optionally, the at least one pre-determined cumulative volume is set to be less than a subject's tidal volume minus anatomic dead space volume such that the entire volume of the first composition is destined to enter a subject's alveolar space.

Optionally, the alternate composition is a neutral gas.

Optionally, the alternative composition is a percentage composition of a constituent gas as low as 0%, wherein the constituent gas is of a type determined by a user to warrant conservation by reducing delivery to the anatomical dead space.

Optionally, a threshold cumulative volume for a respective breath [i] may be set to deliver a target total inspiratory volume of a first gas composition over a series of inspiratory cycles [iji ot [i]_n.

By way of example only, n may be 7 and the series may include a current inspiratory cycle [i]. Delivering 500 ml of a gas over 7 breaths: If after 6 breaths, 470 ml of the gas has been delivered, in the 7^th breath the threshold volume is computed and set to be 30 ml.

Optionally, the processor is configured to simulate gas delivery from at least a virtual first gas reservoir and a second gas source, optionally a virtual second gas reservoir, wherein:

(a) the first gas reservoir and the second gas source e.g. gas reservoir contain a gas of at least specifiable or specified composition;

(b) at least the first gas reservoir is assumed to contain a gas corresponding to a first portion of a breath, the processor configured to send a control signal to signal to the gas delivery apparatus to deliver a gas of a specified composition of the first gas reservoir for the first part of a respective inspiratory cycle [i], the first gas reservoir set to contain a volume of gas adapted to be depleted in each inspiratory cycle at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor; and (c) the processor generates a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to the specifiable or specified composition of the at least second gas reservoir for a second part of a respective inspiratory cycle [i] when the first gas reservoir is depleted.

Optionally, the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is continually filled with a gas of a specified composition at a specifiable or specified reservoir-specific fill rate which is less than the reservoir specific depletion rate.

Optionally, the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is full at the start of an inspiratory cycle, the volume selected to be a volume that can be predicted to be depleted at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor.

Optionally, the apparatus is configured to deliver a first gas of a first composition for a first part of each inspiratory cycle [i] and a second gas of a second composition for a second part of each inspiratory cycle [i].

Optionally, the apparatus is configured to simulate gas delivery from two gas sources e.g. gas reservoirs, wherein the first gas source e.g. reservoir is exclusively depleted in a first part of each inspiratory cycle [i], and the second gas source e.g. reservoir is exclusively delivered in a second part of each inspiratory cycle [i]. The second gas source e.g. gas reservoir is optionally associated with a parameter such as volume or fill rate, however especially if the second gas source is set to have no volume limit, for example where the second gas source is drawn upon for the remainder of any given inspiratory cycle, whether or not it is depleted may be moot.

Optionally, the fill rate of the first reservoir is less than -the subject's total inspired volume minus the total volume of gas inspired into the anatomic dead space volume over a measurement interval. Optionally, the measurement interval is one minute.

Optionally, the composition of gas delivered in the second part of each inspiratory cycle [i] is neutral with respect to at least one constituent gas of the inspiratory gas.

According to another aspect, the VSGD invention is directed to a computer program product or a programmable IC chip comprising program code for controlling a gas delivery apparatus which is adapted to deliver an inspiratory gas of variable composition comprising:

Program code for obtaining input from a flow sensor adapted to monitor in real time the rate of inspiration of a gas;

Program code for configuring a processor, for a plurality of respective inspiratory cycles [i]¹to [i]ⁿ, throughout each inspiratory cycle [i], to (a) use output from the flow sensor to monitor the volume of inspired gas in the respective inspiratory cycle; (b) execute an algorithm to compute, specify or obtain input of a desired composition of the inspired gas using as input at least the cumulative volume of inspired gas in the respective inspiratory cycle;

(c) generate a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to the computed composition.

Optionally, the program code configures the processor to simulate gas delivery from a plurality of gas reservoirs, wherein:

(a) each reservoir contains a gas of specifiable or specified composition;

(b) at least one reservoir (the one containing gas adapted to be delivered in a first portion of a breath), optionally each reservoir, is continually filled with a gas of the associated composition at a specifiable or specified reservoir specific fill rate;

(c) at least the one and optionally each reservoir is continually depleted at a specifiable reservoir specific depletion rate. Optionally, the sum of the individual depletion rates equal to the inspiratory flow rate measured by the flow sensor; (d) wherein the program code configures the processor to generate a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to a blend of the reservoir gases weighted by their associated depletion rates.

Where a depletion rate is specified only for the gas reservoir containing a gas adapted to be delivered in a first portion of a breath the second reservoir may assumed never to be depleted, depleted over a time course corresponding to the duration of the remainder of a cycle of inspiration or depleted after consumption of a particular constituent gas over a period of use. Hence this model may be interchangeable with a model in which only one reservoir is present and depleted, the at least one gas of an alternative composition delivered only the remaining portion of an inspiratory cycle.

Optionally, the patient is a spontaneously breathing patient. Depletion of at least the first delivered gas represents an embodiment of an algorithm adapted to send a control signal to signal the gas delivery apparatus to deliver a gas of second composition which is specifiable or specified based on a different criteria which demarcates a juncture at or preceding the juncture at which inspired gas has already filled the alveoli and begins to fill the anatomical dead space, Accounting for the fact that some not all of an inspired gas will enter a subject's alveolar space is useful for a variety of purposes including enabling an expensive gas to be conserved or enabling a neutral gas or air to be delivered in each inspiratory cycle.

Optionally, the program code adapts the apparatus to deliver a first gas of a first composition for a first part of each inspiratory cycle [i] and a second gas of a second composition for a second part of each inspiratory cycle [i].

Optionally, the program code adapts the apparatus to simulate gas delivery from two gas reservoirs, wherein the first reservoir is exclusively depleted in a first part of a each inspiratory cycle [i], and the second reservoir is exclusively delivered in a second part of each inspiratory cycle [i]. Optionally, the fill rate of the first reservoir is less than the subject's total inspired volume minus the total volume of gas inspired into the anatomic dead space volume over a measurement interval.

Optionally, the measurement interval is one minute.

According to one aspect, the VSGD invention is directed to a method using a gas delivery apparatus for delivering an inspiratory gas of variable composition and a computer program product or programmable IC chip adapted to implement the method, the gas delivery apparatus operatively connected to a processor, comprising

A. obtaining output from a flow sensor adapted to monitor in real time the rate of inspiration of a gas;

B. using output from the flow sensor to monitor the cumulative volume of gas inspired in the respective inspiratory cycle at any given time point [fy to [t]_n over the course of a respective inspiratory cycle [i];

C. executing an algorithm to determine a desired composition of the inspired gas based on whether or not at least one threshold cumulative volume of a gas composition has been inspired in the respective inspiratory cycle, the desired composition including a composition selected from a first composition corresponding to a first portion of a breath and at least one alternate nth composition;

D. generating a control signal effective to signal the gas delivery apparatus to deliver the first composition in the first part of a respective inspiratory cycle [i] and at least one alternate nth composition during the course of the inspiratory cycle based on whether or not the at least one pre-determined threshold cumulative volume has been reached. Optionally, the composition corresponding to a first portion of a inspiratory cycle is determined using at least one first criterion and wherein the at least one alternate composition is determined using at least one different criterion.

Optionally, the at least one pre-determined cumulative volume is set to be less than a subject's tidal volume minus anatomic dead space volume such that the entire volume of the composition corresponding to a first portion of a inspiratory cycle is destined to enter a subject's alveolar space.

Optionally, the alternative composition is a neutral gas.

Optionally, the method and the computer program product simulate gas delivery from at least a virtual first gas reservoir and a virtual second gas reservoir, wherein:

(a) the first gas reservoir and the second gas reservoir contain a gas of specifiable or specified composition;

(b) at least the first gas reservoir is assumed to contain a gas corresponding to a first portion of a inspiratory cycle, the method comprising sending a control signal to signal to the gas delivery apparatus to deliver a gas of a specified composition of the first gas reservoir for the first part of a respective inspiratory cycle [i], the first gas reservoir programmed to contain a volume of gas adapted to be depleted in each inspiratory cycle at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor;

(c) generating a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to the specifiable or specified composition of the at least second gas reservoir for a second part of a respective inspiratory cycle [i] when the first gas reservoir is depleted. To carry out the method, the computer program product includes program code which specifies or enables specification of the composition of the first gas reservoir and the second gas reservoir, program code for sending a control signal to signal to the gas delivery apparatus to deliver a gas of a specified composition of the first gas reservoir for the first part of a respective inspiratory cycle [ij; program code for specifying the volume and/or fill rate of the first gas reservoir, wherein the first gas reservoir contains a volume of gas adapted to be depleted in each inspiratory cycle at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor; and program code for generating a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to the specified composition of the at least second gas reservoir for a second part of a respective inspiratory cycle [i] when the first gas reservoir is depleted.

Optionally, the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is continually filled with a gas of an associated composition at a specifiable or specified reservoir-specific fill rate which is less than the reservoir specific depletion rate.

Optionally, the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is full at the start of an inspiratory cycle, the Volume selected a volume that can be predicted to be depleted the reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor.

Optionally, the method is adapted to deliver a first gas of a first composition for a first part of each inspiratory cycle [i] and a second gas of a second composition for a second part of each inspiratory cycle [i].

Optionally, the method is adapted to simulate gas delivery from two gas reservoirs, wherein the first reservoir is exclusively depleted in a first part of each inspiratory cycle [i], and the second reservoir is exclusively drawn upon e.g. depleted in a second part of each inspiratory cycle [i]. Optionally, the fill rate of the first reservoir is less than the subject's total inspired volume minus the total volume of gas inspired into the anatomic dead space volume over a measurement interval.

Optionally, the measurement interval is one minute.

Optionally, the cumulative volume in a respective inspiratory cycle [i] is computed to achieve a target total inspiratory volume of a gas of a first gas composition over a series of inspiratory cycles, the series optionally at least including the current inspiratory cycle [i].

For example, if a volume X (e.g. 500 ml) is set to be delivered over Y inspiratory cycles (e.g.7 inspiratory cycles), the processor is programmed, e.g. after (Y-1) inspiratory cycles have delivered a volume Z (e.g. 470 ml of the gas) to compute the threshold volume for the last inspiratory cycle to be X-Z (i.e. 30 ml.).

A. a gas delivery apparatus operatively connected to a processor;

B. at least one device adapted to monitor at least one condition representing a juncture in a respective inspiratory cycle [i] which satisfies at least one the following criteria: a) a specifiable or specified volume of a desired gas composition has already been inspired in the respective inspiratory cycle; b) a specifiable or specified amount of at least one constituent gas X has been inspired in the respective inspiratory cycle; 3

c) a volume of gas yet to be inspired in the respective inspiratory cycle exceeds a subject's anatomical dead space volume; wherein, for a plurality of respective inspiratory cycles to [i]_n the processor is configured to:

(a) use output from the at least one device to monitor the at least one condition based on the at least one criteria;

(b) execute an algorithm to determine a desired composition of the inspired gas based on whether or not the condition is satisfied, the desired composition including a composition selected from a first composition selected for delivery for a first portion of a inspiratory cycle and at least one alternate nth composition;

(c) generate a control signal effective to signal the gas delivery apparatus to deliver the first composition during a first portion of an inspiratory cycle at least one alternate composition during the course of a inspiratory cycle based on whether the condition is satisfied.

The device may include at least one of a measurement device such as a flow sensor, gas analyzer or a pressure sensor, a device adapted to control the tidal volume of a subject (e.g. a ventilator), a subject operated input device or a prompting device. A subject operated input device may be of any time in which enables a subject to signify the commencement of an end of an inspiratory cycle (i.e. winding down of the subject's inspiratory effort). A prompting device may include a device which enables a subject to readily target a value within range of values of a parameter that is correlated to volume of or duration of an inspiratory effort. Optionally, the system includes at least one measurement device that monitors in real time the cumulative volume of gas inspired in at least a first portion of an inspiratory cycle. Optionally, the system includes at least one measurement device that monitors in real time the pressure in a patient airway interface or conduit leading to patient airway interface, for example to monitor the progression, commencement and/or completion of an inspiratory and/or expiratory 2014/000473

effort. Optionally, the system includes at least one measurement device that monitors in real time the concentration of at least one constituent gas.

According to one embodiment, the VSGD invention is directed to simulating a breathing circuit of a respiratory gas delivery system (a reference circuit and a reference system) using an alternative system so that the gas delivered to the patient - at least one of flow and composition - is substantially the same when using the alternate system and the reference circuit (i.e. with respect to a given output - flow or composition or both - the two circuits are functionally interchangeable at least in the sense that the alternate system performs the function of the reference system, albeit, optionally, in at least one respect, in a relatively advantageous manner. For example, the alternative system may be safer (e.g. less prone to failure), more robust, less bulky from the standpoint of making caregiver access to the patient easier, etc.

Functional equivalence, in term of flow, means that the pattern of flow. In at least one aspect this alternate system of the invention virtualizes components of the reference breathing circuit in the sense that a control algorithm of the alternative system supplants structural features (e.g. at least one structural component) of the reference circuit, for example, a physical gas reservoir with an accumulator in computer memory.

Thus, according to one aspect, the VSGD invention is directed to a respiratory gas delivery system adapted for use with a first breathing circuit, the first breathing circuit optionally having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes at least one structural feature, optionally at least one structural component, optionally at least one set of structural parts of a reference, second breathing circuit, the respiratory gas delivery system including: a) at least one device adapted for selecting a juncture during an inspiratory cycle for switching between a first gas composition and at least one alternate, nth gas composition, optionally a juncture that demarcates a juncture preceding a point at which inspired gas has already filled the alveoli and begins to fill the anatomical dead space, optionally a juncture identified by monitoring at least one parameter in real time, optionally a parameter selected from at least one of volume, pressure and gas concentration, optionally volume, optionally a flow sensor, positioned in relation to the first breathing circuit, for at least determining the volume gas inhaled via the patient airway interface;

b) a gas delivery apparatus for delivering a gas comprising a plurality of component or constituent gases into the patient airway interface, the gas delivery apparatusoperatively connected to a computer; and optionally

c) a gas analyzer for analyzing the gas concentration of one or more gases inhaled and/or exhaled by the subject;

wherein the computer is optionally configured to supplant the at least structural component, optionally at least one set of structural parts of the reference breathing circuit, the set of structural parts optionally including at (east one part selected from a gas reservoir, a valve and a conduit, by using at least one of an algorithmic and a mathematical model of the at least one set of structural parts to generate gas delivery characteristics that simulate the functions of said set of structural parts. Optionally, the at least one set of structural parts simulated by a respiratory gas delivery system according to the invention comprises or consists of a set of structural parts adapted to direct gas flow from a first circuit flow path, optionally adapted to be open at the start of each inspiratory cycle, to at least one alternate, nth (e.g. second) circuit flow path during the course of a given inspiratory cycle. Optionally, the first circuit flow path is adapted to provide a gas of a first gas composition and the at least one alternate flow path is adapted to provide gas of at least one alternate nth gas composition. Optionally the first circuit flow path is operatively connected to a first gas source (the system simulates gas flow characteristics of the first gas source, optionally a maximum volume or rate of flow and/or a composition) optionally a first gas reservoir and the respiratory gas delivery system of the invention simulates cyclical replenishment and depletion of at least first gas reservoir. Optionally, the at least one alternate nth circuit flow path of the reference breathing circuit is a second gas source and the system of the invention simulates the gas flow characteristics of at least one second gas source, optionally the composition of the at least one second gas source. Optionally, the at least one second gas source is a reservoir, optionally a reservoir that holds a subject's exhaled gas, the at least one alternate circuit flow path of the reference breathing circuit optionally adapted to deliver the subjects last expired gas from the immediately preceding breath first.

According to one embodiment, the respiratory gas delivery system of the VSGD invention accounts for how the supplanted component(s) of a reference breathing circuit work within a reference respiratory gas delivery system which the system of the invention simulates qualitatively and/or quantitatively, for example so that the respiratory gas delivery system of the invention is functionally equivalent (able to perform the same functions), to the extent desired (a system of the invention can be considered to function equivalently to a reference system if it performs the same general function without one or more limitations or inessential attributes), to the reference system.

As exemplified herein, at least one principal physical difference between two systems, apart from the computer control system, lies in differences between the first breathing circuit and the reference (second) breathing circuit. Implicitly, if the first breathing circuit and a reference breathing circuit (denoted for convenience as a "second" breathing circuit) are different, the respiratory gas delivery system of the VSGD invention, having regard to its operation within any reference respiratory gas delivery system, can be made compensatorily equivalent to the extent that the two systems are to intended to generally function equivalently. For example, features of the system of the invention and reference gas delivery system that may be made equivalent by simulating the features of the reference system may include a rate of flow from the gas delivery apparatus, cessation of flow e.g. to a patient airway interface (such as a breathing mask) to simulate cessation of flow upon expiration or a change of composition (e.g. volume triggered, for example, depletion of a volume of gas in a gas reservoir that is cyclically replenished, and depleted by inspiration) to simulate switching access between a gas reservoir and another flow path leading from an alternate gas source, optionally a reservoir or inlet, that may be used to introduce gas of a potentially different composition. Accordingly, the VSGD invention is also directed to a respiratory gas delivery system including, or adapted for use with, a first breathing circuit optionally having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes gas flow characteristics of a reference respiratory gas delivery system that includes a reference breathing circuit, the gas flow characteristics of the reference respiratory gas system dictated at least in part by structural features, for example components or parts, of the reference breathing circuit, the respiratory gas delivery system including: a) a flow sensor, optionally positioned in or proximal to the patient airway interface; for determining, for example, the volume of gas entering the patient airway interface in a given breath or breath segment e.g. an inspiratory cycle or any portion thereof);

b) a gas delivery apparatus adapted to deliver a gas ( the gas optionally comprising a plurality of component or constituent gases) into the patient airway interface, optionally into the gas conduit ( the gas delivery apparatus may include an on-board computer for controlling the gas delivery apparatus and/or may adapted to receive input from an external computer); and optionally

c) a gas analyzer, for determining, for example, the composition of gas exhaled by a subject, optionally at the end of exhalation, wherein the gas analyzer is optionally positioned in or proximal to the patient airway interface; and optionally

d) a pressure transducer, optionally positioned in or proximal to the patient airway interface for determining, for example the beginning and end of each inspiratory cycle wherein the computer is programmed to control the gas delivery characteristics, particularly the gas output characteristics of the gas delivery apparatus such that the gas output characteristics of the gas delivery apparatus supplant structural features of the reference breathing circuit that dictate, at least in part, delivery characteristics of the reference respiratory gas delivery system. The term "gas delivery characteristics" means any characteristic of a reference breathing circuit that affects gas flow to a subject that is dictated at least in part by a component of the circuit that is absent in the first breathing circuit. Optionally, the gas flow characteristic is dictated by one or more components or parts selected from a valve and a gas container such a reservoir, a conduit or compliance. Gas "delivery characteristics" or "flow characteristics" may include circuit pressure, the concentration of a gas constituent in a gas or in a component of a gas (for example as dictated by a change in the source or path of flow from a first circuit flow path to an alternate circuit flow path from which a gas of different composition emanates,) a rate or volume of flow of a gas or gas component or constituent, flow generation or restriction (e.g. via a valve such as a one-way valve, a proportional control valve, a PID control valve or an on/off type) or release of a flow restriction (e.g. via a valve) including the chronology of same (for example, the order/timing of delivery of component gases, for example from alternative sources or flow paths, such as imposed by a passive valve (which may have a predetermined opening pressure) or active valve (e.g. a balloon valve), and the capacity, qualitative and optionally quantitative, to accumulate a gas such as in a compliance, conduit or reservoir. In one embodiment, as described below, the respiratory gas delivery system virtualizes the gas delivery characteristics of a reference delivery system employing a sequential gas delivery circuit, for example, of the type having an inspiratory gas reservoir (which may be replenished - e.g. filled at a selected rate), an expiratory gas reservoir or ambient air inlet, and a flow control system which allows gas to flow to the patient from the expiratory gas reservoir or ambient air inlet, only when the inspiratory reservoir is temporarily emptied (it may be refilled, for example by the gas delivery apparatus e.g. in the form of a gas blender before each next inspiratory cycle).

The term "reservoir" means a containment chamber, optionally of defined volume and may include a bag, tubing etc. The term "flow control system" or "air flow control system" means a system in which components or parts such as valve(s) and conduit(s) control the origin and/or destination of flow when alternative airflow pathways are exploitable.

The term "component" used in the context of the phrase structural component of a breathing circuit means any portion of a breathing circuit and includes an assembly of interacting parts designed to perform a function, for example an inspiratory limb of a breathing circuit, an expiratory limb of a breathing circuit, a reservoir with an inlet and outlet portion etc. The term part is used interchangeably with the proviso that the term part in this connection denotes any part, but in contrast to component is not intended to denote an assembly of parts if any part is of the type that would typically be produced or sold as an indivisible unit i.e. a part is exemplified by a part of a valve or a valve typically produced or sold as a unit but not a valve connected between two independent air conduits.

The term "computer" is used broadly to refer to any device (constituted by one or any suitable combination of components) which may be used in conjunction with discrete electronic components and/or parts e.g. valves to perform the functions contemplated herein, including computing and obtaining input signals and providing output signals, and optionally storing data for computation, for example inputs/outputs to and from electronic components and application specific device components as contemplated herein. As contemplated herein a signal processor or processing device in the form of a computer may use machine readable instructions or dedicated circuits to perform the functions contemplated herein including without limitation by way of digital and/or analog signal processing capabilities, for example a CPU, for example a dedicated microprocessor embodied in an IC chip which may be integrated with other components, for example in the form of a microcontroller. Key inputs may include input signals from - a pressure transducer, a gas analyzer, any type of input device for inputting parameters or values (for example, a knob, dial, keyboard, keypad, mouse, touch screen etc.), input from a computer readable memory etc. Key outputs may include output to a flow controller (e.g. PI control or PID control etc.). The term "processor" and "computer" are used interchangeably. [Excluded from the VSGD invention are respiratory gas delivery systems used to monitor pressure in a system to control active valves leading to two physical reservoirs containing gases of differing compositions. The system of the invention obviates reliance on two circuit flow path leading to two gas reservoirs, and the related requirement to coordinate flow between the paths, for example, if desired to avoid any interruption in flow or conjoining of different sources of gas flow.

The term "virtua!izes" refers to programmed gas delivery in accordance with a model of a practical or "theoretical" circuit, the virtual circuit of the model replacing or obviating completely ("supplanting") structural features of a reference gas delivery system, particularly at least one component of a reference breathing circuit, which the reference delivery system is adapted to operate with. The structural component(s) is thereby supplanted by delivery apparatus output characteristics.

The term "sequential gas delivery (SGD for short) valve" means any valve that enables two gases to be delivered in sequence when a physical or virtual criterion is met. For example, the criterion may be depletion of a reservoir set to contain a limited amount (e.g. expressed as volume) of a gas so that at least one other gas is delivered in the same breath. Such a physical valve may be an active valve (e.g. a balloon valve) or a passive valve with an elevated opening pressure which provides for gas flow e.g. in the context of a re-breathing circuit, responsive only to depletion of a first gas source which is accessible at a lower pressure e.g. via a valve with a lower opening pressure (see Figures 2 and 3 and WO/2004/073779 which discloses examples of such valves and related circuits).

According to one embodiment of the VSGD invention, a theoretical circuit is exemplified by a circuit can be idealized to function free of a particular limitation that is hard to realize to a near ideal extent in practice, but for the invention which simulates the circuit functioning close to ideally (e.g. in at least one manner selected from less complex, less bulky, less prone to failure, capable of instantaneous changes in composition to simulate switching between different gas sources e.g. where cessation of flow from one source and commencement of flow from another source is hard to synchronize when the sources are switched physically as opposed to virtually e.g. by modeling the sources and the criteria for switching e.g. temporary depletion of a source which is alternately replenished and depleted at a selectable or ascertainable rate, triggering flow from an alternate source when depleted (in virtual terms - a change in composition upon depletion where the criterion for specifying the composition, if variable, from that alternate source, so dictates). Such a virtual circuit can be seen to do away with the switching apparatus of a breathing circuit (optionally including the physical source itself e.g. a gas reservoir, as well as associated gas conduits and valves e.g. an SGD valve) and the need for multiple physical sources of the breathing circuit. Modeling of the sources can be accomplished in terms of at least one parameter selected from composition and pattern of flow including at least one of rate of flow, volume of flow, duration of flow, flow pressure.

Optionally, the gas delivery characteristics of the reference breathing circuit are dictated in part by an inspiratory limb of the circuit including an inspiratory gas reservoir. The inspiratory gas reservoir may be supplanted in the first breathing circuit by control of the gas delivery apparatus so as to simulate replenishment e.g. filling (simulated by flow to the patient of a component gas of first composition) and depletion (for example, as measured by a flow sensor positioned to measure the actual inspiratory flow rate of a subject) of the inspiratory gas reservoir (arrest of flow of the component gas of first composition). The term "inspiratory gas reservoir" is used to refer to a reservoir for a gas composition that provides the first part of the gas content of each breath, for example: (1) the patient's primary respiratory requirements or (2) a gas that is primarily intended to create a concentration gradient to promote gas exchange with the pulmonary circulation. By contrast, the goal of delivering an exhaled gas or gas of similar composition (a neutral gas) is on the contrary (intended to avoid creating such a concentration gradient) except, optionally, in so far as its delivery is also secondarily intended to conserve a gas e.g. oxygen, an anesthetic or other therapeutic/diagnostic gas. The term "delivery" or "deliver" is used to refer to making a gas available to a subject for inspiration and does not imply that a pressurized source is opened to a subject. For example, a gas may be made available from a reservoir or conduit (passively) when no resistance exists to its inhalation or such resistance is able to be overcome by an inspiratory effort of a subject with or without mechanical assistance.

Optionally the flow characteristics of the reference breathing circuit are dictated in part by a flow control system which directs gas flow from a first source or circuit flow path for a first gas component, for example an inspiratory reservoir of the reference breathing circuit, to an alternate source or circuit flow path for a second gas component, for example, an air intake port or a second gas reservoir (for example an expiratory gas reservoir) when structural features of the reference breathing circuit arrest flow from the first gas source, for example when the volume of the inspiratory reservoir is depleted or when a valve is set to restrict flow from the first gas source. The flow control system is optionally supplanted in the first breathing circuit by programmed gas output characteristics which first match those of the first gas source or circuit flow path, and subsequently, corresponding to when flow switches to the alternate gas source or circuit flow path, match those of the alternate gas source or circuit flow path. For example, the gas flow characteristics may include concentration and/or volume of at least one constituent of gas emanating from the first gas source or circuit flow path (a constituent of the first gas component) and the concentration of at least one constituent gas of the gas emanating from the second gas source or circuit flow path (a constituent of the second gas component).

According to one aspect, the VSGD invention is directed to a respiratory gas delivery system including or adapted for use with a first breathing circuit optionally comprising or consisting of at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system is adapted to virtualize, for example, simulate the function, for example selected gas flow (delivery) characteristics, of a reference respiratory gas delivery system which includes or is adapted for use with a second, reference breathing circuit, that is structurally different (e.g. less wasteful of gas and/or less complex (e.g. fewer parts or parts more easy to assemble, integrate or coordinate) and/or less bulky, and/or less expensive and/or less prone to failure or physical limitations), the respiratory gas delivery system including: a) a flow sensor, optionally positioned in or proximal to the patient airway interface;

b) a gas delivery apparatus adapted to deliver a gas comprising a plurality of component or constituent gases into the patient airway interface, optionally into the gas conduit ( the gas delivery apparatus may include an on-board computer for controlling the gas delivery apparatus and/or may adapted to receive input from an external computer); and optionally

c) a gas analyzer, wherein the gas analyzer is optionally positioned in or proximal to the patient airway interface; wherein control of the gas delivery apparatus simulates selected flow characteristics of the reference gas respiratory gas delivery system that:

1. are defined at least in part by structural features, for example, structural parts of the reference breathing circuit;

2. define the source or circuit flow path and/or order of delivery of one or more component gases, and/or the composition and volume of the gas or a component or constituent of the gas made available for inspiration in a breath, series of breaths, breath segment or series of breath segments, or time period; and wherein the computer is programmed provide inputs to the gas delivery apparatus to:

A) control the gas delivery apparatus by executing an algorithm that employs as inputs data obtained from the flow sensor (and optionally the gas analyzer) and at least a mathematical model of the second, reference breathing circuit, including parameters that describe supplanted structural features e.g. structural parts of the second, reference breathing circuit, the supplanted features e.g. structural parts: a. defining at least in part the selected gas delivery characteristics;

b. absent in the first breathing circuit; and

B) generate an output signal to the gas delivery apparatus that accounts for the supplanted structural features of the second, reference breathing circuit, such that when the respiratory gas delivery system outputs gas to the first breathing circuit the selected gas output characteristics of the respiratory gas delivery system simulate portions of the reference respiratory gas delivery system defined by the supplanted parts of the second reference breathing circuit- In one embodiment of the VSGD invention, the reference breathing circuit is a rebreathing circuit including an inspiratory gas reservoir that is absent in the first breathing circuit, the computer programmed to obtain input of at least one rate at which the inspiratory gas reservoir is filled and at least one rate at which the inspiratory gas reservoir is emptied and to control the gas delivery apparatus to deliver a carbon dioxide containing gas after simulated depletion of the inspiratory gas reservoir.

In one embodiment of the VSGD invention, the reference breathing circuit is a rebreathing circuit including an inspiratory gas reservoir and an expiratory gas reservoir that are absent in the first breathing circuit, the computer supplanting the inspiratory and expiratory gas reservoirs, optionally by obtaining input of at least one rate at which the inspiratory gas reservoir is filled (this is optional since a first gas reservoir of a selected volume can simply be assumed to be replenished at beginning of each inspiratory cycle) and at least one rate at which the inspiratory gas reservoir is emptied, and controlling the gas delivery apparatus to deliver a carbon dioxide containing gas after each simulated depletion of the inspiratory gas reservoir. A rebreathing circuit may be a sequential gas delivery circuit if component gases are delivered in sequence. A sequential gas delivery circuit does not imply that the gas delivered after the first gas composition is or has the composition of at least one component e.g. C0₂of an exhaled gas in an amount corresponding to a last exhaled end tidal gas, or a target concentration of an end tidal gas if the respiratory gas delivery system is adapted to control same.

In one embodiment, the respiratory gas delivery system includes a gas analyzer and the reference breathing circuit is a sequential gas delivery circuit. The first delivered gas may be of a composition that primarily corresponds to the patient's physiological and/or therapeutic gas requirements while the second delivered gas may be exhaled gas or a gas formulated by the gas delivery apparatus e.g. a gas blender containing at least those constituents of the exhaled gas in amounts that justify its delivery e.g. delivery of carbon dioxide in amount that represents its intended function as a "neutral gas" as defined below.

In one embodiment, the respiratory gas delivery system includes a gas analyzer, and the reference breathing circuit comprises an inspiratory gas reservoir, an expiratory gas reservoir and air flow control system for directing the flow of gas to the patient only when the inspiratory gas reservoir is depleted. The airflow control system may typically include one or more active and/or passive valves (activated when a threshold pressure is reached, e.g. negative pressure resulting from depletion of the inspiratory gas reservoir). The reference breathing circuit may include a flow control system including a by-pass limb interconnecting an inspiratory and expiratory limb of the circuit or a bypass limb located exclusively within an expiratory limb of the circuit and therefore functioning to utilize negative inspiratory pressure to draw on the expiratory gas flow path when gas sourced from inspiratory flow path is depleted. Alternatively, one or more active valves can be used to effect sequential gas delivery (see US Patent Publication No. 2007/0062534). The inspiratory reservoir, expiratory gas reservoir and/or flow control system may absent from the first breathing circuit. The gas delivery apparatus may be programmed to control the concentration and rate of flow of the gas to simulate one or more cycles of filling and depletion of the inspiratory gas reservoir, optionally based on at least one rate of flow of gas into the inspiratory gas reservoir and at least one rate at which the inspiratory gas reservoir is depleted, and where input of at least one constituent of the gas exhaled by the subject is obtained from the gas analyzer for setting the gas delivery apparatus to (e.g. subsequently or contemporaneously) deliver a gas containing the at least one constituent in a selected concentration, for example a concentration that matches or approximates the concentration measured by the gas analyzer (optionally carbon dioxide).

With reference to any aspect of the VSGD invention, in one embodiment, the second, reference breathing circuit is a rebreathing circuit, and the gas delivery apparatus optionally simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation. In this manner, the entirety of a first delivered gas of selected composition makes its way into the alveolar volume of the lung (as opposed to the anatomic dead space). A gas that has a composition that corresponds to that of subject's exhaled gas from a breath n-1 may then be delivered in each breath n, for example, upon simulated depletion of the inspiratory gas reservoir. In a broader sense, the second delivered gas may a "neutral gas" (defined below), for example, in the sense that its composition, in terms of at least one of its constituents e.g. carbon dioxide, contributes minimally to establishing a partial pressure gradient between the lung and pulmonary circulation. In one embodiment, the selected gas output characteristics comprise at least one of the following:

(i) the order or timing of delivery of two components of the gas, for example, wherein delivery of one component of the gas is first, followed by, a second component of the gas, optionally, delivery of the first component ceasing pending delivery of second component of the gas and vice versa, in cycles. Preferably the respiratory gas delivery system simulates a reference respiratory gas delivery system in which the rate of flow of the first component is less than the subject's minute ventilation minus anatomic dead space ventilation sueh the entire volume of the first delivered component enters the alveolar space, in each cycle, the second component being a neutral gas;

(ii) the volume and composition per breath or breath segment of the gas or at least one constituent of the gas; (iii) the volume of a component or constituent of the gas relative to a total delivered volume of the gas, over a plurality of breaths or breath segments or over any time period [t];

(iv) a concentration of at least one component or constituent of the gas in each incremental unit of volume of the gas output from the gas delivery apparatus;

(v) a subject's effective alveolar ventilation in a breath [i] or over a plurality of breaths [n] or over a selected time period [t]. The term "effective alveolar ventilation" means the part of the volume of delivered gas that reaches the alveoli and establishes a concentration gradient for gas exchange (excludes the "neutral gas" component).

According to one aspect, the VSGD invention is directed to a respiratory gas delivery system adapted for use with a first breathing circuit having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes structural components a reference breathing circuit, the respiratory gas delivery system including: a) a flow sensor, positioned for at least determining the volume gas inhaled via the patient airway interface;

b) a gas delivery apparatus including or controlled by a computer for delivering a gas comprising a plurality of component or constituent gases into the patient airway interface; and optionally

c) a gas analyzer for analyzing the gas concentration of one or more constituent gases inhaled and/or exhaled by the subject;

wherein the computer is programmed to supplant one or more components of the reference breathing circuit by using a mathematical model of the supplanted structural components to generate gas delivery characteristics that supplant said components.

As suggested, the term supplants includes making one or more components superfluous (unnecessary to have a physical counterpart in the first breathing circuit) or replacing it/them with another/other component(s), for example, such that the supplanted circuit needs fewer, and/or less bulky and/or less complex or costly and/or components less prone to failure.

Optionally, the respiratory gas delivery system comprises virtual components which simulate components of a reference breathing system.

For example, in one embodiment, the supplanted component is an inspiratory gas reservoir which may be superfluous in the first breathing circuit. For example, the respiratory gas delivery system may be programmed to deliver a gas which, in effect, repeatedly (cyclically) provides the composition of the inspiratory gas reservoir in volumes which match the virtual content of inspiratory gas reservoir as it filled and refilled virtually having regard to the timing rate of flow in and out of the virtual reservoir, so that a counterpart physical reservoir is obviated in the first breathing circuit and accordingly in the design of the respiratory gas delivery system as a whole.

For example, in one embodiment, the supplanted component is a sequential gas delivery valve or valve set which may be superfluous in the first breathing circuit. A sequential gas delivery valve or valve set means a valve or valve set that alternately directs flow from a first flow path to a second flow path, for example so that differently constituted and/or sourced gases may be delivered, for example a first gas that supplies some part of the content requirements of the gas inspired in a given inspiratory cycle and a second gas that supplies the other part of that content (for example a "neutral" gas e.g. an end tidal gas. For example, the respiratory gas delivery system may be programmed to first deliver a gas which, in effect, repeatedly (cyclically) provides the composition of an inspiratory gas reservoir, and then ambient air inlet or the putative content of a virtual second gas reservoir. Accordingly, in terms of physical components of the first breathing circuit a single conduit leading to the patient airway interface may replace the aforementioned valves and optionally a second gas reservoir e.g. an expiratory gas reservoir. 4 000473

The term "component" used with reference to delivery of a portion of a gas refers to a distinct functional subset of the gas that may, if desired, be delivered separately by the respiratory gas delivered system (and conventionally is delivered separately in the reference respiratory gas delivery system), for example over a different time frame e.g. in sequence with another component as in a sequential gas delivery (SGD) circuit, whereas a "constituent" of the gas is considered by definition already part of a blend of gases of different chemical composition (even in the reference system) that can no longer be delivered separately unless first separated. Typically, constituents include individual or blended gases stored in a tanks for use in conjunction with a gas delivery apparatus in the form a gas blender for example as disclosed, in WO/2007/012197, for example to target an end tidal concentration of a gas X which is present alone or in a blend of gases from a particular tank or source (preferably stored or deliverable under pressure). An end tidal concentration of gas X may be controlled by methods well known to those skilled in the art including the method disclosed in WO/2007/0 2197 and Slessarev M. et al., J Physiol 581.3 (2007) p. 1207. A constituent gas is therefore considered indivisible without forced separation of its component parts. For example, to deliver a gas composition that targets a partial pressure of carbon dioxide of 50 mm. Hg a gas composition that empirically causes an increase in the partial pressure of C02 to the desired partial pressure e.g. 8% C0₂ and the algorithm disclosed in WO/2007/012197 can be used to maintain this partial pressure.

The term "mathematical model" is used broadly to refer to any model in which any form Of a mathematical relationship or computation underlies or is involved in a process executed by a computer and for greater certainty includes a model embodied in a look up table.

The term "algorithm" or related terms such as "algorithmic" (e.g. algorithmic model") refers to any process or set of rules to be followed by a computer in performing a function of the computer, in particular, simulation of one or more components of a reference breathing circuit. As used in this Section B, in the context of simulating structural features of a reference breathing circuit, and in particular, a sequential gas delivery circuit, simulation could not be carried without at least one if not both of a "mathematical model" and an "algorithmic model" and each may be understood to encompass the other.

As used herein the term "specifiable" implies that a convenient input means is available to a user to specify a parameter or value whereas the term "specified" implies that some parameter or value is set, regardless of whether it is pre-set or obtained by such convenient input. Hence unless used in the phrase "specifiable or specified" the term "specified" does not imply that a value or parameter was not specifiable. The phrase "specifiable or specified" is used herein for convenience to imply that the facility for user input either is or is not readily available without commenting on whether a facility to make a parameter or value "specifiable" is necessary. The convenience of having the facility of a specifiable input can generally be understood to be optional and generally preferred (for potential non-immediate or anticipated or unanticipated future uses, or testing) regardless of whether this facility is needed for using the invention to the most advantageous or most practical extent of its capability, redundant or of no foreseen value provided that the invention can be used only for very narrow purposes or to only modest advantage without this facility.

The term "gas delivery apparatus" as used throughout the specification is any apparatus that is capable of modulating the composition of an inspiratory gas, for example any device that can make a gas of variable / selectable composition available for inspiration.

The gas delivery apparatus may be used in conjunction with a ventilator or any other respiratory assistance device associated with a breathing circuit from which the subject is able to inspire a gas of variable/controllable composition.

Preferably, the composition of the gas and/or flow rate is under computer control. For example, a gas delivery apparatus may be adapted to deliver at least one gas (pure or pre-blended) at a suitable pre-defined rate of flow. The rate of flow may be selectable using a form of input device such a dial, lever, mouse, key board, touch pad or touch screen. Preferably the gas delivery apparatus provides for one or more pure or blended gases to be combined i.e. "a gas blender".

The term "reached" when used to describe reaching a threshold volume means attained or exceeded.

The term "criterion" means any state or condition for which input needed to determine whether or not the condition is satisfied or the state is present is usable by a processor operatively associated with a respiratory gas delivery system of the invention, optionally input from a measurement device of any kind (e.g. pressure, flow, concentration) that is operatively associated with the respiratory gas delivery system, optionally a measurement device operatively associated a breathing circuit within or proximal to a patient airway interface. 0473

A "rebreathing circuit" or "partial rebreathing circuit" is any breathing circuit in which a subject's gas requirements for an inspiratory cycle are made up in part by a first gas of a selectable composition and a rebreathed gas to the extent that the first gas does not fully satisfy the subject's volume gas requirements for the breath. The first gas must be selectable in at least one of composition or amount Preferably the amount and composition of the first gas is selectable. The rebreathed gas composition optionally consists of previously exhaled gas that has been stored or a gas formulated to have the same concentration of gas X as previously exhaled gas or a second gas has a gas X concentration that is selected to correspond (i.e. has the same concentration) to that of the targeted end tidal gas composition for a respective breath [i]. Aspects of invention related to the sequential delivery of such components may not apply where the subject's requirements for a breath are over-estimated or where it otherwise not necessary that the entirety of the first gas component make it the alveolar portion of the lung.

Preferably the circuit is designed or employable so that the subject receives the entirety of or a known amount of the first gas in every breath or in a consecutive series of breaths forming part of gas delivery regimen. In a general sense a re-breathed gas serves a key role in that it does not contribute significantly to the partial pressure gradient for gas flow between the lung and the pulmonary circulation when intake of the gas at least fills the entirety of the anatomic dead space. Therefore, in the case of a spontaneously breathing subject (whose tidal volume is not controlled e.g. via a ventilator) the subject's unpredictable tidal volume does not defeat prospective computation of the controlled gas composition required to attain or target an end tidal partial pressure of a gas x (PetXfi]) for a respective breath [i].

Optionally, the "rebreathed gas" may be constituted by or substituted by a prepared gas (in terms of its gas X content). Thus, according to one embodiment of the invention, the second gas has a gas X concentration that is selected to correspond to that of the targeted end tidal gas composition for a respective breath [i]. The volume of the first inspired gas may also be adjusted (e.g. reduced) to target PetX[i]T for a respective breath [i] such that the subject receives an optimal amount of a gas having a gas X concentration that corresponds to a target PetX[i]T. Target end tidal concentrations of gas x may be achieved with a device called a Respiract™ (see WO/2007/012197) .

As alluded to above, it will be appreciated that the gas X content of a prepared gas can be formulated to represent a gas of a "neutral" composition. Thus the total inspired gas for a respective breath [i] will comprise a first inspired gas having a controlled volume and gas X concentration (FIX) and a second gas which has a gas X content whose contribution to establishing a partial pressure gradient between the lung and pulmonary circulation is optionally minimized. In a broader sense, the second inspired gas content of gas X can be optimized to attain a targeted end tidal concentration (for a universal set of circumstances) and in a sub-optimal sense this concentration at least does not defeat the ability to prospectively compute an FIX for the purposes of attaining or targeting a PetXfi] for a respective breath [i] (i.e. not knowing the subject's tidal volume for a respective breath [i] will not preclude such computation).

The term "sequential gas delivery circuit" means a breathing circuit in which a first gas, optionally of selectable first composition (e.g. using a gas blender) is delivered first, and a second gas of second composition is delivered later than, optionally after delivery of the first gas, optionally when the first gas is depleted. A sequential gas delivery circuit optionally comprises first and second gas reservoirs and optionally a flow control system (e.g. a valve or series of valves and conduits) for switching repeatedly, optionally in each inspiration cycle, between a first circuit flow path in which the first gas reservoir is drawn upon and a second circuit flow path in which the second gas reservoir is drawn upon. Optionally, the trigger for switching between first and second flow paths is circuit pressure, for example the trigger is generated by an increase in circuit negative pressure when the first gas reservoir is depleted (opening a passive valve leading to second circuit flow path) or for example, a pressure transducer serves as input to alternatively open and close the first and second flow paths. The elapse of time, a gas analyzer reading etc. may also be a trigger. As seen in Figure 10, the gas entering the lung may be schematically divided into the alveolar portion 70 which contributes to gas exchange with the pulmonary circulation and the anatomical dead space portion 10, which includes the trachea, bronchi, and bronchioles, namely portions of the lung which carry gas to and from the alveoli, but do not directly contribute to gas exchange. According to one example of a reference breathing circuit, a sequential gas delivery circuit, best seen in Figure 12, by setting the rate of flow of gas into an inspiratory reservoir to be less than the minute ventilation, optionally less than the minute ventilation minus anatomical dead space ventilation. Gas sourced from a freshly filled inspiratory gas reservoir, when delivered first, occupies a portion of alveolar space 20 which therefore defines the effective alveolar ventilation, since the remainder of the gas making up the subject's inspiratory requirements 30 may be a second delivered gas which is an end tidal gas or a gas of the same approximate composition, which is "neutral" from the standpoint of gas exchange (i.e. it is already equilibrated with the partial pressure of those gases in the pulmonary circulation).

Accordingly, during any inspiration, the gas that is inspired first reaches the alveoli, while the gas inspired towards the end of the inspiratory cycle remains in the anatomical dead space. Many gases administered in clinical or research situations must enter the blood through the alveoli to exert the intended physiological effect. Inhalational anaesthetics such as nitrous oxide or isoflurane are a common example. The portion of such a gas that remains in the anatomical dead space does not enter the blood and do not produce any physiological effect. This portion of the gas is therefore wasted. It would be advantageous to deliver these gases only during the first part of inspiration that enters the alveoli.

This invention can accomplish this by signalling the gas delivery device to provide the gas of interest for a first defined volume of every inspiration, and then turning off delivery of the gas of interest only (setting its concentration in the inspired gas mixture to zero) in any volume inspired beyond the first volume. In one aspect the invention, is directed to. a gas delivery apparatus programmed to modulate the composition of the inspiratory gas throughout the inspiratory phase of the breath. The composition of the inspiratory gas may optionally be changed according to the cumulative volume of gas inspired. The invention may be used to provide inspiratory gases to a subject, which are equivalent to those that would have been inspired through a particular physical breathing circuit, for example as illustrated in Figures 11 and 12 . Alternatively, the invention simulates a breathing circuit for which there is no practical physical embodiment. It will be appreciated that certain features of a reference breathing circuit that would be impractical to construct owing to technical challenges (for example, an SGD manifold that is small enough not to be obstructive, flexible gas tubing which does not expand under pressure etc.) may be able to be sufficiently "simulated" by the respiratory gas delivery system of the invention to obviate or minimize such technical challenges. Hence, the terms "respiratory gas delivery system" and "first breathing circuit" encompass virtual systems and circuits which are limited only by the physical limitations of any necessary components selected from at least one of flow sensors, gas analyzers, gas delivery devices (e.g. valves) and flow controllers (e.g. response time, volumetric capability, sensitivity and precision) associated with implementing gas blending and delivery into a simple conduit connected to a patient airway interface.

Similarly the term "simulated" broadly refers to any algorithm which models a practical or "only theoretically" feasible system/circuit, which system/circuit is susceptible of algorithmic modelling, graphical representation and/or mathematical definition to implement a physical system which uses the simulation algorithm as input. For greater certainty, it is to be understood that while at least one component of the reference system of interest (including at least one component of the reference breathing circuit) is being simulated, inputs to the simulation algorithm (e.g. inspiratory flow) may be obtained from a real (i.e. not simulated) system (e.g. a flow sensor connected to a real patient) and the outputs from the simulation algorithm directed to a real (i.e. not simulated) system (e.g. a gas delivery apparatus which may then deliver gas to a real subject). Accordingly, the at least one component of the breathing is circuit may "simulated" in order to replace at least one component of an otherwise embodied ("real") system usable for therapeutic and/or diagnostic or experimental gas delivery, not to be confused with an in silico system that resides solely on a computer for teaching, training or other modelling purposes. In the result, a breathing circuit may be "simulated" at least in part in order to provide the same physical function as that provided by, or postulated for, a reference circuit, for example, using a mathematical function (equation) or a look-up table such that real physical measurements may be obtained and used to calculate and then control a matching output of gas. from a gas controller.

The term "matches" and related terms and "tracks" and related terms (implying an equivalent amount or rate) imply a substantial identity which is substantially functionally equivalent qualitatively and quantitatively (subject to only optional correction or avoidance of inferior or inconsequential features).

The subject breathes from gas delivered by a gas delivery apparatus. According to one embodiment, the invention contemplates that a flow sensor is positioned proximal to the subject's airway to measure the flow of inspired gas. The apparatus also comprises a computer in the form of a microprocessor or other computing means. The microprocessor reads the output of the flow sensor. The flow signal may be integrated to compute inspired volume. The microprocessor signals the gas delivery apparatus to deliver specific compositions of inspired gas based on the cumulative inspired volume.

For example, according to one embodiment, illustrated in Figure 11 , the function of the reference Hi-Ox 80 circuit may be approximated by this respiratory gas delivery system according to the present invention. As seen in Figure 11 , one example of a reference breathing circuit is a sequential gas delivery circuit 80 including an inspiratory limb of the circuit 88 comprising a first gas inlet 16 that fills a gas reservoir 14 in the form of an inspiratory gas reservoir. A one-way inspiratory valve 18 enables, for example, a spontaneously breathing subject, to draw on gas in the inspiratory gas reservoir 14 so that gas enters a bifurcated portion of the circuit 36 (optionally a y-piece) to the patient. The patient exhales through one-way expiratory valve 12. When the inspiratory gas reservoir 14 is depleted, valve 22, which opens at a higher pressure than one-way valve 18, responds to the increase in negative pressure, enabling a subject to draw fresh air from the ambient air port 98 for the remainder of that inspiration.

As seen in Figure 13, according to one embodiment of a respiratory gas delivery system according to the invention, a reference breathing circuit is virtualized using a gas blender 46 to control gas delivery characteristics (at least one of flow rate and composition) of the gas flowing through conduit 65. Gas inspired by the patient is drawn from the stream flowing though conduit 65 via conduit 64. The flow rate though conduit 65 is greater than the maximum inspiratory flow of the patient. The flow sensor 40 associated with conduit 64 determines the volume of gas inspired by the patient. One or more gas analyzers 42 may be used to analyze gas in conduit 64. For example gas exhaled by the patient may be analyzed in conduit 64, for example, depending on the gas of interest, via an N02 analyzer and/or a C02 analyzer. Gas blender 46 blends gas from two pressurized sources 50 and 48 and is controlled by microprocessor 44 which receives input from the gas analyzer 42 and flow sensor 40. The microprocessor signals the gas delivery apparatus to provide oxygen for a first predefined volume of any inspiration, and air for any volume inspired beyond the first volume.

This is an only approximation of the Hi-Ox 80 since the volume of high oxygen gas inspired during the first part of the inspiratory cycle is fixed, while with the Hi-Ox 80 it is dependent on the volume accumulated in the reservoir.

Alternatively, the function of the Hi-Ox 80 may be more exactly simulated by the device by accounting for the filling of the reservoir. Here, the microprocessor can be programmed to calculate the volume of oxygen that would be in the reservoir of a Hi-Ox 80, and switch the composition of the inspired gas to air when the calculated volume in the virtual reservoir is zero. In this embodiment, the operator programs the microprocessor with a virtual rate at which the virtual reservoir is to fill. The microprocessor continually increases the volume in the virtual reservoir at the specified virtual flow rate throughout the entire breath. For the first part of any inspiration, the microprocessor signals the gas delivery device to deliver oxygen to the subject. While the subject inspires oxygen, the volume in the virtual reservoir is decreased at the inspiratory flow rate measured by the flow sensor. When the virtual reservoir is empty, the microprocessor signals the gas delivery device to deliver air for the remainder of the current inspiration. While the subject inspires air, the volume of the virtual reservoir is not decreased at the inspiratory flow rate. In this way, the invention allows a subject to inspire the exact same gases as with a physical Hi-Ox 80 circuit with an oxygen reservoir that is being filled at a constant flow rate.

As shown in Figure 14 , according to one embodiment of a respiratory gas delivery system according to the invention, the gas delivery apparatus consists of a gas blender (GB) 46, a simulated sequential gas delivery circuit (SSGDC) 200 optionally comprising a gas conduit 100 and a patient airway interface optionally in the form of mask 101 (alternatives include an endotracheal tube), one or more gas analyzers (GA), a flow sensor (FS) 40, a computer (CPU) 44 (optionally a microprocessor), an input device (ID) 102, and a display (DX) 103. The gas blender 46 optionally contains three rapid flow controllers (not shown) which are capable of delivering accurate mixes of three source gases 104 (SG1 , SG2, SG3) to the circuit 200. The gases are delivered to the circuit via a gas delivery tube connecting the outlet of the gas blender 105 to the inlet 106 of the simulated sequential gas delivery circuit 200 which comprises or consists of a gas conduit 100 operatively connected to the flow sensor 40, gas analyzer(s) 42 and patient airway interface. The gas analyzer(s) 42 measures the partial pressures of gases at the airway throughout the breath. The analyzer(s) samples gas for analysis proximal to the subject's airway via a sampling catheter (not shown). A small pump (not shown) is used to draw gases from the subject's airway through the gas analyzers. Optionally, a pressure transducer 107 is used for measurement of the breath period (BP) and end- tidal detection, and also connected by a sampling catheter proximal to the subject's airway. The gas analyzers 42, flow sensor 40 and pressure transducer 107 communicate with the computer 44 via analog or digital electrical signals. The computer 44 optionally runs a software implementation of a simulation algorithm and demands the required mixtures from the blender via analog or digital electrical signals. The operator optionally enters reference breathing circuit parameters, for example the composition and flow rate into an inspiratory gas reservoir of a simulated reference SGD circuit 200 and any subject parameters. The display 103 optionally displays data/fields for inputs and outputs with respect to fixed or alterable input parameters and fixed or variable output parameters.

The respiratory gas delivery system according to the invention may be directed to supplant, in whole or part, a reference breathing circuit in the form of an SGD circuit 500 similar to the Hi-Ox 80. As seen in Figure 12, an inspiratory limb at the 202 reference circuit 500 comprises a first gas inlet 234. Inlet 234 fills a gas reservoir 200 in the form of an inspiratory gas reservoir. A one way inspiratory valve 230 enables, for example a spontaneously breathing subject, to draw on gas in the inspiratory gas reservoir 200, so that gas enters a bifurcated portion of the circuit (optionally a y-piece) leading to the patient. The patient exhales through one-way expiratory valve 228. When the inspiratory gas reservoir 200 is depleted, valve 226 which opens at a higher pressure than one-way valve 230 responds to the increase in negative pressure, enabling a subject to draw on a second expiratory gas reservoir 220. The subject's expired air is collected in the second reservoir 220 and the inlet side 224 of the valve 226 is connected to reservoir 220. Therefore, this circuit is similar to the Hi-Ox 80 except that upon depletion of the first gas reservoir 200, the subject draws the remainder of the inspiratory cycle from the reservoir 220 containing previously expired gas as opposed to air.

This circuit may be simulated by the invention in the same way as the Hi-Ox 80 except that upon depletion of the virtual reservoir, instead of air, the microprocessor signals the gas delivery device to deliver gas with a fractional concentration of at least one gas e.g. oxygen and carbon dioxide equal to that in the gas expired in the previous breath. Optionally, the oxygen content of the gas expired in the previous breath is analyzed with an oxygen analyzer and carbon dioxide analyzer whose output is read by a microprocessor.

According to one embodiment, a virtual circuit simulates any breathing circuit, or part thereof, which operates to vary the composition and/or pattern of flow of the gas inspired by the subject by:

1. Developing a mathematical or algorithmic formulation of the behavior of the circuit, and

in real-time:

2. Obtaining the inputs required to use the mathematical or algorithmic formulation to compute the composition and/or pattern of flow of the gas that would be delivered by the circuit

3. Compute the composition and/or pattern of flow of the gas that would be delivered by the circuit using the mathematical or algorithmic formulation

4. Direct an apparatus capable of controlling the composition and/or pattern of flow of inspired gas to deliver gas of a composition and/or pattern of flow equal to that the gas that would be delivered by the circuit as determined using the obtained inputs and mathematical formulation.

For example simulating SGD to vary composition only:

1. Develop mathematical formulation

BagVol = BagVol + GIFlow; lf(lnsp)

if(Bag=1)

BagVol = BagVol - InspFlow; lf(BagVol == 0)

Bag = 2; lf(Bag=1) Composition = G1 Composition

lf(Bag=2)

Composition = Last PetC02 or TargetPetC02

If(Exp)

Bag =1;

2. Obtain inputs

From the formulation, it is obvious that the required inputs are G1 Flow (input by user), G1 Composition (input by user), Last PetC02 (C02 sensor), InspFlow (Flow sensors)

3. Use the algorithm in 1 and the inputs in 2 to compute composition

4. Direct the real-time gas-blender to deliver composition

Example: Simulating a ventilator with a mechanical pop-off valve. In this case, the ventilator will deliver some desired insp flow to the subject, and if the airway pressure exceeds the mechanical pop-off, all the delivered flow is vented and subject gets 0 flow. This can easily be simulated with with a pressure sensor and control of the blower.

1. Develop mathematical formulation of behavior if(AirwayPressure < PressureLimit)

BlowerFlow = Desired Insp Flow

else

BlowerFlow = 0

2. Obtain inputs

From the formulation, it is obvious that the required inputs are Desired Insp Flow (ventilator setting), AirwayPressure (pressure sensor), PressureLimit (input by user = mechanical pop-off limit).

3. Use the algorithm in 1 and the inputs in 2 to compute BlowerFlow

4. Direct the blower to deliver BlowerFlow

Theoretically the invention can be applied to any circuit, but preferably the simulated circuit is advantageous in at least one of the following ways: less expensive, more robust, more efficient, etc. (see above) that the original circuit. In the case of SGD, this is certain.

Example 1

In one embodiment the respiratory gas delivery system is programmed to obtain the inputs related to the volume, rate of fill and depletion of an inspiratory reservoir, inspiration v. expiration, concentration of gas in inspiratory reservoir, concentration of gas in expiratory reservoir, which bag is being accessed, outputs including signaling the gas delivery device to turn off during expiration, switch concentrations when the inspiratory reservoir is depleted, switch to inspiratory reservoir concentration when inspiration is over etc. as further exemplified below:

// Variables numeric inspiratory_flow; // Inspiratory flow in ml/min numeric g1_bag_volume; // Volume in the g1 bag in ml numeric g1_bag_flow; // Fill rate of the g1 bag in ml/min numeric lastjime; // Last time the main loop was

// executed in ms numeric delta_t; // Time elapsed since last execution

// of the main loop in ms numeric desired_conc_x; // Concentration of gas x to be delivered

// to the subject for inspiration numeric conc_x_g1 ; // Concentration of gas x in the g1 bag numeric conc_x_g2; // Concentration of gas x in the g2 bag boolean isjnspiration; // indicates inspiration or expiration

// Inspiration = true, Expiration = false boolean is_bag_1 ; // Indicates bag being inspired from

// Inspiring from g1 bag = true, otherwise

// Main loop do(forever)

{

// Determine amount of time that has elapsed in ms

/ getJimeO ^is a function that returns time // with ms resolution deltaj = getJimeQ - lastjime;

lastjime = get_time();

// Determine instantaneous flow in ml/min

// read_inspiratory_flow_sensor() returns the

// latest flow measurement in ml/min inspiratory_flow = read_inspiratory_flow_sensor();

// Determine bag parameters:

// - Fill rate of g1 bag

// - Concentration of gas x in g1 bag

// - Concentration of gas x in g2 bag

// These parameters may be sent to the device running

// this code by the operator or another device. For example,

// this code may be run on a micro-processor and these

// parameters sent to this micro-processor by a PC.

// The function read_in() is assumed to populate the values

// of these parameters. read_in(g 1_bag_flo ,conc_x_g1 , conc_x_g 1 );

// Determine if inspiration or expiration:

// Switch to inspiration if currently expiring and

// inspiratory flow exceeds a threshold. Switch

// to expiration if currently inspiring and flow

// drops below a threshold. In this case, the threshold

// is 500 ml/min but could be set depending on the size of

// the subject and the resolution/noise of the flow sensor.

if(is_inspiration = false AND inspiratory_flow > 500 ml/min) {

isjnspiration = true;

}

else if(is_inspiration = true AND inspiratory_flow < 500 ml/min) {

isjnspiration = false;

}

// Increase the volume in the g1 bag by the gas // flow that has accumulated since the last time

// the main loop was executed

// 60000 converts ml/min to ml/ms g1_bag_volume += g1_bag_flow ^* deltaj * 60000;

// Inspiring from the g1 bag if(is_inspiration = true AND is_bag_1 = true)

{

// Decrease the volume in the g1 bag by the

// gas that has been inspired since the last

// time the main loop was executed

// 60000 converts ml/min to ml/ms g1_bag_volume -= inspiratory_flow ^* deltaj * 60000;

// Signal the gas delivery device to

// deliver the concentration of gas x

// in the g1 bag desired_conc_x = conc_x_g1;

// If the g1 bag is empty switch to the g2 bag

if(g1_bag_volume <= 0) {

bag = 2;

}

// Inspiring from the g2 bag

else if(is_inspiration = true AND is_bag_1 = false) {

// Signal the gas delivery device to

// deliver the concentration of gas x

// in the g2 bag

desired_conc_x ~ conc_x_g2; // Expiration

else

{

// Signal the gas delivery device to // turn off during expiration

desired_conc_x = 0;

// When the inspiration is over, switch // bag to the g1 bag for the next breath

is_bag_1 = true;

}

// Signal the gas delivery device to

// deliver the desired concentration

// of gas x:

// set_inspired_concentration_of_gas_x() // is a function which accepts the desired // concentration of gas x, and signals // the gas delivery device to deliver the // desired concentration

set_inspired_concentration_of_gas_x(desired_conc_x); } // End of main loop

Section C: Description of Invention: Prospective Model For End Tidal Targeting, Targeting Sequences and Various Applications of End Tidal Targeting Algorithms (hereinafter optionally referred to as the Prospective Model Based Targeting invention of P BT invention, for ease of reference)

The following description is contained in PCT application no. PCT/CA2013/000427 filed April 30, 2013 (published as WO/2013/163735) which claims priority from US application no. 61/640,570 filed April 30, 2012. This application, the content of which is hereby incorporated by reference, references a prospective model for end tidal targeting, and also particular sequences which are ramp target sequences in contrast to steps up or down in relatively large steps (e.g. jumps up or down in PetX of at least 5 or 10 mm Hg in a particular breath as logistically feasible). Importantly, it will be additionally appreciated that the present invention facilitates use of a negative feedback algorithm to ramp up or down end PetX^T in relatively fine increments.

The end-tidal partial pressures of gases are determined by the gases inspired into the lungs, the mixed venous partial pressures of gases in the pulmonary circulation, and the exchange of gases between the alveolar space and the blood in transit through the pulmonary capillaries. Changes in the end-tidal partial pressures of gases are reflected in the pulmonary end-capillary partial pressures of gases, which in turn flow into the arterial circulation. The gases in the mixed-venous blood are determined by the arterial inflow of gases to the tissues and the exchange of gases between the tissue stores and the blood, while the blood is in transit through the tissue capillary beds.

Robust control of the end-tidal partial pressures of gases therefore requires precise determination of the gas storage, transport, and exchange dynamics at the lungs and throughout the body. Previous attempts at controlling the end-tidal partial pressures of gases have failed to account for these complex dynamics, and have therefore produced mediocre results.

In the simplest approaches, manipulation of the end-tidal partial pressures of gases has been attempted with fixed changes to the composition of the inspired gas. However, without any additional intervention, the end-tidal partial pressures of gases vary slowly and irregularly as exchange occurs at the lungs and tissues. Furthermore, the ventilatory response to perturbations in the end-tidal partial pressures of gases is generally unpredictable and potentially unstable. Often, the ventilatory response acts to restore the condition of the blood to homeostatic norms. Therefore, any changes in the end-tidal partial pressures of gases are immediately challenged by a disruptive response in the alveolar ventilation. Consequently, fixed changes in the inspired gas composition provoke only slow, irregular, and transient changes in blood gas partial pressures. In more complex approaches, manipulation of the end-tidal partial pressures of gases has been attempted with negative feedback control. These approaches continuously vary the composition of the inspired gas so as to minimize error between measured and desired end-tidal partial pressures of gases. Technically, such a system suffers from the same limitations as all negative feedback control systems - an inherent trade-off between response time and stability.

Consequently, there is a need to overcome previous limitations in end-tidal gas control, allowing for more precise and rapid execution of end tidal gas targeting sequences in a wide range of subjects and environments.

According to one aspect the instant invention is directed to a method for attaining a target partial pressure of at least one gas X (PetX^T) in a spontaneously breathing mammal's (subject's) blood by integrating into a control algorithm a sequential gas delivery algorithm, preferably as hereinabove defined, and a negative feedback control algorithm, for example as more particularly described above. Optionally, a predictive algorithm is also contemporaneously employed to attain a target partial pressure of at least one gas X (PetX^T), optionally a predictive algorithm as described with reference to the PMBT invention hereafter.

According to one aspect the PMBT invention is directed to a method of controlling an amount of at least one gas X in a subject's lung to attain at least one targeted end tidal partial pressure of the at least one gas X, comprising the steps of: a. Obtaining input of a logistically attainable end tidal partial pressure of gas X (PetX[i]^T) for one or more respective breaths [i];

b. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation, wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and optionally 2014/000473

c. Controlling the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

For present purposes a mass balance equation is understood to be a mathematical relationship that applies the law of conservation of mass (i.e. the amount of at least one gas X) to the analysis of movement of at least one gas X, in and out of the lung, for the purpose of prospectively targeting an end tidal partial pressure of gas X. Optionally, where an end tidal partial pressure of gas X is sought to be changed from a baseline steady state value or controlled for a sequence of respective breaths [i] the mass balance equation will account for the transfer of a mass of gas X between a subject's lung and pulmonary circulation (i.e. the mixed venous blood entering the pulmonary capillaries (C_MVXti])); so that this key source of flux affecting the end tidal partial pressure of gas X in the breath(s) of interest, is accounted for.

Preferably the mass balance equation is computed based on a tidal model of the lung as described hereafter.

In one approach, a concentration of gas X (F|X), for example in a first inspired gas (the first inspired gas also referred to, in one embodiment of the P BT invention, as a controlled gas mixture) is computed to target or attain PetX[i]^T in a respective breath [i].

Optionally, the mass balance equation is solved for F|X.

It will be appreciated that F|X may be output from the mass balance equation by testing iterations of its value without directly solving for F|X.

Optionally, the volume of gas delivered to the subject is a fixed tidal volume controlled by a ventilator.

Optionally, the volume of gas delivered to the subject in a respective breath [ij comprises a first inspired gas of known volume and a second inspired neutral gas. In accordance with a tidal model of the lung, in one embodiment of the PMBT invention, the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

According to another aspect, the PMBT invention is directed to a method of controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressure of the at least one gas X, comprising the steps of: a. Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVX[I));

b. Obtaining input of a logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

c. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C_MvX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and optionally

d. Controlling the amount gas X in a volume of gas delivered to the subject in a respective breath [ί] to target the respective PetX[i]^T based on the prospective computation.

Optionally, a concentration of gas X (FiX) is computed to target or attain PetX[i]^T in a respective breath [i].

Optionally, the mass balance equation is solved for F|X.

According to one embodiment of the method, the mass balance equation is computed based on a tidal model of the lung. In accordance with a tidal model of the lung, in one embodiment of the invention, the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

According to another embodiment of the method, the method comprises the step of tuning one or more inputs required for computation of F|X, for example, with respect to any terms and/or by any methods described in this application.

According to another embodiment of the method, the volume of Inspired gas entering the subject's alveoli is controlled by fixing a tidal volume of an inspired gas containing gas X using a ventilator and subtracting a volume of gas corresponding to an estimated or measured value for the subject's anatomic dead space volume.

According to another embodiment of the method, the gas inspired by the subject is inspired via a sequential gas delivery circuit (as defined below). Optionally, the rate of flow of gas into the sequential gas delivery circuit is used to compute the volume of inspired gas entering the subject's alveoli in a respective breath [i].

Optionally, the gas inspired by the subject in each respective breath [i] comprises a first inspired gas and a second inspired optionally neutral gas, wherein the first inspired gas is delivered in the first part of a respective breath [i] followed by a second inspired neutral gas for the remainder of the respective breath [i], the volume of the first inspired gas selected so that intake of the second inspired neutral gas at least fills the entirety of the anatomic dead space. F|X is computed prospectively from a mass balance equation expressed in terms which correspond to all or an application-specific subset of the terms in equation 1 and the first inspired gas has a concentration of gas X which corresponds to F|X for the respective breath [i]

A "tidal model of the lung" means any model of the movement of gases into and out of the lung that acknowledges that inspiration of gas into, and the expiration of gas from the lung, occurs in distinct phases, each inspiration-expiration cycle comprising a discrete breath, and that gases are inspired in to, and expired from, the lungs via the same conduit.

In terms of computing a mass balance equation and capturing relevant aspects of movement of gases into and out of the lung, a tidal model of lung is preferably understood to yield a value of F|X on a breath by breath basis from a mass balance equation. The mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i]. Optionally, the mass balance equation is solved for F|X,

Preferably for optimal prospective model accuracy in a universal set of circumstances, all these discrete volumes are accounted for in the mass balance equation. However, it is possible for the invention to be exploited sub-optimally or for individual circumstances in which the relative sizes of certain of these respective volumes (e.g. anatomic dead space, volume of gas X transferred between the pulmonary circulation and lung and even tidal volume (shallow breaths) may be relatively small (compared to other volumes) depending on the circumstances and hence failing to account for all of these volumes may affect achievement of a target end tidal partial pressureto an acceptable extent particularly where less accuracy is demanded .

In one embodiment of the PMBT invention, the mass balance equation (optionally written in terms of one or more concentration of gas X in one or more discrete volumes of gas) : a. Preferably accounts for the total amount of gas X in the lung following

inhalation of the inspired gas in a respective breath [i] (M_LX[i]) including transfer of gas X between the lung and the pulmonary circulation;

b. Assumes distribution of M(X[i] into compartments including the subject's FRC (M[X[i]FRc), a fixed or spontaneously inspired tidal volume (Μ|_Χ[ί]ντ) and preferably the subject's anatomic dead space volume ( _LX[i]vD); c. Assumes uniform distribution of the M| X[i]_FRC a and M_LX[i]vr in the cumulative volume FRC+V_T;

d. Preferably includes a term that accounts for re-inspiration in a respective breath [i] of an amount of gas X left in the dead space volume after exhalation in a previous breath [i-1].

As detailed below, according to one embodiment, in which the PMBT invention is implemented via sequential gas delivery, the individual respective tidal volume for a breath [i] may consist of a first inspired gas having a concentration of gas X corresponding to F|X and second inspired neutral gas. The volume of the first inspired gas may be fixed, for example by controlling the rate of flow of first inspired gas into a sequential gas delivery circuit.

In one embodiment of the PMBT invention the mass balance equation comprises terms corresponding to all or an application-specific subset of the terms in equations 1 or 2 forth below as described hereafter. An "application-specific subset" means a subset tailored to either a minimum, intermediate or logistically optimal standard of accuracy having regard to the medical or diagnostic application of the invention in question or the sequence of PetX[i]^T values targeted. Optional terms and mandatory inclusions in the subset may be considered application-specific as a function of the sequence of PetX[i]^T values targeted in terms of the absolute size of the target value and/or the relative size of the target value going from one breath to the next as discussed below. For example, in most cases, the O2 or C0₂ re-inspired from the anatomical dead space ( V_D) is small compared to the 0₂ or CO2 in the other volumes that contribute to the end-tidal partial pressures. For example, where the volume of O2 or CO2 in the first inspired gas is very large, in trying to induce a large increase in the target end-tidal partial pressures, the 0₂ or C0₂ transferred into the lung from the circulation may be comparatively small and neglected. Neglecting any terms of the mass balance equations will decrease computational complexity at the expense of the accuracy of the induced end-tidal partial pressures of gases. The demands of a diagnostic application may be ascertained empirically or from the literature. For example, a measure of short response times of brain blood vessels to hypercapnic stimulus can be determined to require a square wave change in the stimulus such as a change of 10 mmHg PETC0₂ fr m one breath to the next. Another example is when measuring response of BOLD signal with MRI to changes in partial pressure of CO2 in the blood, the changes needed may be determined to be abrupt as the BOLD signal has considerable random drift over time.

Optionally, one or more inputs for computation of PetX[i]^T are "tuned" as defined below to adjust, as necessary or desirable, estimated or measured values for FRC and/or total metabolic production / consumption of gas X so as to reduce the discrepancy between targeted and measured end tidal partial pressures of gas X i.e. an actual value, optionally measured at the mouth. Tuning can be done when a measured baseline steady state value of PetX[i] is defined for a series of test breaths.

According to another aspect, the PMBT invention is directed to an apparatus for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressure of the at least one gas X, comprising:

(1) a gas delivery device;

(2) a control system for controlling the gas delivery device including means for: a. Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i]

c. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX[I], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and d. Controlling the amount of gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T solely based on the prospective computation.

In one embodiment of the method, a concentration of gas X (F|X) is computed to target or attain PetX[i]^T in a respective breath [i].

Optionally, the mass balance equation is solved for F|X.

It will be appreciated the control system may implement one or more embodiments of the method described in this section C.

In one embodiment of such an apparatus the gas delivery device is a sequential gas delivery device.

In one embodiment of the apparatus, the control system is implemented by a computer. In one embodiment of the apparatus, the computer provides output signals to one or more rapid flow controllers.

In one embodiment of the apparatus, the apparatus is connected to a sequential gas delivery circuit.

In one embodiment of the apparatus, the computer receives input from a gas analyzer and an input device adapted for providing input of one or more logistically attainable target end tidal partial pressureof gas X (PetX[i]^T) for a series of respective breaths [i]. In one embodiment of the apparatus, the control system, in each respective breath [ij, controls the delivery of at least a first inspired gas and wherein delivery of the first inspired gas is coordinated with delivery a second inspired neutral gas, wherein a selected volume of the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired neutral gas for the remainder of the respective breath [i], wherein volume of the first inspired gas is fixed or selected for one or more sequential breaths by way of user input so that intake of the second inspired neutral gas at least fill the entirety of the anatomic dead space.

In one embodiment of the apparatus, the gas delivery device is a gas blender. In one embodiment of the apparatus, the control system implements program code stored in a computer readable memory or comprises a signal processor embodied in one or more programmable IC chips.

A prospective model may be embodied in a computer program product for use in conjunction with a gas delivery device to control an amount of at least one gas X in a subject's lung to attain a target end tidal partial pressure of a gas X in the subject's lung, comprising program code for:

a. Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVXII]);

c. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C vX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

d. Controlling the amount in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

In one embodiment of the method, a concentration of gas X (F|X) is computed to target or attain PetX[iJ^T in a respective breath [I].

Optionally, the mass balance equation is solved for F|X.

It will be appreciated the computer program product may be used in conjunction with a gas delivery device, to at least partially implement a control system for carrying out one or more embodiments of the method described herein.

The program code may be stored in a computer readable memory or embodied in one or more programmable IC chips. The present invention is also directed to the use of an aforementioned method, apparatus or computer program product to:

a) Provide a controlled vasoactive stimulus for measurement of vascular reactivity; b) Provide a controlled vasoactive stimulus for measurement of cerebrovascular reactivity; c) Provide a controlled vasoactive stimulus for measurement of liver, kidney, heart or eye vascular reactivity; or d) Simultaneously change the subject's end tidal partial pressuresof oxygen and carbon dioxide to selected values, for example to potentiate a diagnosis or treat cancer.

According to another aspect, the present invention is directed to a method of controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising the steps of: a. Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C_MVX[i]); b. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX[I], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation, the mass balance equation comprising terms corresponding to all or an application-specific subset of the terms set forth in:

eq. 1

c. Controlling the amount of gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

The terms referred to the equations are defined herein. in one embodiment of the method, a concentration of gas X (F|X) is computed to target or attain PetX[i]^T in a respective breath [i].

Optionally, the mass balance equation is solved for F|X.

According to one embodiment, the gas inspired by the subject in each respective breath [i] comprises a first inspired gas and a second inspired neutral gas (as define hereafter), wherein a selected volume of the first inspired gas is delivered in the first part of a respective breath [i] followed by a second inspired neutral gas for the remainder of the respective breath [i], the volume of the first inspired gas selected so that intake of the second inspired neutral gas at least fills the entirety of the anatomic dead space.

The verb "target" used with reference to achieving a logisticaliy attainable PetX[i]^T value for a respective breath [i] means "attain" with the relative precision pragmatically demanded by the particular therapeutic or diagnostic application in question or the sequence of targets sought to be attained in both absolute and relative (between contiguous breaths) terms. For example, as discussed below, by "tuning" values for certain inputs into equation 1 or 2 (particularly functional residual capacity and total metabolic consumption or production of gas X) a logisticaliy attainable end tidal partial pressureof gas X could be attained with relative precision in one breath. The logisticaliy attainable PetX[i value could theoretically be attained with a clinically acceptable reduced precision by not tuning those values or foregoing other optimizations, as described herein, for example, by tuning total metabolic production or consumption of gas X without tuning F C, which would be expected to delay getting to the target value more precisely by several breaths.

For purposes herein, it is understood that limitations of a physiological or other nature may impinge on attaining a PetX[i]^T. Given a logistically attainable target for which parameters known to impinge on accuracy, that can be optimized (described herein e.g. tuning FRC and total metabolic consumption/production of gas X) are optimized, we have found that a PetX[i]^T can be considered to be "attained" as a function of the difference between the targeted value and a steady state value measured for an individual. For example, assuming a measurement error of +/- 2 mm. of Hg, in the case of C0_2l for a PetX[i]^T between 30 and 50 mmHg, a measured PetC0₂ value that is within 1 to 3 mm. of Hg of PetX[i]^T can be considered to be "attained". Tuning to an extent that achieves a measured value within this range will serve as an indicator as to whether tuning has been successfully completed or should be continued. However in principle, tuning may be iterated until the difference between the measured and targeted PetX is minimized. However, for a PetC0₂[i]^T between 51 and 65 mmHg, a measured PetX value that is within (i.e +/-) 1 to 5 mm. of Hg of PetC0₂[i]^T can be considered to be "attained" and the success of a given tuning sequence can be judged accordingly.

In the case of oxygen, a measured Pet0₂ value that is within 5-10% of Pet02[i]^T can be considered to be one which has "attained" Pet02p]^T- For example, if the target PetOz value is between 75 mm of Hg and 150 mm of Hg a range of measured values that proportionately is within (i.e. +/-) 4 mm and 8 mm of Hg (5 and 10% of 75 respectively) to +/- 8 mm to 5 mm of Hg (5-10% of 150) can be considered to be attained (similarly for a target of 100 mm of Hg, +/- 5-10 mm of Hg; and for a Pet02[i]^T of 200 mm Hg, +/- 10-20 mm of Hg).

However, as described above, depending on the demands of the application and the circumstances, a PetX[i]^T can be considered to be "targeted" with a deliberately reduced precision (as opposed to "attained" as a goal) if parameters known to impinge on accuracy, that can be optimized (described herein e.g. tuning FRC and total metabolic consumption / production of gas X) are deliberately not optimized. The invention as defined herein (not to the exclusion of variations apparent to those skilled in the art) is nevertheless exploited inasmuch as various aspects of the invention described herein provide for a prospective targeting system, a system that can be judiciously optimized (or not) to accommodate a variety of circumstances and sub- optimal uses thereof. A PetX[i]^Tcan be considered to have been "targeted" by exploiting the invention as defined, in one embodiment, after executing a sequence of tuning breaths, wherein the tuning sequence optionally establishes that the optimizations defined herein make the target "attainable".

According to another aspect, the present invention is also directed to a preparatory method for using a gas delivery device to control an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising the step of executing a sequence of "tuning" breaths as described hereafter.

Optionally, one or more inputs for computation of PetX[i]^T are " tuned" as defined below to adjust, as necessary or desirable, estimated or measured values for FRC and/or total metabolic production / consumption of gas X so as to reduce the discrepancy between targeted and measured end tidal partial pressure of gas X i.e. an actual value, optionally measured at the mouth. Tuning is preferably done when a measured baseline steady state value of PetX ] is ascertained for a series of ensuing test breaths.

According to one embodiment of the invention, an estimated or measured value for the subject's functional residual capacity (FRC) is tuned.

Optionally, FRC is tuned in a series of tuning breaths by:

a. changing the targeted end tidal partial pressure of gas X between a tuning breath [i+x] and a previous tuning breath [i +x -1]; b. comparing the magnitude of the difference between the targeted end tidal partial pressure of gas X for said tuning breaths [i+x] and [i+x-1]with the magnitude of the difference between the measured end tidal partial pressure of gas X for the same tuning breaths to quantify any discrepancy in relative magnitude; and c. adjusting the value of FRC in proportion to the discrepancy to reduce the discrepancy in any subsequent prospective computation of F₍X. 00473

Optionally, FRC is tuned in a series of tuning breaths in which a sequence of end tidal partial pressuresof gas X is targeted at least once by:

(a) obtaining input of a measured baseline steady state value for PetX[i] for computing F|X at start of a sequence;

(b) selecting a target end tidal partial pressure of gas X (PetX[i]^T) for at least one tuning breath [i+x] wherein PetX[i+x]^T differs from PetX[i+x-1]^T; and

(c) comparing the magnitude of the difference between the targeted end tidal partial pressureof gas X for said tuning breaths [i+x] and [i+x-1] with the magnitude of the difference between the measured end tidal partial pressure of gas X for the same tuning breaths to quantify any discrepancy in relative magnitude;

(d) adjusting the value of FRC in proportion to any discrepancy in magnitude to reduce the discrepancy in a subsequent prospective computation of F₍X including in any subsequent corresponding tuning breaths[i+x-1] and [i+x] forming part of an iteration of the sequence.

According to one embodiment of the invention, an estimated or measured value of the subject's total metabolic production or consumption of gas X is tuned.

Optionally, the total metabolic production or consumption of gas X is tuned in a series of tuning breaths by comparing a targeted end tidal partial pressure of gas X (PetX[i+x]^T) for the at least one tuning breath [i+x] with a corresponding measured end tidal partial pressure of gas X for the corresponding breath [i+x] to quantify any discrepancy and adjusting the value of the total metabolic production or consumption of gas X in proportion to any discrepancy to reduce the discrepancy in any subsequent prospective computation of F|X.

Optionally, the total metabolic consumption or production of gas X is tuned in a series of tuning breaths in which a sequence of end tidal partial pressuresof gas X is targeted at least once by: (a) obtaining input of a measured baseline steady state value for PetX[i] for computing F|X at start of a sequence;

(b) targeting a selected target end tidal partial pressureof gas X (PetX[i]^T) for each of a series of tuning breaths [i+1...i+n], wherein PetXfi differs from the baseline steady state value for PetX[i];

(c) comparing the targeted end tidal partial pressureof gas X (ΡβίΧ[ϊ+χ]^η for at least one tuning breath [i+x] in which the targeted end tidal gas concentration of gas X has been achieved without drift in a plurality of prior breaths [1+x-1, 1+x-2...] with a corresponding measured end tidal partial pressureof gas X for a corresponding breath [i+x] to quantify any discrepancy and adjusting the value of the total metabolic consumption or production of gas X in proportion to the discrepancy to reduce the discrepancy in a subsequent prospective computation of F[X including in any

subsequent corresponding tuning breath [i+x] forming part of an iteration of the sequence.

All key inputs for computing F|X are itemized below.

We have found that a prospective model which predicts an F|X that is required to target a logistically attainable end tidal partial pressureof a gas X is simplified and enhanced by using a sequential gas delivery system (alternatively called a sequential gas delivery device, or sequential rebreathing).

According to another embodiment, the apparatus according to the invention is a "sequential gas delivery device" as defined hereafter. The sequential gas delivery device optionally comprises a partial rebreathing circuit or a sequential gas delivery circuit as defined hereafter.

The rate of gas exchange between the subject's mixed venous blood and alveoli for a respective breath [i] may be controlled by providing a partial re-breathing circuit through which the subject inspires a first gas in which the concentration of gas X is F|X and a second gas having a partial pressure of gas X which is substantially equivalent to the partial pressure of gas X in the subject's end tidal expired gas prior to gas exchange in the current respective breath [i] (the subject's last expired gas which is made available for re-breathing) or a gas formulated in situ to match a concentration of gas X which would have been exhaled in a prior breath . Practically, this may be accomplished by setting the rate of gas flow into the partial rebreathing circuit for a respective breath [i] to be less than the patient's minute ventilation or minute ventilation minus anatomic dead space ventilation (i.e. such that the last inspired second gas at least fills the anatomical dead space if not also part of the alveolar space) and using this rate or the volume of inspired gas it represents in a current breath to compute FiX for a respective breath [i].

With reference to parameters used to compute terms in equation 1 or 2, it is understood that phrases like "obtaining input" and similar expressions are intended to be understood broadly to encompass, without limitation, input obtained by or provided by an operator of a gas delivery device through any form of suitable hardware input device or via programming or any form of communication or recordation that is translatable into an electronic signal capable of controlling the gas delivery device.

According to another aspect, the invention is also directed to a method of controlling an amount of at least one gas X in a subject's lung to attain, preliminary to or during the course of a diagnostic or therapeutic procedure, at least one target end tidal partial pressureof a gas X.

A PetX[i] attained for any immediately previous breath is: a. alterable, prospectively, to any other logistically attainable value, in one breath, using a method or apparatus according to the invention; b. maintainable, prospectively, without drift, in a respective breath [i] or in breath [i] and in one or more subsequent breaths [i+1]

[i+n] using a method or apparatus according to the invention.

According to one embodiment of the invention, a input of a concentration of gas X in the mixed venous blood entering the subject's lung for gas exchange in the respective breath [i](CwivX[i]) can be obtained (e.g. predicted) by a compartmental modelling of gas 00473

dynamics. "Compartmental modeling of gas dynamics" means a method in which body tissues are modeled as system of one or more compartments characterized in terms of parameters from which the mixed-venous return of gas X can be predicted. These parameters include the total number of compartments, the fraction of the total cardiac output received by the respective compartment, the respective compartment's storage capacity for gas X and the fraction of the overall production / consumption of gas X that can be assigned to the compartment.

The total number of compartments (ncomp) in the model must be known or selected, and then each compartment (k) is assigned a fraction of the total cardiac output (qk), a storage capacity for gas X (dXk), and a fraction of the overall production/consumption rate of gas X (vXk). In general, the storage capacity for any gas X in a compartment is known for an average subject of a particular weight, and then scaled proportional to the actual weight of the subject under test.

Modeling/predicting the mixed-venous return can be done for any gas X using the following information:

1. A formula for conversion of end-tidal partial pressures to blood content of gas X (i.e. determining the content of the gas X in the pulmonary end-capillary blood based on data with respect to partial pressures).

2. the fraction of the overall production/consumption of the gas X which occurs in the compartment;

3. the storage capacity of the compartment for gas X;

4. blood flow to/from the compartment.

Some examples of gas X include isoflorane, carbon dioxide and oxygen.

Compartmental modeling of gas dynamics may be simplified using a single

compartment model.

Means for controlling gas delivery typically include suitable gas flow controllers for controlling the rate of flow of one or more component gases. The gas delivery may be controlled by a computer for example an integrated computer chip or an external computer running specialized computer readable instructions via which inputs, computations and other determinations of parameter and controls are made/handled. The computer readable instructions may be embodied in non-transitory computer readable medium which be distributed as a computer program product.

It will be appreciated that logistically attainable target values for end tidal partial pressuresof gas X may be set for respective breaths within a series breaths which are taken preliminary to or as part of a diagnostic or therapeutic procedure. Typically these values are defined in advance for the series or for at least part of the series of breaths. As described below, these individually logistically attainable values may be used to attain values in multiple breaths that are not logistically attainable in one breath.

The term "tuning" and related terms (e.g. tune, tuned etc.) means that a value for an estimated or measured parameter that is required to compute F|X is adjusted, as necessary or desirable, to enable more precise computation of the F|X required to achieve a PetX[i]^T, preferably based on observed differences between the target PetX[i]^T set for one or more respective breaths and actual PetX[i] value(s) obtained for the respective breath(s), if any, such that post-adjustment observed value(s) more closely match the respective target value(s). The tuned parameter(s) can be understood to fall into two categories: lung and non-lung related parameters. Preferably, the lung related parameter is FRC. A step change in the end tidal partial pressureof gas X is required to tune this parameter. Non-lung related parameters are preferably tissue related parameters, preferably those required for computing a compartmental model of gas dynamics, preferably parameters governing total metabolic production or consumption of gas X in the body or the overall cardiac output, optionally parameters affecting assessment of the contribution of a respective compartment to the mixed venous content of gas X, preferabiy as a function of the production or consumption of gas X in the respective compartment, the assigned storage capacity for gas X in the respective compartment and the contribution of blood flow from the respective compartment to the total cardiac output, for example, by observing that a repeatedly targeted value does not drift when attained. Drift can be defined in the negative or considered to have been corrected for, for example, if an adjusted value for a tissue related parameter results in a variation of no greater than 1 to 2 mm of Hg (ideally approximately 1 mm of Hg or less) between observed and targeted end tidal values of gas X for a series of 5 consecutive breaths (i.e. where the end tidal partial pressureof gas X is sought to be maintained for a series of breaths e.g. 30 breaths and observed drift is corrected).

Tuning F C is important for transitioning accurately between end-tidal values. Tuning non-lung related parameters e.g. VC02 is important so that the steady state error between end-tidal values is small. The tuning requirements depend on the goals of the targeting sequence.For example, in the case of inducing a step increase in the end-tidal partial pressure of C02 from 40 mmHg to 50 mmHg, if attaining 50 mmHg in the first breath is important, FRC is preferably tuned. If achieving 50 mmHg in the first breath is not vital, but achieving this target in 20 breaths is all that may matter, a non-lung related parameter such as VC02 should be tuned. If the goal of the end tidal targeting sequence is to achieve 50mmHg in one breath, and then maintain 50 mmHg for the ensuing 20 breaths , both FRC and a non-lung related parameter should be tuned. If you don't care if you get to 50 mmHg in the first breath, and then drift to 55 after 20 breaths, don't tune either.

The following are examples of end tidal values that would be achieved for each combination. Assume transition is made on the second breath (bold):

Tuned FRC (good transition), untuned VC02 (bad steady state error) - 40, 50, 51 , 52, 53, 54, 55, 55, 55, 55, 55, 55

Untuned FRC (bad transition), tuned VC02 (no steady state error) - 40, 59, 56, 53, 52, 51 , 50, 50, 50, 50, 50

Tuned FRC (good transition), tuned VC02 (no steady state error) - 40, 50, 50, 50, 50, 50, 50, 50, 50

Untuned FRC (bad transition), untuned VC02 (bad steady state error) - 40, 62, 60, 58, 57, 56, 55, 55, 55, 55.

For example, to achieve a progressively increasing end tidal partial pressureof gas X where the actual or absolute values are not of concern, only that the values keep increasing in each breath, it would not be necessary to tune FRC or VC02. However, to transition from 40 to 50 mmHg (for example, where gas X is C02), though not necessarily in one breath, it would be preferable to tune a non-lung related parameter e.g. VC02 but not FRC. If it were important to transition from 40 mmHg to 50 mmHg in one breath, but not so important if the end tidal values drifted away from 50 mmHg after the first breath, it would be important to tune FRC but not VC02 etc. Nevertheless, a target would be set for each respective breath [i] and that target would be effectively attained with a degree of accuracy and immediacy necessary for the application in question. Accordingly, a tidal based model for targeting end tidal partial pressureof a gas X provides a tunable flexible system for attaining those targets in line with a wide variety of objectives of the user.

It is to be understood that this tuning can be applied independently to each of the gases that are being targeted, as each gas can be targeted independently of the other gases.

An attainable target may be maintained in one or more subsequent breaths by setting the target end tidal value for the respective breath to be the same as PetX[i-1]. A target that is not attainable in one breath may be obtained in a series of breaths [i] ...[i+n].

As suggested above and discussed below, it is possible that a particular end tidal partial pressureis not logistically attainable in one breath. If logistically attainable at all, such a target may be logistically attained only after multiple breaths. In contrast to methods requiring negative feedback, such as dynamic end tidal forcing, in one aspect of the method of the present invention this number of breaths may be pre-defined

prospectively. This number of breaths may also be minimized so that the ultimate end tidal target is attained as rapidly as logistically feasible, for example by simple computational trial and error with respect to an incremented series of target. As described below, logistic constraints could be seen as limitations to inhaling the amount of the gas X that needs to be inhaled to reach a target concentration on the next breath; this could be because of limitations of available concentration X, or volume of inspired gas or both. Mandatory constraints are at least those inherent in any method of controlling the end tidal partial pressureof a gas X by way of inhalation of concentrations of gas X in that F₍X cannot be less 0% and greater than 100% for any given breath. Constraints may also be selected as a matter of operational necessity or efficiency - so called "operational constraints" which may be self-imposed but not mandatory in all cases. For example, practically speaking, it may be inadvisable for safety reasons to administer a gas X (especially where gas X is not oxygen) in the highest feasible concentrations due to patient safety risks accompanying failure of the system.

Accordingly, for safety reasons it may be advisable for a component gas comprising gas X to have at least 10% oxygen thereby defining an optional logistical limit of the method. Therefore what is logistically achievable is understood to be operationally limited by the composition of all the gas sources to which the apparatus is connected at any point in time. Furthermore, as described below, sequential gas delivery is typically effected by delivering a gas of a first composition followed by a neutral gas. The rate of flow and hence volume of the first gas generally controlled to within certain parameters so that the second gas at least fills the anatomic dead space. This is operationally mandatory in the sense that not all values for this parameter are workable, especially if a medically relevant target end tidal partial pressureof gas X is sought to be achieved in one breath as opposed to incrementally over several breaths, What is logistically attainable will be dictated by the extant rate of flow, if unvaried, or if varied, by the range of logistically practicable rates of flow. Hence, what is logistically attainable may be tied to

independently controlled parameters which may or may not be varied. Hence, some of these operational parameters may be mandatory in a particular context or in a universal sense (running the system so that it always works without reset e.g. recalculation of prospectively calculated F|X values for a dynamic set of breaths of interest if the tidal volume falls outside established controls.

According to one embodiment of the method, the model of gas dynamics that is used to predict C_MvX[i] in the mixed venous blood entering the subject's lung for gas exchange in the respective breath [i] estimates a value of CMVXM) by. (a) dividing tissues to which the subject's arterial blood circulates into one or more compartments (k); and (b) determining the contribution of a respective compartment to the mixed venous content of gas X as a function of the production or consumption of gas X in the respective compartment, the assigned storage capacity for gas X in the respective compartment and the contribution of blood flow from the respective compartment to the total cardiac output or pulmonary blood flow. For example, where gas X is carbon dioxide the content of carbon dioxide in the mixed venous blood leaving a compartment C_vC02_k[i] is determined by assigning to a compartment a fraction of the overall metabolic carbon dioxide production (vco2_k), a fraction of the total cardiac output (q_k) and a storage capacity for carbon dioxide (dC02_k).

In contrast to a negative feedback system, the afore-described system is a prospective end-tidal targeting system. Prior to execution of an end-tidal targeting sequence, the tissue model is used to predict the time course of the mixed-venous blood gases that will result from ideal execution of the sequence.

The time course of predicted mixed-venous gases is used to compute the series of inspired gas mixtures required to realize the target end-tidal partial pressures of gases. In this way, assuming that the end-tidal partial pressures of gases adhere to the targets allows prediction of the mixed-venous gases, and prediction of the mixed-venous gases allows a priori calculation of the inspired gas mixtures required to accurately implement the end-tidal targets. There is no requirement to modify the series of the inspired gas mixtures calculated before execution of the sequence based on deviations of the measured end-tidal partial pressures of gases from the targets during execution of the sequence.

Instead, the system is tuned to obtain tuned values for certain parameters before execution of the sequence so that the end-tidal partial pressures of gases induced during sequence execution closely adhere to the target functions without the need for any feedback control.

Optionally, the program code includes code for directing a suitable gas delivery device such as a rapid flow controller to deliver a gas X containing gas having an F|X output from a mass balance equation. The term "gas delivery means" by contrast to gas delivery device refers to a discrete component of a gas delivery device that is used to control the volume of gas delivered at a particular increment in time such as a rapid flow controller. It will be appreciated that each of the key method steps for carrying out the invention can be functionally apportioned to different physical components or different computer programs and combinations of both. Furthermore a device according to the invention will optionally comprise one or more physical components in the form of a gas analyzer, a pressure transducer, a display, a computer, a gas delivery device such as a rapid flow controller, a gas channeling means (gas conduits / tubes), standard electronic components making up a PCB, input devices for setting parameters etc. The various means for carrying out these steps include without limitation one in the same physical means, or different physical means on different devices, the same device or the same device component. Depending on the number of added gases these components may multiplied or where possible shared.

In another aspect, the present invention is also directed to a device comprising an integrated circuit chip configured for carrying out the method, or a printed circuit board (comprising discrete or integrated electronic components). The device optionally includes at least one gas delivery means such as a rapid flow controller. The device optionally includes an input device for inputting various parameters described herein. The parameters can be input via a variety of means including, but not limited to, a keyboard, mouse, dial, knob, touch screen, button, or set of buttons.

It is understood that any input, computation, output, etc. described herein can be accomplished by a variety of signal processing means including, but not limited to, a programmable processor, a programmable microcontroller, a dedicated integrated circuit, a programmable integrated circuit, discrete analog or digital circuitry, mechanical components, optical components, or electrical components. For example, the signal processing steps needed for executing the inputs, computations and outputs can physically embodied in a field programmable gate array or an application specific integrated circuit.

The term "blending" may be used to describe the act of organizing delivery of one gas in conjunction with at least one other and hence the term blending optionally encompasses physical blending and coordinated release of individual gas components. The term "computer" is used broadly to refer to any device (constituted by one or any suitable combination of components) which may be employed in conjunction with discrete electronic components to perform the functions contemplated herein, including computing and obtaining input signals and providing output signals, and optionally storing data for computation, for example inputs/outputs to and from electronic components and application specific device components as contemplated herein. As contemplated herein a signal processor or processing device in the form of a computer may use machine readable instructions or dedicated circuits to perform the functions contemplated herein including without limitation by way of digital and/or analog signal processing capabilities, for example a CPU, for example a dedicated microprocessor embodied in an IC chip which may be integrated with other components, for example in the form of a microcontroller. Key inputs may include input signals from - a pressure transducer, a gas analyzer, any type of input device for inputting a target end tidal partial pressureof gas X (for example, a knob, dial, keyboard, keypad, mouse, touch screen etc), input from a computer readable memory etc. Key outputs include output of the flow and/or composition of gas required to a flow controller.

For example of a compartmental model for mixed venous blood carbon dioxide dynamics may assign body tissues to k compartments e.g. 5 compartments and assign the contribution of a respective compartment to the mixed venous content of carbon dioxide as a function of the production of carbon dioxide in the respective compartment, the assigned storage capacity for carbon dioxide in the respective compartment and the contribution of blood flow from the respective compartment to the total cardiac output.

In one aspect, the present invention is directed to a non-transitory computer readable memory device having recorded thereon computer executable instructions for carrying out one or more embodiments of the above-identified method. The invention is not limited by a particular physical memory format on which such instructions are recorded for access by a computer. Non-volatile memory exists in a number of physical forms including non-erasable and erasable types. Hard drives, DVDs/CDs and various types of flash memory may be mentioned. The invention, in one broad aspect, is directed to a non-transitory computer readable medium comprising computer executable instructions 3

for carrying out one or more embodiments of the above-identified method. The instructions may take the form of program code for controlling operation of an electronic device, the program code including code for carrying out the various steps of a method or control of an apparatus as defined above.

A "gas delivery device" means any device that can make a gas of variable / selectable composition available for inspiration. The gas delivery apparatus may be used in conjunction with a ventilator or any other device associated with a breathing circuit from which the subject is able to inspire a gas of variable/controllable composition without substantial resistance. Preferably, the composition of the gas and/or flow rate is under computer control. For example, such a device may be adapted to deliver at least one gas (pure or pre-blended) at a suitable pre-defined rate of flow. The rate of flow may be selectable using a form of input device such a dial, lever, mouse, key board, touch pad or touch screen. Preferably the device provides for one or more pure or blended gases to be combined i.e. "a gas blender".

A "gas blender" means a device that combines one or more stored (optionally stored under pressure or delivered by a pump) gases in a pre-defined or selectable proportion for delivery a selectable rate of flow, preferably under computer control. For example or more stored gases may be combined with pumped room air or a combination of pure or blended (each blended gas may have at least 10% oxygen for safety) gases respectively contain one of carbon dioxide, oxygen and nitrogen as the sole or predominant component. Optionally, the selectable proportion is controlled automatically using an input device, optionally by variably controlling the flow of each stored gas (pure or pre-blended) separately, preferably using rapid flow controllers, to enable various concentrations or partial pressures of a gas X to be selected at will within a pre-defined narrow or broad range. For example, a suitable blender may employ one or more gas reservoirs, or may be a high flow blender which blows gas past the mouth i.e. in which gas that is not inspired is vented to the room.

A "partial rebreathing circuit" is any breathing circuit in which a subject's gas requirements for a breath are made up in part by a first gas of a selectable composition, and a rebreathed gas to the extent that the first gas does not fully satisfy the subject's 0473

volume gas requirements for the breath. The first gas must be selectable in at least one of composition or amount. Preferably the amount and composition of the first gas is selectable. The rebreathed gas composition optionally consists of previously exhaled gas that has been stored or a gas formulated to have the same concentration of gas X as previously exhaled gas or a second gas has a gas X concentration that is selected to correspond (i.e. has the same concentration) as that of the targeted end tidal gas composition for a respective breath [i].

Preferably the circuit is designed or employable so that the subject receives the entirety of or a known amount of the first gas in every breath or In a consecutive series of breaths forming part of gas delivery regimen. In a general sense a re-breathed gas serves a key role in that it does not contribute significantly to the partial pressure gradient for gas flow between the lung and the pulmonary circulation when intake of the gas at least fills the entirety of the anatomic dead space. Therefore, in the case of a spontaneously breathing subject (whose tidal volume is not controlled e.g. via a ventilator) the subject's unpredictable tidal volume does not defeat prospective computation of the controlled gas composition required to attain or target PetX[i] for a respective breath [i].

Optionally, the "rebreathed gas" may be constituted by or substituted by a prepared gas (in terms of its gas X content). Thus, according to one embodiment of the invention, the second gas has a gas X concentration that is selected to correspond to that of the targeted end tidal gas composition for a respective breath [i]. The volume of the first inspired gas may also be adjusted (e.g. reduced) to target PetX[i]^T for a respective breath [i] such that the subject receives an optimal amount of a gas having a gas X concentration that corresponds to PetX[i]^T.

As alluded to above, it will be appreciated that the gas X content of a prepared gas can be formulated to represent a gas of a "neutral" composition. Thus the total inspired gas for a respective breath [ij will comprise a first inspired gas having a controlled volume and gas X concentration (F|X) and a second gas which has a gas X content whose contribution to establishing a partial pressure gradient between the lung and pulmonary circulation is optionally minimized. In a broader sense, the second inspired gas content of gas X can be optimized to attain a targeted end tidal concentration (for a universal set of circumstances) and in a sub-optimal sense this concentration at least does not defeat the ability to prospectively compute an F|X for the purposes of attaining or targeting a PetX[i] for a respective breath [i] (i.e. not knowing the subject's tidal volume for a respective breath [i] will not preclude such computation).

"Prospectively" or a "prospective computation" means, with reference to a determination of an amount of gas X required to be inspired by the subject in an inspired gas to attain or target a PetX[i]^T for a respective breath [i] (optionally computed in terms of F|X), using inputs required to compute a mass balance equation (preferably including C_mX \), without necessary recourse to feedback to attain rapidly and repeatably . In contrast, to a negative feedback system, which relies on ongoing measurements of PetX[i] to provide feedback for continually adjusting computed F]X values to minimize the discrepancy between target and measured PetX[i] values, the system of the present invention is adapted to attain logistically achievable end tidal values rapidly and accurately (as defined herein) without recourse to feedback. As discussed herein, a negative feedback system suffers from an inherent trade-off between response time and stability. According to the present invention, recourse to feedback is designed to be unnecessary for the purpose of attaining logistically achievable PetX targets rapidly and predictably.

Of further consideration are the delays associated with measurement of the end-tidal partial pressures of gases which are required for feedback into the system. Gas composition analysis is performed by continuously drawing gas from proximal to the subject's airway into a gas analyzer through a sampling catheter. The gas analyzer returns a time varying signal of gas composition which is, however, delayed from the actual ventilatory phase of the subject by the travel time through the sampling catheter and the response time of the gas analyzer. Therefore, at the start of any inspiration, the end-tidal partial pressures of gases from the immediately previous breath are not yet known. Where the sampling catheters are long, such as in an MRI environment where the patient is in the MRI scanner and the gas analyzers must be placed in the control room, this delay can reach three or more breaths. As in any negative feedback system, this delay in measuring the controlled parameter will further destabilize and limit the response time of the system.

A "sequential gas delivery device" means, with respect to delivering a gas in successive respective breaths [i], a device for delivery of a controlled gas mixture in the first part of a respective breath [i] followed by a "neutral" gas in the second part of the respective breath [i]. A controlled gas mixture is any gas that has a controllable composition with respect to one or more gases of interest used to compose it. Accordingly, where the gas of interest is a gas X, the controlled gas mixture has an amount of gas X, optionally defined in terms of a concentration of gas X denoted as F|X. The controlled gas mixture may be referred to, for convenience, as a first inspired gas. Gas inspired in any breath is "neutral", inter alia, if it has the same composition as gas expired by the subject in a previous breath. The term "neutral" gas is used because the gas in question is one which has the same partial pressure of one or more gases of interest as the blood, in the alveoli, or in the pulmonary capillaries, and hence, upon inspiration into the alveolar space, in the second part of a respective breath, this gas does not exchange any gas with the pulmonary circulation. Unless otherwise defined explicitly or implicitly a gas of interest is generally one for which the end tidal partial pressureis sought to be controlled according to the invention.

A volume of gas that enters the alveolar space and exchanges gas with the pulmonary circulation for a breath [i] may be defined independently of a fixed tidal volume, for example by: a. setting the rate of flow of a controlled gas mixture (also termed fresh gas flow rate) in a rebreathing circuit to be less than the patient's minute ventilation or minute ventilation minus anatomic dead space ventilation (i.e. such that the last inspired second gas at least fills the anatomical dead space if not also part of the alveolar space); b. obtaining input of the rate of flow or volume of the controlled gas mixture into the circuit for the respective breath (this rate can be maintained from 14 000473

breath to breath or varied) and computing the effective volume of alveolar gas exchange for the respective breath based on the rate of fresh gas flow for the respective breath.

According to one embodiment, the rebreathing circuit is a sequential gas delivery circuit.

According to another embodiment, volume of gas that enters the alveolar space and exchanges gas with the pulmonary circulation is determined by utilizing a fixed tidal volume set for the respective breath (e.g. using a ventilator) and subtracting a volume corresponding to the subject's anatomic dead space volume.

The FiX may be set independently of the concentration of any other component of the inspiratory gas.

Optionally, a gas X and a gas Y are components of the inspired gas and a target arterial concentration of gas X and a target arterial concentration of a gas Y are selected for a respective breath, independently of each other, and, if present, independently of the concentration of any other component Z of the inspiratory gas.

A mass balance equation that comprises terms "corresponding to" all or an application- specific subset of the terms in equations 1 or 2 above means that the same underlying parameters are accounted for.

According to one aspect of the PMBT invention (which may be implemented in connection with any one or more of compatible embodiments of the invention defined hereinabove), the invention is directed to an apparatus for controlling an amount of at least one gas X in a subject's lung to attain a series of targeted end tidal partial pressures of at least one gas X (PetX^T), the series of targeted end tidal partial pressures of at least one gas X (PetX^T) adapted to stimulate a physiological response, the apparatus comprising:

(1 ) a gas delivery device; (2) a control system for controlling the gas delivery device, wherein the control system is adapted to target a series of PetX^T values for a respective series of intervals, the control system including means for: a. Obtaining input of a series of logistically attainable PetX^T values for the series of respective intervals; and b. Determining an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval; c. Controlling the amount of gas X in a volume of gas delivered to the subject in a respective interval to target the respective PetX^T for the interval.

The series of PetX^T values preferably comprise at least one of a set of PetX^T increments and a set of PetX^T decrements.

The term "interval" is used broadly to mean a time interval of selected length, an interval defined by the duration of a respective inspiratory cycle and a previous or ensuing expiratory cycle, for example, a respective breath [i] defined by an inspiratory cycle and the expiratory cycle which follows it, and/or an interval defined by a pattern of a physiological response. The term 'pattern of a physiological response' means a pattern sufficient to define a dose-response (stimulus-response) relationship for a full range of the physiologic response or for at least a part thereof that reveals a pattern of interest, wherein the increments in dose or stimulus are selected to disclose the true shape of the dose response curve. A portion of interest may of diagnostic or medical interest to define a normal pattern of the response for example to differentiate between variations in a normal response for different groups e.g. ages, and optionally a differential response e.g. particular range or prevalence of a response or a different or pathologic response, associated with a condition or disease. For example, a pattern may disclose a linear, exponential or sigmoidal dose response curve for an individual or group of common individuals selected from at least one of persons having a "normal' physiological response and persons disclosing a different or pathological physiological response. For example, a pattern may disclose that a response is sigmoidal and not linear (e.g. it is only linear over a certain range of the stimulus) when a fuller range of the response is probed using a suitable range and series of smaller changes in stimulus. For example, an interval of diagnostic interest may be a fraction of the amount of time required to observe the time course of the response wherein the fraction is sufficiently small to obtain a set of values defining the pattern of response. The ramp sequence may also be selected to determine a time course of a full or partial range of a physiological response by tracking signals signifying that a particular condition, associated with a direct or indirect measure of the response, has been met, the condition preferably of the type satisfied by attainment or projected attainment of a threshold amount change in a measurable parameter correlated with a physiologic response to a stimulus comprising or consisting of an increment or decrement in a subject's end tidal partial pressure of gas X. A fraction or proportionate amount of a time period required to observe a continuous time course of a physiological response or satisfy a set threshold amount of change in the response (attained or predicted to be attained based on a known or predictable mathematical relationship between the stimulus - an increment or decrement in PetX - and a measurable parameter that defines the time course of the response), is then defined to be sufficient to demarcate the end of a previous interval and the beginning of a next ensuing interval. The time course may be selected to grade individuals in terms of the overall appearance of the pattern (measurement of a continuous variable) or differentiate between populations with respect satisfying one or more individual criteria (e.g. a discontinuous variable eliciting a yes /no answer).

A gas delivery device can be controlled to attain a series of targeted end tidal partial pressures of at least one gas X (PetX^T) by the prospective model described herein; or by a combination of a prospective model and feedback control (known as dynamic end tidal forcing), for example, wherein the feedback loop (e.g. using a PID controller) adds a control signal to adjust a prospective determination of F|X; the control signal generated based on the difference between the target and measured end tidal values. Computation of FIX can be accomplished using the tidal model equations herein by adapting the continuous flow equations published by Robbins and Swanson. According to one aspect of the PMBT invention (which may be implemented in connection with any one or more of compatible embodiments of the invention defined hereinabove), the invention is directed to a method of controlling an amount of at least one gas X in a subject's lung to attain at least one targeted end tidal partial pressure of the at least one gas X, comprising the steps of: a. Obtaining input of a logistically attainable end tidal partial pressure of gas X

(PetX[i]^T) for a series of respective breaths [i]; b. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetXfif for a respective breath [i] using inputs required to compute a mass balance equation, wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and optionally c. Controlling the amount gas X in a volume of gas delivered to the subject in a respective breath [ij to target the respective PetX[i]^T based on the prospective computation; and wherein the respective PetX[i]^T for the series of breaths [i] increases or decreases from the start of the series to the end of the series (from PetX[i¹]^Tto PetX[iⁿ]^T) in accordance with a ramp sequence (as defined below).

Optionally, the respective PetX[i]^Tfor the series of breaths [i] increases every Nth breath in respective selected increments ("Z") from the start of the series to the end of the series (from PetX[i¹]^T to PetX[iⁿ]^T), wherein either N equals 1 and Z is greater than 0 in each breath in the series, or N is greater than 1 and Z may be zero in breaths which are not the Nth breath and Z is greater than 0 in every Nth breath.

Optionally, the respective PetX[i]^T for the series of breaths [i] decreases every Nth breath in respective selected decrements ("Z") from the start of the series to the end of the series (from PetX[i¹]^T to PetX[iⁿ]^T), wherein either N equals 1 and Z is greater than 0, or N is greater than 1 and Z may be zero in breaths which are not the Nth breath and Z is greater than 0 in every Nth breath Accordingly, PetX[i]^T may change every Nth breath in respective selected increments or decrements ("Z") from the start of the series to the end of the series (from PetX[i ]^T to PetX[iⁿ]^T), wherein N equals 1 and Z is greater than 0. In another embodiment, N is greater than 1 and Z may be zero in breaths which are not the Nth breath.

Embodiments in which PetX[i¹]^T increases include the following. In one embodiment, "Z" is greater 0 and is the same in each breath in the series (N=1). For example, N may equal 1 and "Z" may equal 8. Therefore, for example, a target end tidal oxygen concentration may increase every breath (N=1) from [i]¹ to [i]ⁿ from PetX[i¹]^T= 100 mm Hg to PetX[i"]^T= 180 mm Hg over the course of the next 10 contiguous breaths

(respective targets in mm of Hg = 108, 116, 124, 132, 140, 148, 156, 164, 172, 180). As another example, N may equal 5 and same end tidal target value may be maintained at the same target for the 4 breaths in between each 5^th breath such that it would take approximately 50 breath to span the same range of end tidal targets from PetX[i ]^T= 100 mm Hg to [i]⁵⁰ = PetX[i⁵⁰ = 180 mm Hg. This same sequence may be expressed another way i.e. Z is changing and for the series of fifty breaths as follows: Z equals, respectively 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8, 0, 0, 0, 0, 8 0, 0, 0, 0, 8.

In one embodiment, Z is selected to correspond to a selected rate of change in a physiological response to a stimulus (the stimulus being a correlate of PetX[i]^T such as the arterial partial pressure of gas X (PaX)). The selected rate of change corresponds to a rate wherein a targeted physiologic response is substantially realized for each increment/decrement before the next increment/decrement, such that successive measurements of the response are substantially matched to an increment decrement in a change in stimulus. Accordingly, it is possible to plot the change in response with respect to the change in PetX[i]^T with substantial accuracy. For example, where the time course of the response of a physiologic parameter is exponential, the rate of change in PetX[i]^T may be selected such that three time constants in the progress of the response (approximately 95% response) are achieved before the next increment/decrement in PetX[i]^T stimulus is given. A time interval for executing the range in stimulus "R" or the range (extent) of the expected response "r" may be selected and the target change per breath in stimulus readily mathematically determined. For example, with respect to ramping up PetC0₂[i]^T from 35 to 50 mm of Hg over a selected time period (e.g. approx. 5 minutes) increasing PetC0₂[i]^T approx. 0.25 mm Hg every breath may define a suitable ramp sequence. Optionally, this rate may be corroborated. Corroboratively, a greater than 95% CVR response to a change in PaCC>2 may be determined to be achieved in 16-18 seconds. Thus increments of 1 mm of Hg every 16 second would be suitable. Assuming a subject inhales 15 times per minute (1 breath every 4 seconds, this corresponds to 0.25 mm of Hg every breath. Accordingly, according to one embodiment of the invention, optionally, the time interval over which the response is measured and the range of change in stimulus range may be input to facilitate execution of a ramp sequence so that a series of PetC0₂[l]^T targets for the intervening breaths may be correspondingly obtained.

Optionally, with respect to increases in PetC0₂[i]^T, N is advantageously 1, 2 or 3 breaths, optionally 1 breath, and Z is the optionally the same for each increase, depending on the total time interval for executing the range in stimulus Z or desired response range optionally ranging from 0.2 to 2 mm Hg. Optionally, with respect to increases in Pet02[i]^T N is advantageously 1 to 5, optionally 1 , and Z is the optionally the same for each increase, Z ranging from 1 to 20 mm Hg. Simply by way of example, Pet0₂[i may be increased every Nth breath wherein N=1 and Z=8 for each successive breath in the series e.g. ranging from 100 mm Hg to 350 mm Hg) while PetC02[i]^T is maintained constant. In another embodiment, PetC02[i]^T is increased each Nth breath e.g. from 35 mm Hg to 50 mm Hg {N=1 , Z=0.25 for each successive breath in the series) while Pet0₂.i]^T is maintained constant.

Advantageously, as regards such sequences, where the targets are increased or decreased at a rate selected for observing a substantial response to an increment or decrement in stimulus (termed a "ramp sequence"); e.g. with respect to an exponential response, optionally at least a response corresponding to two time constants, optionally at least a 90- 95% response or a response corresponding to three time constants, optionally approximately linearly with respect to time, the response (e.g. CVR) to a change in the end tidal concentration of gas X e.g. carbon dioxide, is substantially achieved within a given time increment e.g. spanning 4 breaths, and is optionally plotted (measurement may be more frequent) approximately every 4 breaths, in contrast to making the change in stimulus in one step, ideally, in one breath, in which case, the continuous plotting of the response reveals the time course of the response to the stimulus.

Accordingly the PMBT invention is also directed to an apparatus for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressure of the at least one gas X, comprising:

(1 ) a gas delivery device;

(2) a control system for controlling the gas delivery device including means for: a. Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVXP]); b. Obtaining input of a logistically attainable end tidal partial pressure of gas X (PetX[i]^T) for a respective breath [i]; c. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CM XP], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and d. Controlling the amount of gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation; and optionally e. Inputting values for execution of a ramp sequence (optionally via means for setting a cumulative time interval for measuring the response and a range of the stimulus or response to be canvassed, or optionally an increment or decrement Z (in the example above 0.25 mm of Hg) for each a series of respective breaths [i]¹ to [i]ⁿ, and optionally N.

N may be fixed at 1 in which case Z will be greater than 0 or or N is greater than 1 and Z may be zero in breaths which are not the Nth breath and Z is greater than 0 in every Nth breath.

The PMBT invention is described hereafter in terms of one or more optional embodiments of a gas X, namely carbon dioxide and oxygen.

Prospective Modelling

Mass balance equations of gases in the lung are conventionally derived from a continuous flow model of the pulmonary ventilation. In this model, ventilation is represented as a continuous flow through the lungs, which enters and exits the lungs through separate conduits. As a consequence, for example, the anatomical dead space would not factor into the mass balance other than to reduce the overall ventilatory flow into the alveolar space. In reality, however, ventilation in humans is not continuous, but tidal. Gas does not flow through the lungs, but enters the lungs during a distinct inspiration phase of the breath and exits during a subsequent expiration phase of the breath. In each breath cycle, gas is inspired into the lungs via the airways and expired from the lungs via the same airways through which gas was inspired. One possible implication, for example, is that the first gas inspired into the alveolar space in any breath is residual gas which remains in the anatomical dead space following the previous expiration. Continuous flow models neglect the inspiration of residual gas from the anatomical dead space, and therefore, since accounting for such a factor is generally desirable, do not accurately represent the flux of gases in the lungs.

As continuous flow models of pulmonary ventilation do not correctly represent the flux of gases in the lungs, the end-tidal partial pressures of gases induced from the inspiration of gas mixtures computed from such a model will, necessarily, deviate from the targets.

By contrast, according to one aspect of the PMBT invention, a mass balance equation of gases in the lungs is preferably formulated in terms discrete respective breaths [i] including respective discrete volumes corresponding to one or more of the F C, anatomic dead space, the volume of gas X transferred between the pulmonary circulation and the lung in a respective breath [i] and an individual tidal volume of a respective breath [i]) is adaptable to account, for example, for inspiration of residual gas from the anatomical dead space into the alveolar space in each breath. Inasmuch as a tidal model more faithfully represents the actual flux of gases in the lungs compared with the conventional model, the induced end-tidal partial pressures of gases, to an extent that the model is fully exploited, it will more closely adhere to the targets compared with results achieved using a continuous flow model.

Moreover, we have found that using a tidal model of pulmonary ventilation, can be synergistically employed with a sequential gas delivery system to facilitate closer adherence to targets in both ventilated and spontaneously breathing subjects without reliance on a negative feedback system.

According to the PMBT invention, a prospective determination of pulmonary ventilation and gas exchange with the blood can efficiently exploited even in spontaneously breathing subjects where the ventilatory parameters are highly variable and difficult to measure.

Where mechanical ventilation is employed, a prospective model of pulmonary ventilation and gas exchange with the blood envisages that the subject's ventilatory parameters can be estimated or measured to a level of accuracy sufficient to employ prospective control of the end-tidal partial pressures of one of more gases.

According to one embodiment of the PMBT invention, a technique of inspiratory gas delivery, sequential rebreathing, which, when using a tidal model of the pulmonary ventilation, significantly reduces or eliminates the dependence of the calculation of the inspired gas composition to be delivered in each breath, and therefore the actual end- tidal partial pressures of gases induced, on the subject's ventilatory parameters.

In parallel to what we have observed from studies with respect to the subject's ventilatory parameters, we have found that when we run a set of standardized tuning sequences, our model of the tissues more accurately reflects the actual dynamics of the gas stored in the subject's tissues.. The model parameters may be refined until the end- tidal partial pressures of gases induced by execution of the tuning sequences sufficiently adhere to the targets without the use of any feedback control.

Sequential Gas Delivery

Sequential rebreathing is a technique whereby two different gases are inspired in each breath - a controlled gas mixture followed by a "neutral" gas. A controlled gas mixture is any gas that has a controllable composition. Gas inspired in any breath is neutral if it has the same composition as gas expired by the subject in a previous breath. Neutral gas is termed as such since it has substantially the same partial pressures of gases as the blood in the pulmonary capillaries, and hence, upon inspiration into the alveolar space, does not substantially exchange any gas with the pulmonary circulation. Optionally, the rebreathed gas has a composition that is selected to correspond (i.e. have the same gas X concentration as that of) the targeted end tidal gas composition for a respective breath [ij. It will be appreciated that a modified sequential gas delivery circuit in which the subject exhales via a port leading to atmosphere and draws on a second gas formulated by a second gas delivery device (e.g. a gas blender) could be used for this purpose, for example where the second gas is deposited in an open ended reservoir downstream of a sequential gas delivery valve, for example within a conduit of suitable volume as exemplified in Figure 7 of US Patent No. 6,799,570.

Sequential rebreathing is implemented with a sequential gas delivery breathing circuit which controls the sequence and volumes of gases inspired by the subject. A sequential gas delivery circuit may be comprised of active or passive valves and/or a computer or other electronic means to control the volumes of, and/or switch the composition or source of, the gas inspired by the subject.

The controlled gas mixture is made available to the sequential gas delivery circuit for inspiration, optionally, at a fixed rate. On each inspiration, the sequential gas delivery circuit ensures the controlled gas mixture is inspired first, for example with active or passive valves that connect the subject's airway to a source of the controlled gas mixture. The supply of the controlled gas mixture is controlled so that it is reliably depleted in each breath.

Once the supply of the controlled gas mixture is exhausted, the sequential gas delivery circuit provides the balance of the tidal volume from a supply of neutral gas exclusively, for example with active or passive valves that connect the subject airway to the subject's exhaled gas from a previous breath.

Gas expired in previous breaths, collected in a reservoir, is re-inspired in a subsequent breath. Alternatively, the composition of gas expired by the subject can be measured with a gas analyzer and a gas with equal composition delivered to the subject as neutral gas.

During inspiration of the neutral gas and expiration, the supply of the controlled gas mixture for the next inspiration accumulates at the rate it is made available to the sequential gas delivery circuit. In this way, the subject inspires only a fixed minute volume of the controlled gas mixture, determined by the rate at which the controlled gas mixture is made available to the sequential gas delivery circuit, independent of the subject's total minute ventilation, and the balance of subject's the minute ventilation is made up of neutral gas.

Examples of suitable sequential gas delivery circuits are disclosed in US Patent Application No. 20070062534.

The fixed availability of the controlled gas mixture may be accomplished by delivering a fixed flow rate of the controlled mixture to a physical reservoir from which the subject inspires. Upon exhaustion of the reservoir, the source of inspiratory gas is switched, by active or passive means, to neutral gas from a second gas source, for example a second reservoir, from which the balance of the tidal volume is provided.

It is assumed that in each breath the volume of the neutral gas inspired at least fills the subject's anatomical dead space. Herein, all of the controlled gas mixture reaches the alveolar space and any of the neutral gas that reaches the alveolar space does not exchange gas with the circulation as it is already in equilibrium with the pulmonary capillary blood.

Sequential gas delivery circuits may be imperfect in the sense thata subject will inspire what is substantially entirely a controlled gas mixture first. However, upon exhaustion of the supply of the controlled gas mixture, when neutral gas is inspired, an amount of controlled gas mixture is continually inspired along with the neutral gas rather than being accumulated by the sequential gas delivery circuit for the next inspiration (2). The result is that the subject inspires exclusively controlled gas mixture, followed by a blend of neutral gas and controlled gas mixture. As a result of the imperfect switching of gases, a small amount of the controlled gas mixture is inspired at the end of inspiration and enters the anatomical dead space rather than reaching the alveolar space. In practise, the amount of controlled gas mixture lost to the anatomical dead space is small, and therefore, the amount of controlled gas mixture that reaches the alveolar space can still be assumed equal to the rate at which the controlled gas mixture is made available to the sequential gas delivery circuit for inspiration. Therefore, the method described herein can be executed, as described, with imperfect sequential gas delivery circuits.

A simple implementation of sequential rebreathing using a gas blender and passive sequential gas delivery circuit is described in references cited below (2; 3). Other implementations of sequential gas delivery are described in patents (4-8).

The contents of all references set forth below are hereby incorporated by reference.

Various implementations of sequential gas delivery have described by Joseph Fisher et al. in the scientific and patent literature.

As seen Figure 15 , which shows a high level overview of the movement of blood and the exchange of gases throughout the entire system, the majority of the total blood flow (Q) passes through the pulmonary circulation. Upon transiting the pulmonary capillaries, the partial pressures of gases in the pulmonary blood equilibrate with the partial pressure of gases in the lungs - the result is partial pressures of gases in the pulmonary end-capillary biood equal to the end-tidal partial pressures of gases in the lungs. The blood gas contents of this blood { can then be determined from these partial pressures. The remaining fraction {s ) of the total blood flow is shunted past the lungs and flows directly from the mixed-venous circulation into the arterial circulation without undergoing any gas exchange. Therefore, the gas contents of the arterial blood (Cjij) are a flow weighted average of the pulmonary end-capillary blood with gas contents equilibrated to that of the lungs, and the shunted blood with gas contents which are equal to the mixed-venous blood entering the pulmonary circulation (C [i^']). The arterial blood flows through the tissue capillary beds, where gases are exchanged between the blood and the tissues. There are one or more tissue capillary beds, each of which receives a fraction of the total blood flow ( q ) and has unique production, consumption, storage, and exchange characteristics for each gas. The gas contents in the venous blood leaving each tissue (C_v [/]) can be determined from these characteristics. The gas contents of the mixed-venous blood leaving the tissues (C _(T) [i]) are given by the flow weighted average of the gas contents in the venous blood leaving each tissue. The mixed-venous blood leaving the tissues enters the pulmonary circulation after the recirculation delay ( n_R ).

Figure 16 - The Tissues

As shown in Figure 16 , the total blood flow (Q) enters the tissue capillary beds from the arterial circulation, where the gas contents of the arterial blood (C_e[/]) are modified by gas exchange between the blood and the tissues. To obtain input of the gas contents of the mixed-venous blood, the flow of blood through the tissues is modelled as a system of one or more compartments where each compartment represents a single tissue or group of tissues. Each compartment is assumed to receive a fraction of the total blood flow {q) and has a unique production or consumption (v) of, and storage capacity ( d ) for, each gas. The content of gases in the venous blood leaving each compartment ( C_v[z^"]) can be determined from the arterial inflow of gases, and the assumed production or consumption, and storage of the gas in the compartment. The blood flows leaving each compartment unite to form the mixed-venous circulation. Therefore, the gas contents of the mixed-venous blood leaving the tissues (<-V_(r) [z]) are given by the flow weighted average of the gas contents in the venous blood leaving each tissue- Figure 17 - The Lungs (no sequential rebreathing)

As shown in Figure 17 , gas enters the lungs in two ways - diffusion from the pulmonary circulation and inspiration though the airways. The pulmonary blood flow is equal to the total blood flow (Q) less the fraction (s ) of the total blood flow that is shunted past the lungs. The flux rate of gas between the lungs and the pulmonary blood flow in a breath (*¾[∑^']) is, by mass balance, the product of the pulmonary blood flow and the difference between the gas contents of the mixed-venous blood (C_w[i]) entering the pulmonary circulation and the gas contents of the pulmonary end-capillary blood leaving the pulmonary circulation.

The starting volume of the lungs in any breath is given by the functional residual capacity (FRC ). This is the gas left over in the lungs at the end of the previous expiration, and contains partial pressures of gases equal to the target end-tidal partial pressures from the previous breath (P_ET [i - f )■ The first part of inspiration draws gas in the anatomical dead space ( V_D )from the previous breath into the alveolar space. The partial pressures of gases in this volume are equal to the target end-tidal partial pressures from the previous breath. Subsequently, a volume of a controlled gas mixture ( G_j ) with controllable partial pressures of gases is inspired.

Figure 18 - The Lungs (sequential rebreathing)

As shown in Figure 18 , gas enters the lungs in two ways - diffusion from the pulmonary circulation and inspiration though the airways. The pulmonary blood flow is equal to the total blood flow ( Q) less the fraction (s ) of the total blood flow that is shunted past the lungs. The flux rate of gas between the lungs and the pulmonary blood flow in a breath ( is, by mass balance, the product of the pulmonary blood flow and the difference between the gas contents of the mixed-venous blood (C^/]) entering the pulmonary circulation and the gas contents of the pulmonary end-capillary blood leaving the pulmonary circulation.

The starting volume of the lungs in any breath is given by the functional residual capacity (FRC ). This is the gas left over in the lungs at the end of the previous expiration, and contains partial pressures of gases equal to the target end-tidal partial pressures from the previous breath (?_CT[i ^ lf ) . The first part of inspiration draws gas in the anatomical dead space {V_D )from the previous breath into the alveolar space. The partial pressures of gases in this volume are equal to the target end-tidal partial pressures from the previous breath. Subsequently, a volume of a controlled gas mixture {VG ) with controllable partial pressures of gases ( ,[ ]) is inspired. The average volume of the controlled gas mixture inspired into the alveoli in each breath (FC¾ ) is given by the flow rate of the controlled gas mixture (FG_l ) to the sequential gas delivery circuit (SGDC) delivered over one breath period {T_B ). The balance of the tidal volume {V_T ) is composed of a volume of neutral gas (VG₂ ). Where a sequential gas delivery circuit is used that provides previously expired gas as neutral gas, this volume contains partial pressures of gases equal to the target end-tidal partial pressures from the previous breath.

Figure 19 - Apparatus

As shown in Figure 19 , according to one embodiment of an apparatus according to the invention, the apparatus consists of a gas blender (GB), a HI^"-OXSR sequential gas delivery circuit (SGDC), gas analyzers (GA), a pressure transducer (PT), a computer (CPU), an input device (ID), and a display (DX). The gas blender contains three rapid flow controllers which are capable of delivering accurate mixes of three source gases (SGi, SG2, SG3) to the circuit. The gases are delivered to the circuit via a gas delivery tube connecting the outlet of the gas blender to the inlet of the sequential gas delivery circuit. The gas analyzers measure the partial pressures of gases at the airway throughout the breath. The analyzers sample gas for analysis proximal to the subject's airway via a sampling catheter. A small pump is used to draw gases from the subject's airway through the gas analyzers. The pressure transducer is used for measurement of the breath period (T_B ) and end-tidal detection, and also connected by a sampling catheter proximal to the subject's airway. The gas analyzers and pressure transducer communicate with the computer via analog or digital electrical signals. The computer runs a software implementation of the end-tidal targeting algorithm and demands the required mixtures from the blender via analog or digital electrical signals. The operator enters the target end-tidal values and subject parameters into the computer via the input device. The display shows the measured and targeted end-tidal gases.

Figure 20 - Tuning

As illustrated in Figure 20 , with reference to examples of gas X (oxygen and carbon dioxide) parameters representing inputs for computation of FiX can be tuned so that the measured end-tidal partia ) and the measured end-tidal partial pressures of C02 uence more closely reflect the target end-tidal partial pr nd the target end-tidal partial pressures of C02 ). To tune the system parameters, standardized tuning sequences are run and the measured results compared to the targets. The difference between measured end-tidal partial pressures and the target end-tidal partial pressures in the standardized tuning sequences can be used to refine the estimates of some physiological parameters.

The tuning sequence optionally sets the target end-tidal partial pressure of 02 at 5 mmHg above the baseline end-tidal partial pressure of 02 (P_ETO2₀ ^M ) throughout the sequence, and executes a 5 mmHg step-change in the end-tidal partial pressure of C02 ) from 5 mmHg above the baseline end-tidal partial pressure of C02 (P_ETCO2₀ ^M) to 10 mmHg above the baseline end-tidal partial pressure of C02 in breath 30 (z = 30 ) of the sequence. Embodiments of mass balance equations:

No SGD: SGD:

Abbreviations and terms are in Figure 21 .

Physiological inputs

This section describes how to obtain measurements or estimates of all the physiological inputs required to execute a prospective end-tidal targeting sequence.

Subject weight, height, age, and sex:

Subject weight (W ), height (H), age (A ), and sex (G ) can be obtained from a subject interview, an interview with a family member, from an attending physician, or from medical records. Weight and height can also be measured.

Bicarbonate:

The bicarbonate concentration ([HCt¾]) can be obtained from a blood gas measurement. If a blood gas measurement is not available or possible, it can be estimated as the middle of the normal range - 24 mmol/L (9; 10).

Temperature:

Body temperature (T ) can be obtained from a recent invasive or non-invasive measurement. If a measurement is not available or possible, it can be estimated as the middle of the normal range - 37 C ( 1 ; 12).

Haemoglobin concentration: The haemoglobin concentration (Hb) can be obtained from a blood gas measurement. If a blood gas measurement is not available or possible, it can be estimated as the middle of the normal range for the subject's sex (G ):

15 g/dL for males

13 g/dL for females (10; 13)

Shunt fraction:

The intrapulmonary shunt fraction {s ) can be measured using a variety of invasive and non-invasive techniques (14-17). If measurement is not available or possible, it can be estimated as the middle of the normal range - 0.05 (18; 19).

Cardiac output:

The cardiac output ( Q ) can be measured using a variety of invasive and non-invasive techniques (20-23). If measurement is not available or possible, it can be estimated from the subject's weight ( W ) according to the relationship:

Q = 1 - (O.066 - W + I A) (24)

Breath period:

The breath period {T_B ) can be measured using a pressure transducer(PT) or flow transducer (FT) proximal to the subject's airway. Alternatively, the subject can be coached to breathe at a predetermined rate using a metronome or other prompter. If the subject is mechanically ventilated, this parameter can be determined from the ventilator settings or ventilator operator.

Recirculation time:

The number of breaths for recirculation to occur (n_R ) can be measured using a variety of invasive and non-invasive techniques (25-27). If measurement is not available or possible, it can be estimated from the breath period {T_B ) and an average recirculation time (0.3 min) (28) according to the relationship: n_R = 0.3/Γ_Β

Metabolic 02 consumption:

The overall metabolic 02 consumption (V02) can be measured using a metabolic cart. If measurement is not available or possible, it can be estimated from the subject's weight (W ), height (H), age (A), and sex (rj) according to the relationship:

n_j . K-w+as-H-s-A+s _{for males}

6.8832

10 -r ₊ 623 -g-5 - -t-l« _{for fema},_{es (29)}

6.8832

Metabolic C02 production:

The overall metabolic C02 production {VC02 ) can be measured using a metabolic cart. If measurement is not available or possible, it can be estimated from the overall metabolic 02 consumption (V02) and average respiratory exchange ratio (0.8 mi C02/ml 02) (30) according to the relationship:

VCO2 = 0.S - VO2 Functional residual capacity:

The functional residual capacity (FRC ) can be measured using a variety of respiratory manoeuvres (31). If measurement is not available or possible, it can be estimated from the subject's height (H), age (A ), and sex (G ) according to the relationship:

FRC = (2.34 · H + 0.01. A - 1.09)^■ 1000 for males

FRC = (2.24 -H + 0.001-^ -1.00)· 1000 for females (32)

Anatomical dead space: The anatomical dead space (V_D ) can be measured using a variety of respiratory manoeuvres (33-35). If measurement is not available or possible, it can be estimated from the subject's weight (W) and sex (G ) according to the relationship:

V_D = 1.765 JF+32.16 for males V_D for females (36)

Rate at which the controlled gas mixture is made available for inspiration when using a sequential gas delivery circuit (SGDC)

When using a sequential gas delivery circuit (SGDC), the rate at which the controlled gas mixture is made available for inspiration (FG_l ) should be set so that the volume of the neutral gas inspired in each breath (VG₂ ) is greater than or equal to the anatomical dead space (V_D ). The subject can be coached to increase their ventilation and/or the availability of the controlled gas mixture decreased until a sufficient volume of the neutral gas is observed to be inspired in each breath.

Tidal volume:

The tidal volume (V_T ) can be measured using a flow transducer (FT) proximal to the subject's airway. If measurement is not available or possible, in spontaneous breathers when using a sequential gas delivery circuit (SGDC), it can be estimated from the rate at which the controlled gas mixture {G_l ) is made available for inspiration (FG ), the breath period {T_B ), and the anatomical dead space {V_D ) according to the empirical relationship:

If FG^ < 15000: V_T = (0.75^■ FG_l + 3750) -T_B +V_D else: V_T ^ FG -T_B +V_D

Alternatively, the subject can be coached or trained to breathe to a defined volume using a prompter which measures the cumulative inspired volume and prompts the subject to stop inspiration when the defined volume has been inspired. If the subject is mechanically ventilated, this parameter can be determined from the ventilator settings or ventilator operator.

Target sequence input

The operator enters a target sequence of n breaths consisting of a target end-tidal partial pressures of 02 ) and a target end-tidal partial pressure of C02

(P_£TC02[iJ) for every breath (z) of the sequence.

Calculation of the inspired gas composition to induce target end-tidal values

The partial pressure of 02 in the controlled gas mixture (_?,0_?( ]) and the partial pressure of C02 in the controlled gas mixture uired to induce the sequence of target end-tidal partial pressures of and target end-tidal partial pressures of C02 can be calculated by executing the steps outlined in sections 6-15 for every breath of the sequence (/,/ - \..n).

Calculate the 02 and C02 partial pressures of pulmonary end-capillary blood

When sequential rebreathing is employed (2; 37; 38), we assume that the partial pressure of 02 in pulmonary end-capillary blood is equal to the target end-tidal and the partial pressure of C02 in pulmonary end- al to the target end-tidal partial pressure of C02

Various other formulas have been proposed to derive blood gas partial pressures from end-tidal partial pressures. For example, see (40; 41). Any of these relationships can be used in place of the above equalities. Calculate the pH pulmonary end-capillary blood

The pH of the pulmonary end-capillary blood (/>H[z]) can be calculated from the Henderson-Hasselbalch equation using the blood bicarbonate concentration ([HQ¾]), the blood C02 partial pressure and the solubility of C02 in blood (0.03 mmol/L/mmHg) (9).

Calculate the 02 saturation of pulmonary end-capillary blood

The 02 saturation of pulmonary end-capillary blood can be calculated from experimental equations using the body temperature (T), the blood pH (pH[z^']), the blood C02 partial pressure (P_pC02]i]), and the blood 02 partial pressure ( (42). 1 3989 ·

67.104406· w herez =

Calculate the 02 content of pulmonary end-capillary blood

The 02 content of pulmonary end-capillary blood {C_p02[i]) can be calculated from the 02 saturation of the blood the blood haemoglobin concentration {Hb), the 02 carrying capacity of haemoglobin (1.36 ml/g), and the solubility of 02 in blood (0.003 ml/dL/mmHg) (43).

Alternative derivations of H, 02 saturation, and 02 content are reviewed in detail in (44).

Calculate the C02 content of pulmonary end-capillary blood

The C02 rom the blood the blood pH

See also (46-^48) for alternative calculations of C02 content. Calculate the 02 and C02 content of arterial blood

The arterial blood is a mixture of the pulmonary end-capillary blood and the blood shunted past the lungs. The percentage of the cardiac output (Q) that is shunted past the lungs is given by the intrapulmonary shunt fraction (s ).

The content of 02 in the arterial bloo is a weighted average of the 02 content of the pulmonary end-capillary blood and the 02 content of the blood which is shunted directly from the mixed-venous circulation (C_w<92[ ]). the C02 nt of the

Calculate the 02 content of the mixed-venous blood

Before returning to the venous circulation, the arterial blood passes through the tissue capillary beds where 02 is consumed and exchanged. This system can be modelled as a compartmental system where each compartment (j) represents a single tissue or group of tissues. Each compartment is assigned a storage capacity for 02 (d02 . ). Each compartment is also modelled as being responsible for a fraction (vo2_j ) of the overall metabolic 02 consumption {V02), and receiving a fraction {q_} ) of the total cardiac output (Q). The content of 02 in the venous blood leaving a compartment {C_r02_j[i]) is equal to the content of 02 in the compartment. Assuming an 02 model with n₀₁ compartments, the 02 content of the venous blood leaving each compartment can be calculated from the 02 content in the compartment during the previous breath the compartment parameters, and the period of the breath (T_B ).

For j = \..n₀₂

The values for a one compartment model ( «₀₂ = 1) are given below. The model assumes a single compartment with a storage capacity for 02 (d02_k ) proportional to the subjects weight (W ) (49). 00473

The mixed-venous 02 content leaving the tissues (C_{JW (r)} 32[i^']) is the sum of the 02 content leaving each compartment (C„02.[i]) weighted by the fraction of the cardiac output (q . ) received by the compartment.

C_W(r)02[/]= ¾_i . -C_F02 [i]

Alternatively, since the storage capacity of 02 in the tissues of the body is small, the 02 content of the mixed-venous blood leaving the tissues (C ,0.?[/]) can be assumed to be equal to the arterial inflow of 02 to the tissues less the overall metabolic 02 consumption of the tissues (V02 ) distributed over the cardiac output (Q).

The 02 content of the mixed-venous blood entering the pulmonary circulation ( ^O [ ]) is equal to the 02 content of the mixed-venous blood leaving the tissues delayed by the recirculation time (^ ₎0 [/-^])

Other 02 model parameters are available from (49; 50). Calculate the C02 content of the mixed-venous blood Before returning to the venous circulation, the arterial blood passes through the tissue capillary beds where C02 is produced and exchanged. This system can be modelled as a compartmental system where each compartment {k) represents a single tissue or group of tissues. Each compartment is assigned a storage capacity for C02 {dC02_k ).

Each compartment is also modelled as being responsible for a fraction {vco2_k ) of the overall metabolic C02 production {VC02 ), and receiving a fraction (q_k ) of the total cardiac output (Q). The content of C02 in the venous blood leaving a compartment is equal to the content of C02 in the compartment. Assuming a C02 model with n_C01 compartments, the C02 content of the venous blood leaving each compartment can be calculated from the C02 content in the compartment during the previous breath {C_vC02_j[i-\}), the compartment parameters, and the period of the breath (T_B ). For k = l~n_C0!

The values for a five compartment model (n_C02 = 5) are given below (51). The model assumes each compartment has a storage capacity for C02 {dC02_k ) proportional to the subjects weight (W).

3 0.16 (9980/70)- W 0.17

4 0.15 (113900/70)· W 0.15

5 0.51 (3310/70)· ΪΡ 0.29

The values for a one compartment model {n_C02 ^ l) are given below. The model assumes a single compartment with a storage capacity for C02 (dC02_h ) proportional to the subjects weight (W). The storage capacity for the single compartment is calculated as the average of the storage capacity for each compartment of the multicompartment model weighted by the fraction of the cardiac output assigned to the compartment.

The mixed-venous C02 content leaving the tissues (C^^CO^]) is the sum of the C02 content leaving each compartment weighted by the fraction of the cardiac output (q_k ) received by the compartment.

The C02 content of the mixed-venous blood entering the pulmonary circulation is equal to the C02 content of the mixed-venous blood leaving the tissues delayed by the recirculation time {c_My(T)C02[i - n_R]) Other C02 mode! parameters are available from (49; 52).

Calculate PI02 and PIC02 to deliver with no sequential gas delivery circuit

On each inspiration, a tidal volume (V_T ) of gas is inspired into the alveoli. When the subject is not connected to a sequential gas delivery circuit, gas is inspired in the following order: a) the gas in the anatomical dead space (V_D ) is re-inspired with a partial pressure of 02 equal to the target end-tidal partial pressure of 02 from the previous breath (P_ET02[i - and a partial pressure of C02 equal to the target end- tidal partial pressure of C02 from the previous breath b) a volume of controlled gas mixture {VG_X ) with controllable partial pressure of 02 ( ₇< 2[ ]) and controllable partial pressure of C02 This inspired gas mixes with the volume of gas in the functional residual capacity (FRC ) with a partial pressure of 02 and C02 equal to the target end-tidal partial pressures from the previous breath.

A volume of 02 is transferred between the alveolar space and the pulmonary circulation ()¾[ ]). The rate of 02 transfer between the alveolar space and the pulmonary circulation depends on the product of the cardiac output (£>) less the intrapulmonary shunt fraction (·*), and the difference between the mixed-venous 02 content entering the pulmonary circulation (0^02]}]) and the pulmonary end-capillary 02 content [C_p02[i]) leaving the pulmonary circulation. This transfer occurs over the breath period

(¾ )^■

VB₀₂ C_p02]i])

A volume of C02 is transferred between the alveolar space and the pulmonary circulation The rate of C02 transfer between the alveolar space and the pulmonary circulation depends on the product of the cardiac output (Q) less the intrapulmonary shunt fraction (s ), and the difference between the mixed-venous C02 content enterin the pulmonary circulation (C^ 02[J]) and the pulmonary end-capillary C02 content leaving the pulmonary circulation. This transfer occurs over the

breath period (T_£ ).

VB_C02 [/] = Q . (l -. _s). T_B -

The average volume of the controlled gas mixture inspired into the alveoli in each breath ( VG_l ) is given by the tidal volume (V_T ) less the anatomical dead space (V_D ).

VG_X= V_T- V_D

The end-tidal partial pressure 02 ) is simply the total volume of 02 in the alveolar space, divided by the total volume of the alveolar space. The end-tidal partial pressure C02 ) is simply the total volume of C02 in the alveolar space, divided by the total volume of the alveolar space.

Total volume of the alveolar space

Since all of these volumes and partial pressures are either known, or can be estimated, the partial pressure of 02 in the controlled gas mixture ( _;02[ζ]) and the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) can be set to induce target end-tidal partial pressures.

In some cases, some of the terms (braced terms in the numerator of the above equations) contributing to the target end-tidal artial pressure of 02 or the target end-tidal partial pressure of C02 may be neglected. For example, in most cases, the 02 or C02 re-inspired from the anatomical dead space {V_D) is small compared to the 02 or C02 in the other volumes that contribute to the end-tidal partial pressures- In a case where the volume of O2 or C0≥ in the controlled gas mixture is very large, for example when trying to induce a large increase in the target end-tidal partial pressures, the 0₂ or C0₂ transferred into the lung from the circulation may be comparatively small and neglected. Neglecting any terms of the mass balance equations will decrease computational complexity at the expense of the accuracy of the induced end-tidal partial pressures of gases.

After re-arranging the above equations for the partial pressure of 02 in the controlled gas mixture and the partial pressure of C02 in the controlled gas mixture, simplification, and grouping of terms:

These equations can be used to calculate the partial pressure of 02 in the controlled gas mixture (_P_;02[i]) and the partial pressure of C02 in the controlled gas mixture and target end-tidal partial pressure of C02 e target end-tidal partial pressure of 02 from the previous bre target end-tidal partial pressure of C02 from the previous b the functional residual capacity (FRC ), the anatomical dead space (V_D ), tidal volume (V_T ), the breath period ( T_B ), cardiac output ( Q ), intrapulrnonary shunt fraction (s ), mixed-venous content of 02 entering the pulmonary circulation (C^02[i]), mixed-venous content of C02 entering the pulmonary circulation pillary content of 02 (C_p02[i]), and pulmonary end-capill are either known, calculated, estimated, measured, or predicted.

Notice that the partial pressure of 02 in the controlle and the partial pressure of C02 in the controlled gas mixture induce a target end-tidal partial pressure of 02 or a target end-tidal partial pressure of C02 depends strongly on the tidal volume ( V_T ), anatomical dead space { V_D ), and the functional residual capacity (FRC ).

It is often useful in practise to maintain the end-tidal partial pressures of gases steady for a predefined number of breaths or period of time. This is a special case of inducing target end-tidal partial pressures of gases where the target end-tidal partial pressure of a gas in a breath is equal to the target end-tidal partial pressure of said gas from the previous breath.

Herein, the above general equations for calculating the composition of the controlled gas mixture reduce to the following:

Notice, these equations still require the estimation, measurement, or determination of many of the subject's ventilatory or pulmonary parameters, namely, tidal volume ( V_T ), functional residual capacity (FRC ), breath period (T_B ), and anatomical dead space (V_D ). Therefore, in the absence of sequential rebreathing, the calculation of the partial pressure of 0₂ in the controlled gas mixture (P_;O2[z]) and the partial pressure of C02 in the controlled gas mixture (P,CO%i]) required to induce a target end-tidal partial pressure of 0₂ ) is highly dependant on the subjects ventilatory and pulmonary parameters. However, some of these parameters, namely functional residual capacity (FRC ) and the anatomical dead space (V_D ), can be measured or estimated prior to execution of the targeting sequence, and can be reasonably assumed not to change over the course of the experiment. Other parameters, namely tidal volume ( V_T ) and breath period (T₃ ), while normally highly variable, are very well controlled and stable in mechanically ventilated subjects. This method, therefore, is optional, especially where a simpler approach is preferred, and the subject's ventilation can be reasonably controlled or predicted.

It will be recognized that the volumes and partial pressures required to calculate the partial pressure of 0₂ in the controlled gas mixture (Ρ₇02[ and the partial pressure of C0₂ in the controlled gas mixture { _jCO^i]) may need to be corrected for differences in temperature or presence of water vapour between the lung and the conditions under which they are measured, estimated, or delivered. The corrections applied will depend on the conditions under which these volumes and partial pressures are measured, estimated, or delivered. All volumes and partial pressures should be corrected to body temperature and pressure saturated conditions. A person skilled in the art will be comfortable with these corrections.

A person skilled in the art will also recognize the equivalence between partial pressures and fractional concentrations. Any terms expressed as partial pressures can be converted to fractional concentrations and vice-versa. For example, the partial pressure of 02 in the controlled gas mixture (i^>2[-]) and the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) may be converted a fractional concentration of 02 in the controlled gas mixture (F_;< 2[i]) and a fractional concentration of C02 in the controlled gas mixture (F_}CO^i]).

¹ PB

Calculate PI02 and PIC02 to deliver to a sequential gas delivery circuit

On each inspiration, a tidal volume (V_T ) of gas is inspired into the alveoli. When the subject is connected to a sequential gas delivery circuit (SGDC) that collects previously expired gas in a reservoir for later inspiration as neutral gas (ex. ΗΪ-OXSR), gas is inspired in the following order: a) the gas in the anatomical dead space (V_D ) is re- inspired with a partial pressure of 02 equal to the target end-tidal partial pressure of 02 from the previous breath (P_ST02[i- if ) and a partial pressure of CO2 equal to the target end-tidal partial pressure of CO2 from the previous breath (P_ETC02[i - i ); b) a volume of controlled gas mixture (Γ with controllable partial pressure of O₂ (^O2[ ] ) and controllable partial pressure of CO2 c) a volume of neutral gas {VG₂ ) with a partial pressure of 02 and CO2 equal to the target end-tidal partial pressures from the previous breath. This inspired gas mixes with the volume of gas in the functional residual capacity (FRC ) with a partial pressure of 02 and CO2 equal to the target end- tidal partial pressures from the previous breath.

A volume of 02 is transferred between the alveolar space and the pulmonary circulation (!¾[/]). The rate of 02 transfer between the alveolar space and the pulmonary circulation depends on the product of the cardiac output (Q) less the intrapulmonary shunt fraction (s), and the difference between the mixed-venous 02 content entering the pulmonary circulation {0^02]}]) and the pulmonary end-capillary 02 content (C_p02[i]) leaving the pulmonary circulation. This transfer occurs over the breath period

(¾ ).

VB₀₂ Q . (l - s)-T_s - (C_w02[/]- C,∞M)

A volume of CO2 is transferred between the alveolar space and the pulmonary circulation (^^[ ]). The rate of CO2 transfer between the alveolar space and the pulmonary circulation depends on the product of the cardiac output (£ ) less the intrapulmonary shunt fraction (s), and the difference between the mixed-venous CO2 content entering the pulmonary circulation and the pulmonary end-capillary CO2 content leaving the pulmonary circulation. This transfer occurs over the

breath period (T_s ).

V _CQ1 - Q · (1 - s )^■ T_B ^■ (C„ C02 [/] - C, C02 Assuming a neutral gas at least fills the subject's anatomical dead space (V_D ), the average volume of the controlled gas mixture inspired into the alveoli in each breath (VG^ ) is given by the rate at which the controlled gas mixture is made available for inspiration (FG_{ ) delivered over a single breath period (T_B ):

VG^ FG_X -T_B

The average volume of neutral gas that is inspired into the alveoli in each breath is given by the tidal volume {V_T ) less the volume of inspired controlled gas mixture (VG_l ) and the volume of gas that remains in the anatomical dead space (V_D ):

VG₂ = V_T -V_D -FG_X -T_B

The end-tidal partial pressure 02 ) is simply the total volume of 02 in the alveolar space, divided by the total volume of the alveolar space. The end-tidal partial pressure C02 is simply the total volume of C02 in the alveolar space, divided by the total volume of the alveolar space.

Total volumeof thealveolarspace

Total volumeo the alveo arspace

Since all of these volumes and partial pressures are either known, or can be estimated, the partial pressure of 02 in the controlled gas mixture (fy92[z^']) and the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) can be set to induce target end-tidal partial pressures.

In some cases, some of the terms (braced terms in the numerator of the above equations) contributing to the target end-tidal artial pressure of 02 ) or the target end-tidal partial pressure of C02 ) may be neglected. For example, in most cases, the 0₂ or CO2 re-inspired from the anatomical dead space (V_D) is small compared to the 0₂ or C0₂ in the other volumes that contribute to the end-tidal partial pressures. In the case where the volume of 02 or C02 in the controlled gas mixture is very large, for example when trying to induce a large increase in the target end-tidal partial pressures, the 02 or C02 transferred into the lung from the circulation may be comparatively small and neglected. Neglecting any terms of the mass balance equations will decrease computational complexity at the expense of the accuracy of the induced end-tidal partial pressures of gases.

The above equations can be used to calculate the partial pressure of 02 in the controlled gas mixture and the partial pressure of C02 in the controlled gas mixture (P_jCO^]) required to induce a target end-tidal target partial pressure of 02 and a target end-tidal partial pressure of C02 ) where the target end-tidal partial pressure of 02 from the previous breath {P_ET02[i-i ), the target end- tidal partial pressure of C02 from the previous breath the functional residual capacity (FRC ), tidal volume (V_T ), rate at which the controlled gas mixture is made available for inspiration (FG^, the breath period cardiac output ( Q), intrapulmonary shunt fraction (s ), recirculation time (¾ ), mixed-venous content of 02 entering the pulmonary circulation mixed-venous content of C02 entering the pulmonary circulation (C_Mf,C02[i^'])₎ pulmonary end-capillary content of 02 and pulmonary end-capillary content of C02 are either known, calculated, estimated, measured, or predicted.

Notice that where this form sequential rebreathing is employed, the anatomical dead space (V_D ) does not factor into the above equations and end-tidal targeting is independent of its measurement or estimation. Notice also that the tidal volume (V_T ) appears only in summation with the functional residual capacity (FRC ). Since the tidal volume is, in general, small compared to the functional residual capacity ( V_r < Q.hFRC), errors in measurement or estimation of the tidal volume have little effect on inducing target end-tidal partial pressures of gases. In fact, the above equations can be used with the tidal volume term omitted completely with little effect on results.

^FET ⁰²\?Y = P_ET02[i-l]^T OR

Notice, these equations do not require the estimation, measurement, or determination of any of the subject's ventilatory or pulmonary parameters, namely, tidal volume ( V_T ), functional residual capacity (FRC ), breath period (T_B ), or anatomical dead space (V_D ).

The reduced or eliminated sensitivity of the equations to the subject's ventilatory parameters makes this method useful in practise with spontaneously breathing subjects. It is, however, not limited to spontaneously breathing subjects, and may also be used in mechanically ventilated subjects.

A person skilled in the art will recognize that the volumes and partial pressures required to calculate the partial pressure of 02 in the controlled gas mixture and the partial pressure of C02 in the controlled gas mixture (^002 ) may need to be corrected for differences in temperature or presence of water vapour between the lung and the conditions under which they are measured, estimated, or delivered. The corrections applied will depend on the conditions under which these volumes and partial pressures are measured, estimated, or delivered. All volumes and partial pressures should be corrected to body temperature and pressure saturated conditions. A person skilled in the art will be comfortable with these corrections.

A person skilled in the art will also recognize the equivalence between partial pressures and fractional concentrations. Any terms expressed as partial pressures can be converted to fractional concentrations and vice-versa. For example, the partial pressure of 02 in the controlled gas mixture ( ₇02[i]) and the partial pressure of C02 in the controlled gas mixture ( ^CO^^']) may be converted a fractional concentration of 02 in the controlled gas m and a fractional concentration of C02 in the controlled gas mixture

P_jC02 i]

PB

Determine if targets are logistically feasible

In practise, many different implementations of gas delivery devices and sequential gas delivery circuits may be used. In general, it is logistically feasible to induce the target end-tidal partial pressures for the current breath , P_BTC02]iJ ) if:

1) The required partial pressures of gases in the controlled gas mixture are physically realizable:

b) 0≤P_ICO2\i]≤PB

2) The gas delivery device is capable of delivering a controlled mixture of the desired composition at the required flow rate

Where sequential rebreaihing is carried out with a HI-OXSR sequential gas delivery circuit and a gas blender:

Assuming n_SG source gases (SG £G ) are blended to deliver the required mixture to the HI-OXSR sequential gas delivery circuit (SGDC). Each gas (m ) contains a known fractional concentration of 02 (fo2_m ) and a known fractional concentration of C02 (fco2_m ). The flow rate of each gas required to deliver the total desired flow rate of the controlled gas ( G, ) with the required partial pressure of 02 ( ,O2[z]) and the required partial pressure of C02 ( _;C02[i]) can be determined by solving the following set of equations:

The target end-tidal partial pressures for the current breath ) are logistically feasible if:

2) <P_jCO2\i]<PB 3) P_jO^+PfiO^PB

4) There exists a solution to the above system of equations, and

6) The gas blender is capable of delivering a controlled mixture of the desired composition at the required flow rate

It is therefore required that ¾≥ 3. It is computationally optimal to have n_SG = 3. One possible set of gases is:

S'G₁ :/co¾ = 0,Jb2₁ = l SG₂ : fco2₂ = \_tfo2₂ = 0

SG₃ : fco2₃ = ,fo2 = 0

It may enhance the safety of the system to use gases with a minimal concentration of 02 and maximum concentration of C02. In this case, a possible set of gases is:

SG₁ : fco = fo2_x = 0.1

The balance of the source gases when not entirely composed of 02 and C02 can be made up of any gas or combination of gases, which may vary depending on the context, The balance of the source gases is most often made up of N2 because it is physiologically inert.

Adjusting parameters to make logistically infeasible targets logistically feasible: It may occur that inducing a target end-tidal partial pressure of 02 ) or a target end-tidal partial pressure of C02 ) in a given breath is not logistically feasible. This may occur because the partial pressure of 02 in the controlled gas mixture (P_;O2[z^']) or the partial pressure of C02 in the controlled gas mixture ( _;CO2[z]) required to induce the target end-tidal partial pressure of 02 or the target end-tidal partial pressure of C02 is either not physically realizable, or there does not exist a blend of the current source gases ( SG .SG„_G ) resulting in the required the partial pressure of 02 in the controlled gas mixture and the required partial pressure of C02 in the controlled gas mixture. If the composition of the controlled gas mixture is not physically realizable for a given set of targets, the targets may be modified and/or the rate at which the controlled gas mixture is made available to the circuit ) modified, or where applicable, the tidal volume (V_T ) modified, until the composition is physically realizable. If the composition of the controlled gas mixture is physically realizable for a given set of targets, but no combination of the source gases results in the required composition, the targets may be modified and/or the rate at which the controlled gas mixture is made available to the circuit modified, or where applicable, the tidal volume (V_T ) modified, and/or different source gases used.

If ) is not logistically feasible because the partial pressure of 02 in the controlled gas mixture (/^[i]) required to induce the target end-tidal partial pressure of 02 is not physically realizable. To make induction of the target logistically feasible, increase the target end-tidal partial pressure of 02. Alternatively, where sequential rebreathing is used, the rate at which the controlled gas mixture is made available to the circuit (FG_L ) may be modified. Where sequential rebreathing is not used, the tidal volume [V_T ) may be modified.

If _/02[ ] > 5 - The target end-tidal partial pressure of 02 ) is not logistically feasible because the partial pressure of 02 in the controlled gas mixture (.P_;O2[ ]) required to induce the target end-tidal partial pressure of 02 is not physically realizable. To make induction of the target logistically feasible, decrease the target end-tidal partial pressure of 02. Alternatively, where sequential rebreathing is used, the rate at which the controlled gas mixture is made available to the circuit {FG_X ) may be modified.

Where sequential rebreathing is not used, the tidal volume (V_T ) may be modified.

If ) is not logistically feasible because the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) required to induce the target end-tidal partial pressure of C02 is not physically realizable. To make induction of the target logistically feasible, decrease the target end-tidal partial pressure of C02. Alternatively, where sequential rebreathing is used, the rate at which the controlled gas mixture is made available to the circuit (FG ) may be modified. Where sequential rebreathing is not used, the tidal volume {V_T ) may be modified.

If ) is not logistically feasible because the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) required to induce the target end-tidal partial pressure of C02 is not physically realizable. To make induction of the target logistically feasible, decrease the target end-tidal partial pressure of C02. Alternatively, where sequential rebreathing is used, the rate at which the controlled gas mixture is made available to the circuit (FG_l ) may be modified. Where sequential rebreathing is not used, the tidal volume (V_T ) may be modified.

If _;O2[z^']+ _/C0 [ ]>P5 - The combination of the target end-tidal partial pressure of 02 and the target end-tidal partial pressure of C02 ) is not logistically feasible because the combination of the partial pressure of 02 in the controlled gas mixture (P_;02[ j) and the partial pressure of C02 in the controlled gas mixture required to induce the targets is not physically realizable. To make induction of the targets logistically feasible, decrease the target end-tidal partial pressure of 02 and/or the target end-tidal partial pressure of C02. Alternatively, where sequential rebreathing is used, the rate at which the controlled gas mixture is made available to the circuit {FG_X ) may be modified. Where sequential rebreathing is not used, the tidal volume (V_T ) may be modified.

If there does not exist a solution to the above system of equations, or there exists a solution for which 0 for any m, then the current source gases (SG_v.SG„_a ) cannot be blended to create the controlled gas mixture. Different source gases must be used to induce the end-tidal target of 02 {P_ET02]i]^T) and the end-tidal target of C02 (P_ETC02]i]^T ), or the desired targets must be changed. Alternatively, it may be possible to modify the rate at which the controlled gas mixture is made available to the circuit ( _j ) until the partial pressure of 02 in the controlled gas mixture (i^<92[z^']) and the partial pressure of C02 in the controlled gas mixture (P_jCO^i]) required to induce the targets are realizable with the current source gases.

Often, the rate at which the controlled gas mixture is made available to the circuit (FG_X ) is modified to make a target end-tidal partial pressure of 02 ) or a target end- tidal partial pressure of C02 ) logistically feasible to induce. However, the rate at which the controlled gas mixture is made available to the circuit should not be increased to a rate beyond which the subject fails to consistently exhaust the supply of the controlled gas mixture in each breath. This maximal rate varies between subjects. However, it is not necessary that the rate at which the controlled gas mixture is made available to the circuit be the same in every breath. Therefore, the rate at which the controlled gas mixture is made available to the circuit may be set to some basal value for most breaths, and only increased in particular breaths in which the inducing the target end-tidal partial pressures is not logistically feasible at the basal rate of flow. The basal rate at which the controlled gas mixture is made available to the circuit should be a rate at which the subject can comfortably, without undo ventilatory effort, exhaust the supply of the controlled gas mixture in each breath. The maximal rate at which the controlled gas mixture is made available to the circuit should be the maximum rate at which the subject can consistently exhaust the supply of the controlled gas mixture in each breath with a maximal ventilatory effort. The subject may be prompted to increase their ventilatory effort in breaths where the rate at which the controlled gas mixture is made available to the circuit is increased.

Initializing the system

Let the index [θ] represent the value of a variable for all breaths before the start of the sequence (all values of i≤ 0). To initialize the system, the subject is allowed to breathe freely, without intervention, until the measured end-tidal partial pressure of 02 (P_ETC02^M ) and the measured end-tidal partial pressure of C02 {P_ETC02^M ) are stable - these are taken as the baseline partial pressure of 02 (P_ETO2₀ ^M ) and the baseline partial pressure of C02 (P_ETCO2₀ ^M ).The measured end-tidal partial pressures are considered stable when there is less than ±5 mmHg change in the measured end-tidal partial pressure of 02 and less than ±2 mmHg change in the measured end-tidal partial pressure of C02 over 3 consecutive breaths. The rest of the variables are initialized by assuming the whole system has equilibrated to a steady state at the baseline end-tidal partial pressures.

Assume that end-tidal partial pressures are equal to the baseline measurements:

Assume pulmonary end-capillary partial pressures are equal to end-tidal partial pressures: P_pCO2[0] = P_ETCO2[0]^T Calculate 02 blood contents assuming steady state:

Pulmonary end-capillary 02 saturation:

- 8532.2289- z + 2121.401 -z² - 67.073989- z +z*

S 02[θ] = 1ΟΟ·

935960.87-31346.258· z + 2396.1674· z¹ -67.104406- z³ + z⁴ where z

Pulmonary end-capillary 02 content:

C_p02[Q] = 1.36 · H¾■ ^SP⁰²^ + 0.003^■ P_B02 ]

" ^{L 1} 100 ^{p 1 1}

Mixed-venous 02 content:

CwrrMo cMo]- ^v02

C^O [0]= C_MO2[0]

Arterial 02 content:

C_DO2[0] = (1 - s). C_pO2[ ]+ s^■ C^O2[0]

02 content of each compartment in the model:

For j = l..n₀₂

Calculate C02 blood contents assuming steady state: Pulmonary end-capillary C02 content:

C , = 0.0301· P_pCO2[0]- (l + 10^^{[ol_6 10})- 2.226

Mixed-venous C02 content:

Arterial C02 content:

C_aCO2[0]= (1 -s)- C_pCO2[ ]+ s · C C02[o]

002 content of each compartment in the model:

For k = l..n, 02 vco2_k - VCQ2

C_vCO2_k[0]= C_BCO2[Q) +-

Tuning the system

-The parameters of the system can be tuned so that the measured end-tidal partial pressures of 02 ) and the measured end-tidal partial pressures of C02 ) during any sequence more closely reflect the target end-tidal partial pressures of 02 {P_ET02[if) and target end-tidal partial pressures of C02 ). To tune the system parameters, standardized tuning sequences are run and the measured results compared to the targets. The difference between measured end-tidal partial pressures and the target end-tidal partial pressures in the standardized tuning sequences can be used to refine the estimates of some physiological parameters.

Example tuning sequence:

The tuning sequence sets the target end-tidal partial pressure of 02 at 5 mmHg above the baseline end-tidal partial pressure of 02 (P_ETO2₀ ^M) throughout the sequence, and executes a 5 mmHg step-change in the end-tidal partial pressure of C02 ) from 5 mmHg above the baseline end-tidal partial pressure of C02

(P_STCO2₀ ^M ) to 10 mmHg above the baseline end-tidal partial pressure of C02 in breath 30 (/^' = 30 ) of the sequence.

The estimate of the functional residual capacity (PRC ) can be refined as a function of the difference between the actual step change induced in the end-tidal C02 (p_ETCO2[3 f and the target step-change

(p_ETCO2[30]^T - P_ETC02[29f = s) in breath 30 (/ = 30 ).

FRC = FRC₀ +a((/^J _£rCO.?[3Q -P_ETC02[l9 )-(P_ETCO2[30f -P_ErC02[29j ))

a = 200 ml/mmHg In general, the correction factor (a) can range from 50-500 ml/mmHg. Lower values of the correction factor will produce a more accurate estimate of the functional residual capacity (FRC ) while requiring more tuning iterations. Higher values will reduce the number of tuning iterations but may cause the refined estimate of the parameter to oscillate around the optimal value.

The estimate of the overall metabolic 02 consumption {V02) can be refined as a function of the difference between the target end-tidal partial pressure of 02 (P_ETO2[60j) and the measured end-tidal partial pressure of 02 (P_ETO2[60fⁱ ) in breath 60 (z^' = 60 ).

V02 = VO2₀ - β(ρ_ΕΤΟ2[60]^Μ - ?_£7O2[60 ) = 10 ml/min/mmHg

In general, the correction factor (β) can range from 5-200 ml/min/mmHg. Lower values of the correction factor will produce a more accurate estimate of the overall metabolic 02 consumption (V02) while requiring more tuning iterations. Higher values will reduce the number of tuning iterations but may cause the refined estimate of the parameter to oscillate around the optimal value.

The estimate of the overall metabolic C02 production {VC02 ) can be refined as a function of the difference between the target end-tidal partial pressure of C02 (P_ETC02[29f ) and the measured end-tidal partial pressure of C02 (P_ETC02[29f ) in breath 29 (i = 29 ).

VC02 - VCO2₀ + y[p_ETC02[29]^M - P_ETC02[29j ) γ = 10 ml/min/mmHg

Alternatively, the estimate of the overall metabolic C02 production (VC02 ) can be refined as a function of the difference between the target end-tidal partial pressure of

C02 (P_ETC02[6Q]^T ) and the measured end-tidal partial pressure of C02 ) in breath 60 (i = 60 )

VC02 = VCO2₀ + _y(p_ETCO2[6 ]^M - P_ETC02[mJ ) y - 10 ml/min/mmHg In general, the correction factor (y) can range from 5-200 ml/min/mmHg. Lower values of the correction factor will produce a more accurate estimate of the overall metabolic C02 production (VC02) while requiring more tuning iterations. Higher values will reduce the number of tuning iterations but may cause the refined estimate of the parameter to oscillate around the optimal value.

General requirements of a tuning sequence:

In breaths where the target end-tidal partial pressures of gases are transitioning between values, the estimate of the functional residual capacity {FRC ) determines the magnitude of the change induced in the actual end-tidal tidal partial pressures of gases. The estimate of the overall metabolic 02 consumption (V02) influences the induced/measured end-tidal partial pressure of 02 ) in steady state. Similarly, the estimate of the overall metabolic C02 production (VC02 ) influences the induced/measured end-tidal partial pressure of C02 ) in steady state.

It therefore follows that a difference between the measured change in the end-tidal partial pressure of 02 - lY) and the targeted change in the end-tidal partial pressure of 02 (p_∑T02[i - P_ET02[i-l ) in breaths where the target end-tidal partial pressure of 02 is not equal to the target end-tidal partial pressure of 02 from the previous breath ≠ P_ET02[i -lf ), or a difference between the measured change in the end-tidal partial pressure of C02 - l]^M ) and the targeted change in the end-tidal partial pressure o _TC02[i-if ) in breaths where the target end-tidal partial pressure of C02 is not equal to the target end- tidal partial pressure of C02 from the previous breath P_ETC02[i- if ), reflect errors in the estimate of the functional residual capacity (FRC).

Conversely, differences between the target end-tidal partial pressure of 02 and the measured end-tidal tidal partial pressure of 02 ) in breaths at the end of a long (20 breath) period of constant target end-tidal partial pressures of 02 ( ^pET⁰²W = ^PET⁰²^ -tf) reflect errors in the overall metabolic 02 consumption {V02). It is assumed that the measured end-tidal partial pressures of 02 will have stabilized (less than ±5 mmHg change in the measured end-tidal partial pressure of 02 over 3 consecutive breaths), although not necessarily at the target end-tidal partial pressure of 02, after 20 breaths of targeting the same end-tidal partial pressures of 02. If, however, the measured end-tidal partial pressure of 02 has not stabilized after 20 breaths of targeting the same end-tidal partial pressures of 02, a longer duration of targeting the same end-tidal partial pressure of 02 should be used for tuning the overall metabolic consumption of 02.

Differences between the target end-tidal partial ) and the measured end-tidal tidal partial pressure of C02 end of a long (20 breath) period of constant target end-tidal partial pressures of C02 = P_ETC02[i -lf ) reflect errors in the overall metabolic C02 production

{VC02 ). It is assumed that the measured end-tidal partial pressures of C02 will have stabilized (less than ±2 mmHg change in the measured end-tidal partial pressure of C02 over 3 consecutive breaths), although not necessarily at the target end-tidal partial pressure of C02, after 20 breaths of targeting the same end-tidal partial pressures of C02. If, however, the measured end-tidal partial pressure of C02 has not stabilized after 20 breaths of targeting the same end-tidal partial pressures of C02, a longer duration of targeting the same end-tidal partial pressure of C02 should be used for tuning the overall metabolic production of C02.

The tuning sequence described above is only an example of one sequence that can be used to tune the estimates of the physiological parameters.

The functional residual capacity (FRC ) can be tuned by observing the difference between the measured change in the end-tidal partial pressure of 02

) and the targeted change in the end-tidal partial pressure of 02 - if ) in breaths where the target end-tidal partial pressure of 02 is not equal to the target end-tidal partial pressure of 02 from the previous breath P_BT02[i -if ), or a difference between the measured change in the end-tidal partial pressure of C02 argeted change in the end-tidal partial pressur in breaths where the target end-tidal partial pressure of C02 is not equal to the target end-tidal partial pressure of C02 from the previous breath ≠ P_ETC02[i-lf ). Therefore, any sequence that targets the induction of a change in the end-tidal partial pressure of 02, or a change in the end-tidal partial pressure of C02, can be used to tune the estimate of the functional residual capacity.

The overall metabolic consumption of 02 {V02) can be tuned by observing the difference between the target end-tidal partial pressure of 02 and the measured end-tidal tidal partial pressure of 02 ) in breaths at the end of a lon (20 breath) period of constant target end-tidal partial pressures of 02 = P_ET02[i-if). It is assumed that the measured end-tidal partial pressures of 02 will have stabilized (less than ±5 mmHg change in the measured end-tidal partial pressure of 02 over 3 consecutive breaths), although not necessarily at the target end- tidal partial pressures of 02, after 20 breaths of targeting the same end-tidal partial pressures of 02. If, however, the measured end-tidal partial pressure of 02 has not stabilized after 20 breaths of targeting the same end-tidal partial pressures of 02, a longer duration of targeting the same end-tidal partial pressure of 02 should be used for tuning the overall metabolic consumption of 02.Therefore, any sequence that targets to maintain the end-tidal partial pressure of 02 constant for a sufficiently long duration may be used to tune the estimate of the overall metabolic consumption of 02.

The overall metabolic production of C02 (VC02 ) can be tuned by observing the difference between the target end-tidal partial pressure of C02 ) and the measured end-tidal tidal partial pressure of C02 ) in breaths at the end of a long (20 breath) period of constant target end-tidal partial pressures of C02 P_ETC02[i -i ). It is assumed that the measured end-tidal partial pressures of C02 will have stabilized (less than ±2 mmHg change in the measured end- tidal partial pressure of C02 over 3 consecutive breaths), although not necessarily at the target end-tidal partial pressure of C02, after 20 breaths of targeting the same end- tidal partial pressures of C02. If, however, the measured end-tidal partial pressure of C02 has not stabilized after 20 breaths of targeting the same end-tidal partial pressures of C02, a longer duration of targeting the same end-tidal partial pressure of C02 should be used for tuning the overall metabolic production of C02. Therefore, any sequence that targets to maintain the end-tidal partial pressure of C02 constant for a sufficiently long duration may be used to tune the estimate of the overall metabolic production of C02.

It is not required that all parameter estimates are tuned in the same sequence. Tuning of all parameters in the example sequence is done only for convenience. Different tuning sequences may be used to tune the estimates of different individual, or groups of, parameters.

Embodiments of mass balance equations: No SGD:

SGD:

As seen in Figures 22a and 22b a ramp sequence reveals the sigmoidal nature of a pattern of a physiological response - mid-cerebral artery blood flow velocity - showing its sigmoidal nature over different time courses depending on whether the subject is a fast or slow responder. Figure 23 blood flow responses to PC0₂ predicted for the model of a brain vascular territory with a partially-stenosed vessel branch and a healthy branch in parallel. Where there is some blood flow resistance upstream from the branches, it causes the partially- stenosed vessel to encroach on its vasodilatory reserve by an auto-regulatory mechanism. A vasodilatory stimulus such as in increase in arterial CO will stimulate all vessels to dilate, but those vessels that have already dilated in response to the increase in upstream resistance have a reduced range of response. The solid red line in Figure 23 depicts the sigmoidal response of a normal branch. The dotted blue line depicts the response of the partially stenosed vessel branch when coupled in parallel with the normal vessel branch, showing steal in hypercapnia and reverse steal in hypocapnia. The slopes of the straight lines show the predicted CVR values for PC0₂ stimulus ranges 40-45 and 40-50 mmHg. The filled circle marks the resting blood flow at resting PCO2 and the open circles show the measured responses for a healthy territory (solid circles and line) and a territory perfused via a stenosed vessel (dotted circles and line).

Figure 23 illustrates the sigmoidal relationship between regional blood flow and PC0₂ predicts that CVR in a vascular territory with adequate vasodilatory reserve will be greater for increases in PCO2 from 40 to 45 mmHg vs. increases from 40 to 50 mmHg. By contrast, a vascular territory downstream from a hemodynamically significant stenosis may have a positive CVR when the PC0₂ change is in a range where some vasodilatory reserve is preserved, but, with a greater stimulus range such as 40-50 mmHg PC0₂, these vessels reach their vasodilatory limit and the continued vasodilatory capacity in other regions will induce steal.

The model outlined in Figure 23 was investigated a comprehensive manner by using it to predict the change in CBF region by region in response to graded changes in PETCO2 in a patient with steno-occlusive disease.

Figure 24 shows an example of the development of steal with hypercapnia, and reverse steal (Robin Hood effect) with hypocapnia [Lassen, 1968 #16325]. Both of these conditions were observed in the same patient, confirming that steal and reverse steal are a function of the changes taking place in the parallel branches of the vascular bed with intact cerebral autoreguiation. The CVR map in response to a hypercapnic change in PETC0₂ from 30 to 50 mmHg is shown in Figure 24A and colour coded with the scale shown. We interpret the blue colour of the right MCA territory as signifying a vascular bed with reduced vasodilatory reserve (presumably as a result of MCA stenosis). The CVR maps for an axial slice at different PETCO2 ranges for a 18 year old male patient with moya moya disease affecting the right MCA territory are divided as follows (A) CVR map calculated for a hypocapnic PETCO* change from 40 to 30 mmHg. (B) CVR map calculated for a hypercapnic PETC0₂ change from 30 to 40 mmHg. (C) CVR map calculated for a hypercapnic PETC0₂ change from 40 to 50 mmHg. (D) CVR map calculated for a hypocapnic PETCO2 change from 50 to 40 mmHg. (E) CVR map calculated over the full hypercapnic PETCO≤ change from 30 to 50 mmHg. In this subject, inducing a reduction of PETCO2 from 40 mmHg to 30 mmHg produces a robust constriction in the healthy left brain territory and a decrease in the blood flow and BOLDsignal (Figure 24 ,CVR A). The CVR is color coded as before, but with the convention that its sign follows the BOLD change, so the CVR map is predominantly blue in the 'normal' vascular beds. However, a careful inspection of Figure 24 (CVR A) shows some yellow and orange colouration in the right MCA territory, indicating areas of increasing blood flow and CVR due to reverse steal, as predicted by the model demonstrated in Figure 23 . With another change in the direction of the stimulus, the hypercapnic increase in PETC0₂ from 30 to 40 mmHg produces a large increase in flow in the healthy left MCA region, but a lesser increase in the compromised right MCA region (Figure 24 , CVR B). Within this range of PETCO2 hypercapnia, the right MCA territory demonstrates some vasodilatory reserve. Nevertheless, as predicted and illustrated in Figure 23 , further hypercapnia to 50 mmHg results in a greater steal and the CVR values are negative, and the map is coloured blue (Figure 24 , CVR C). Finally, our conceptual model predicts that withdrawal of the vasodilatory stimulus will abolish the steal and induce a reverse steal via the Robin Hood effect. Once again, this result is observed in Figure 24 (CVR D); this CVR map is virtually the reverse image of the CVR map calculated for the full range of 30 to 50 mmHg change in PETCO (Figure 24 , CVR E). In Figure 24 the BOLD signal vs. time is presented for the whole brain, an average value of all voxels.

Example 1 00473

An apparatus according to the invention was used to target end tidal gas concentrations of CO2 and 0₂ in 35 subjects. We targeted the following sequence (values attained in brackets): normocapnia (60 seconds a PetCO₂=40 mm Hg, SD=1 mm; PetO₂=100 mm Hg, SD-2 mm), Hypercapnia (60 seconds at PetCO₂=50 mm Hg, SD=1 mm; PetO₂=1Q0 mm Hg, SD=2mm), normocapnia (lOOseconds), hypercapnia (180 seconds), and normocapnia ( 0 seconds). Figure 25, comprise a partial raw data set for 6 subjects.

The content of all of the patent and scientific references herein is hereby incorporated by reference.

1. Robbins PA, Swanson GD, Howson MG. A prediction-correction scheme for forcing alveolar gases along certain time courses. J Appl Physiol 1982 May;52(5):1353- 1357.[cited 2011 Oct 11 ]

2. Slessarev M, Han J, MardimaeA, Prisman E, Preiss D, Volgyesi G, Ansel C, Duffin J, Fisher JA. Prospective targeting and control of end-tidal C02 and 02 concentrations. J. Physiol. (Lond.) 2007 Jun;581(Pt 3): 1207-12 9. [cited 2011 Oct 6 ]

3. Banzett RB, Garcia RT, Moosavi SH. Simple contrivance "clamps" end-tidal and despite rapid changes in ventilation. Journal of Applied Physiology 2000 May;88(5): 597 -1600.[cited 2011 Oct 7 ]

4. Fisher J. Breathing circuits to facilitate the measurement of cardiac output during ...

[Internet]. [date unknown];[cited 2011 Oct 11] Available from: http:/ www.google.com/patents/about7idsRSqbAAAAEBAJ

5. Fisher J. Method of measuring cardiac related parameters non-invasively via the lung ... [Internet], [date unknown];[cited 2011 Oct 11] Available from: http://www.google.com/patents/about7idsQiqbAAAAEBAJ . Fisher JA. Method And Apparatus For Inducing And Controlling Hypoxia [Internet], [date unknown];[cited 2011 Oct 11] Available from: http://www.google.com/patents/about?id=Cd7HAAAAEBAJ Slessarev . Method and Apparatus to Attain and Maintain Target End Tidal Gas Concentrations [Internet], [date unknown];[cited 2011 Oct 11] Available from: http ://www. google, com/patents/about? id=23XGAAAAE BAJ Stenzler A. High FI02 oxygen mask with a sequential dilution feature [Internet], [date unknown]; [cited 2011 Oct 11] Available from: http:/ www.google.com/patents/about?id=v1VVlAAAAEBAJ Bray J, Cragg PA, Macknight A, Mills R, Taylor D. Lecture Notes on Human Physiology. 4th ed. Wiley-Blackwell; 1999. Kratz A, Lewandrowski KB. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values. N. Engl. J. Med. 1998 Oct;339(15):1063-1072.[cited 2011 Oct 6 ] Sund-Levander M, Forsberg C, Wahren LK. Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review. Scand J Caring Sci 2002 Jun;16(2):122-128.[cited 2011 Oct 6 ] Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992 Sep;268( 2):1578-1580.[cited 2011 Oct 6 ] Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006 Mar;107(5):1747-1750. [cited 2011 Oct 6 ] Peyton PJ, Poustie SJ, Robinson GJB, Penny DJ, Thompson B. Non-invasive measurement of intrapulmonary shunt during inert gas rebreathing. Physiol Meas 2005 Jun;26(3):309-316.[cited 2011 Oct 6 ] Peyton PJ, Robinson GJB, McCall PR, Thompson B. Noninvasive measurement of intrapulmonary shunting. J. Cardiothorac. Vasc.Anesth. 2004 Feb;18(1):47- 52.[cited 2011 Oct 6 ] Hope DA, Jenkins BJ, Willis N, Maddock H, Mapleson WW. Non-invasive estimation of venous admixture; validation of a new formula. Br J Anaesth 1995 May;74(5):538-543.[cited 2011 Oct 6 ] Smith HL, Jones JG. Non-invasive assessment of shunt and ventilation/perfusion ratio in neonates with pulmonary failure. Arch. Dis. Child. Fetal Neonatal Ed. 2001 Sep;85(2):F127-132.[cited 2011 Oct 6 ] Finley TN, Lenfant C, Haab P, Piiper J, Rahn H. Venous admixture in the pulmonary circulation of anestethetized dogs. J Appl Physiol 1960 May; 15:418- 424.[cited 2011 Oct 6 ] Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolving perspective in the era of liver transplantation. Hepatology 1990 Jan;11(1):138-142.[clted 2011 Oct 6 ] Reuter DA, Goetz AE. Measurement of cardiac output. Anaesthesist 2005 Nov;54(11 ): 1135-115 ; quiz 1152-1153.[cited 2011 Oct 6 ] Ehlers KC, Mylrea KC, Waterson CK, Calkins JM. Cardiac output measurements/A review of current techniques and research. Ann Biomed Eng 1986;14(3):219- 239. [cited 2011 Oct 6 ] Geerts BF, Aarts LP, Jansen JR. Methods in pharmacology: measurement of cardiac output Br J Clin Pharmacol 2011 Mar;71(3):316-330.[cited 2011 Oct 6 ] Pugsley J, Lerner AB, Cardiac output monitoring: is there a gold standard and how do the newer technologies compare? Semin Cardiothorac Vase Anesth 2010 Dec;14(4):274-282.[cited 2011 Oct 6 ] Jegier W, Sekelj P, Auld PA, Simpson R, McGregor M. The relation between cardiac output and body size. Br Heart J 1963 Jul;25:425-430.fcited 2011 Oct 6 J Ross DN. Theophylline-ethylenediamine in the measurement of blood circulation time. Br Heart J 1951 Jan;13(1):56-60.[cited 2011 Oct 6 J Zubieta-Calleja GR, Zubieta-Castillo G, Paulev P-E, Zubieta-Calleja L Noninvasive measurement of circulation time using pulse oximetry during breath holding in chronic hypoxia. J. Physiol. Pharmacol. 2005 Sep;56 Suppl 4:251- 256. [cited 2011 Oct 6 ] Sowton E, Bloomfield D, Jones NL, Higgs BE, Campbell EJ. Recirculation time during exercise.Cardiovasc. Res. 1968 Oct;2(4):341-345.[cited 2011 Oct 6 ] Chapman CB, Fraser RS. Studies on the effect of exercise on cardiovascular function. I. Cardiac output and mean circulation time. Circulation 954 Jan;9(1):57- 62.[cited 2011 Oct 6 ] Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty SA, oh YO. A new predictive equation for resting energy expenditure in healthy individuals. Am. J. Clin. Nutr. 1990 Feb;51(2):241-247.[cited 2011 Oct 6 ] Lenfant C. Time-dependent variations of pulmonary gas exchange in normal man at rest J Appl Physiol 1967 Apr;22(4):675-684.[cited 2011 Oct 6 ] Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson D, Macintyre N, McKay R, Miller MR, Navajas D, Pellegrino R, Viegi G, Standardisation of the measurement of lung volumes. Eur. Respir. J. 2005 Sep;26(3):511-522.[cited 2011 Oct 6 ] Stocks J, Quanjer PH. Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on Lung Volume Measurements. Official Statement of The European Respiratory Society. Eur. Respir. J. 1995 Mar;8(3):492-506.[cited 2011 Oct 6 ] Arnold JH, Thompson JE, Arnold LW. Single breath C02 analysis: description and validation of a method. Crit Care Med. 1996 Jan;24(1):96-102.[cited 2011 Oct 6 ] Heller H, Konen-Bergmann M, Schuster KD. An algebraic solution to dead space determination according to Fowler's graphical method. Comput.Biomed. Res. 1999 Apr;32(2):16M67.[cited 2011 Oct 6 ] Williams EM, Hamilton RM, Sutton L, Viale JP, Hahn CE. Alveolar and dead space volume measured by oscillations of inspired oxygen in awake adults. Am. J. Respir. Crit. Care Med. 1997 Dec;156(6):1834-1839.[cited 2011 Oct 6 ] Hart MC, Orzalesi MM, Cook CD. Relation between anatomic respiratory dead space and body size and lung volume. Journal of Applied Physiology 1963 May;18(3):519 -522.[cited 2011 Oct 6 ] Ito S, Mardimae A, Han J, Duffin J, Wells G, Fedorko L, Minkovich L, Katznelson R, Meineri M, Arenovich T, Kessler C, Fisher JA. Non-invasive prospective targeting of arterial PC02 in subjects at rest. J. Physiol. (Lond.) 2008 Aug;586(Pt 15):3675- 3682.[cited 2011 Oct 6 ] Somogyi RB, Veseiy AE, Preiss D, Prisman E, Volgyesi G, Azami T, Iscoe S, Fisher JA, Sasano H. Precise control of end-tidal carbon dioxide levels using sequential rebreathing circuits. Anaesth Intensive Care 2005 Dec;33(6):726-732. [cited 2011 Oct 6 ] Fierstra J, Machina M, Battisti-Charbonney A, Duffin J, Fisher JA, Minkovich L. End-inspiratory rebreathing reduces the end-tidal to arterial PC02 gradient in mechanically ventilated pigs. Intensive Care Med 2011 Sep;37(9):1543-1550.[cited 2011 Oct 6 ] Jones NL, Robertson DG, Kane JW, Campbell EJ, Effect of PC02 level on alveolar- arterial PC02 difference during rebreathing. J Appl Physiol 1972 Jun;32(6):782- 787.[cited 2011 Oct 6 ] Raine JM, Bishop JM. A-a difference in 02 tension and physiological dead space in normal man. J Appl Physiol 1963 Mar;18:284-288.[cited 2011 Oct 6 ]

Kelman GR. Digital computer subroutine for the conversion of oxygen tension into saturation. J Appl Physiol 1966 Jul;21(4):1375-1376.[cited 2011 Oct 6 ] 43. Wheeler DS, Wong HR, Shanley TP. Pediatric Critical Care Medicine: Basic Science and Clinical Evidence. 1st ed. Springer; 2007.

44. Burnett RW, Noonan DC.Calculations and correction factors used in determination of blood pH and blood gases.Clin. Chem. 1974 Dec;20(12):1499-1506.[cited 2011 Oct 6 ]

45. Loeppky JA, Luft UC, Fletcher ER. Quantitative description of whole blood C02 dissociation curve and Haldane effect. Respir Physiol 1983 Feb;51(2):167- 181. [cited 2011 Oct 6 ]

46. Douglas AR, Jones NL, Reed JW. Calculation of whole blood C02 content. J. AppI.

Physiol. 1988 Jul;65(1):473-477.[cited 2011 Oct 6 ]

47. Kelman GR. Digital computer procedure for the conversion of PC02 into blood C02 content Respir Physiol 1967 Aug; 3(1 ): 111 -115.[cited 2011 Oct 6 ]

48. Olszowka AJ, Farhi LE. A system of digital computer subroutines for blood gas calculations- Respir Physiol 1968 Mar;4(2):270-280. [cited 2011 Oct 6 ]

49. Cherniack NS, Longobardo GS. Oxygen and carbon dioxide gas stores of the body.

Physiol. Rev. 1970 Apr;50(2):196-243.[cited 2011 Oct 6 ]

50. Cherniack NS, Longobardo GS, Palermo FP, Heymann M. Dynamics of oxygen stores changes following an alteration in ventilation. J AppI Physiol 1968 Jun;24(6):809-816.[cited 2011 Oct 6 ]

51. Farhi LE, Rahn H. Dynamics of changes in carbon dioxide stores. Anesthesiology 1960 Dec;21 : 604-614. [cited 2011 Oct 6 ]

52. Cherniack NS, Longobardo GS, Staw I, Heymann M. Dynamics of carbon dioxide stores changes following an alteration in ventilation. J AppI Physiol 1966 May;21(3):785- 793.[cited 2011 Oct 6 ]

Pubmed Cross-Referenced References 1: Mutch WA, Patel SR, Shahidi AM, Kulasekara SI, Fisher JA, Duffin J, Hudson C. Cerebral oxygen saturation: graded response to carbon dioxide with isoxia and graded response to oxygen with isocapnia. PLoS One. 20 3;8(2):e5788 . doi: 10.1371/journal.pone.0057881. Epub 2013 Feb 28. PubMed PMID: 23469096; PubMed Central PMCID: PMC3585256.

2: Tancredi FB, Gauthier CJ, Madjar C, Bolar DS, Fisher JA, Wang DJ, Hoge RD. Comparison of pulsed and pseudocontinuous arterial spin-labeling for measuring C02 -induced cerebrovascular reactivity. J Magn Reson Imaging. 2012 Aug;36(2):312-21. doi: 10.1002/jmri.23658. Epub 2012 Apr 27. PubMed PMID: 225447 1.

3: Han JS, Abou-Hamden A, Mandell DM, Poublanc J, Crawley AP, Fisher JA, Mikulis

DJ, Tymianski M. Impact of extracranial-intracranial bypass on cerebrovascular reactivity and clinical outcome in patients with symptomatic moyamoya vasculopathy. Stroke. 2011 Nov;42(11):3047-54. doi:

10.1161/STROKEAHA.111.615955.

Epub 201 Sep 8. PubMed PMID: 21903951.

4: Fierstra J, Spieth S, Tran L, Conklin J, Tymianski M, ter Brugge KG, Fisher

JA, Mikulis DJ, Krings T. Severely impaired cerebrovascular reserve in patients with cerebral proliferative angiopathy. J Neurosurg Pediatr. 2011 Sep;8(3):3 0-5. doi: 10.3171/2011.6.PEDS1170. PubMed PMID: 21882924.

5: Han JS, Mikulis DJ, Mardimae A, Kassner A, Poublanc J, Crawley AP, deVeber GA, Fisher JA, Logan WJ. Measurement of cerebrovascular reactivity in pediatric patients with cerebral vasculopathy using blood oxygen level-dependent MRI.

Stroke. 2011 ay;42(5):1261-9. doi: 10.1161/STROKEAHA. 10.603225. Epub 2011 Apr

14. PubMed PMID: 21493907.

6: Fierstra J, Conklin J, Krings T, Slessarev M, Han JS, Fisher JA, Terbrugge K, Wallace MC, Tymianski , Mikulis DJ. Impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations. Brain. 201 Jan;134(Pt 1):100-9. doi: 10. 093/brain/awq286. Epub 2010 Nov 24. PubMed PMID: 21109501.

7: Winter JD, Fierstra J, Dorner S, Fisher JA, St Lawrence KS, Kassner A. Feasibility and precision of cerebral blood flow and cerebrovascular reactivity MRI measurements using a computer-controlled gas delivery system in an anesthetised juvenile animal model. J Magn Reson Imaging. 2010 Nov;32(5):1068-75. doi: 10.1002/jmri.22230. PubMed PMID: 21031510.

8: Mark CI, Fisher JA, Pike GB. Improved fMRI calibration: precisely controlled hyperoxic versus hypercapnic stimuli. Neuroimage. 2011 Jan 15;54(2): 1102-11. doi: 10.1016/j.neuroimage.2010.08.070. Epub 2010 Sep 7. PubMed PMID: 20828623. 9: Mark CI, Slessarev M, Ito S₍ Han J, Fisher JA, Pike GB. Precise control of end-tidal carbon dioxide and oxygen improves BOLD and ASL cerebrovascular reactivity measures. Magn Reson Med. 2010 Sep;64(3):749-56. doi: 10.1002/mrm.22405. PubMed PMID: 20648687.

10: Battisti A, Fisher JA, Dufffn J. Measuring the hypoxic ventilatory response.

Adv Exp Med Biol. 2010;669:221-4. doi: 0. 007/978-1 -44 9-5692-7_44. PubMed PMID:

20217353.

11: Heyn C, Poublanc J, Crawley A, Mandell D, Han JS, Tymianski M, terBrugge K, Fisher JA, Mikulis DJ. Quantification of cerebrovascular reactivity by blood oxygen level-dependent MR imaging and correlation with conventional angiography in patients with Moyamoya disease. AJNR Am J Neuroradiol. 2010 May;31(5): 862-7. doi: 0.3174/ajnr.A1922. Epub 2010 Jan 14. PubMed PMID: 20075092. 12: Cohen-Adad J, Gauthier CJ, Brooks JC, Slessarev M, Han J, Fisher JA, Rossignol S, Hoge RD. BOLD signal responses to controlled hypercapnia in human spinal cord. Neuroimage. 2010 Apr 15;50(3): 1074-84. doi: 10.1016/j.neuroimage.2009.12.122. Epub 2010 Jan 11. PubMed PMID: 20060914. 13: Venkataraman ST, Hudson C, Rachmiel R, Buys YM, Markowitz SN, Fisher JA, Trope GE, Flanagan JG. Retinal arteriolar vascular reactivity in untreated and progressive primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2043-50. doi: 10.1167/iovs.09-3630. Epub 2009 Nov 11. PubMed PMID: 19907031.

14: Han JS, Mandell DM, Poublanc J, Mardimae A, Slessarev M, Jaigobin C, Fisher JA, Mikulis DJ. BOLD-MRI cerebrovascular reactivity findings in cocaine-induced cerebral vasculitis. Nat Clin Pract Neurol. 2008 Nov;4(1 ):628-32. doi:

10.1038/ncpneuro0918. Epub 2008 Oct 7. PubMed PMID: 18839005.

15: Mandell DM, Han JS, Poublanc J, Crawley AP, Kassner A, Fisher JA, Mikulis DJ. Selective reduction of blood flow to white matter during hypercapnia corresponds with leukoaraiosis. Stroke. 2008 Jul;39(7): 1993-8. doi:

10.1161/STROKEAHA.107.501692. Epub 2008 May 1. PubMed PMID: 18451357. 16: Ito S, Mardimae A, Han J, Duffin J, Wells G, Fedorko L, Minkovich L,

Katznelson R, Meineri M, Arenovich T, Kessler C, Fisher JA. Non-invasive

prospective targeting of arterial P(C02) in subjects at rest. J Physiol. 2008 Aug 1;586(Pt 15):3675-82. doi: 10.1113/jphysiol.2008.154716- Epub 2008 Jun 19. PubMed PMID: 18565992; PubMed Central PMCID: PMC2538829.

The content of all the references in this document is hereby incorporated by reference.

Claims

Claims:

1. Λ system for controlling an amount of at least one gas X in a subject's lung to target at least one end tidal partial pressure of at least one gas X (PetX^T), the system comprising:

(1) a gas delivery device adapted for connection to a breathing circuit, the breathing circuit configured to connect the gas delivery device to a patient airway interface;

(3) a control system for controlling the gas delivery device, wherein the control system is configured to target a PetX^T for at least one in a series of respective intervals, the respective intervals defined by a series of respective inspiratory cycles of variable size or a length of time including a series of respective inspiratory cycles of variable size, the control system including a processor configured to, for a respective breath [i]:

B. obtain input from the measurement system of at least one measured PetX value attained as a result of gas exchange in a previous interval, preferably in an immediately preceding respective breath

C. determine an amount of gas X required to be inspired by the subject in at least a first portion of an inspiratory cycle of a respective breath [i] to target the PetX^T for a respective interval, the gas delivery device adapted to set a volume of the first portion of the inspiratory cycle in a respective breath [i] to be equal to or preferably less than the subject's baseline minute ventilation minus the subject's anatomic dead space ventilation;

D. Controlling the amount of gas X in a volume of gas delivered to the subject in a first portion of the inspiratory cycle of a respective breath [i] and in a second remaining portion of that inspiratory cycle, to target the PetX^T for the interval, the breathing circuit or the control system configured to make available to a subject, for inspiration: (a) a first inspired gas of a first composition determined by the processor for the first portion of the inspiratory cycle of a respective breath[i]; and

(b) when the subject's ventilation in a respective breath [i] exceeds the first inspired available for a breath, a second inspired gas of second

composition having a partial pressure of gas X (PX) selected from a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i-1], or a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i];

and wherein the control system implements a feedback algorithm which compares a PetX^T for a respective breath [i] of variable size and preferably a respective currentPetX value measured by the measurement system, to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

2. A system as claimed in claim 1, wherein the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively based on a predictive algorithm, and wherein a feedback control signal is added to the control signal generated as a result of the prospective determination.

3. A system as claimed in claim 2, wherein the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively on a breath by breath basis, and wherein the feedback control signal is generated using a feedback control algorithm selected from a group comprising a PD, a PI and a PID control algorithm.

4. A system as claimed in claim 3, whereinthe predictive algorithm comprises: a. obtaining input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i]

(CMVXRD;

b. obtaining input of a logistically attainable end tidal partial pressureof gas X (PetX[i ) for a respective breath [i];

c. obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C_MvX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

5. An system as claimed in claim 4, wherein the mass balance equation is computed based on a tidal model of the lung.

6. An system according to claim 5, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes comprising or corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

7. A system according as claimed in claim 6, wherein a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [i].

8. A system as claimed in claim 7, wherein the mass balance equation is solved for F|X.

9. A system as claimed in any one of claims 2 to 8, comprising obtaining inputs required to compute an F|X to target PetX[i]^T for a respective breath [i], wherein F|X is computed prospectively using a mass balance equation which comprises terms corresponding to all or an application-specific subset of the terms in:

eq. 1

10. A system according any of the preceding claims, wherein the control system is implemented by a computer, the computer configured to provide output signals to one or more rapid flow controllers.

11. A system according to any of the preceding claims, wherein the gas delivery device is a gas blender and wherein the measurement system includes at least one flow sensor positioned to measure flow of an inspiratory gas stream to a subject and wherein the gas blender is controlled to add a variable amount of a gas containing a gas X to the inspiratory gas stream based on measurements obtained from the flow sensor to deliver an amount of gas X required to be inspired by the subject to target the PetX^T for a respective interval.

12. A system as claimed in any one of the preceding claims wherein the breathing circuit includes a patient airway interface, a distally located one way inspiratory valve and a distally located one way expiratory valve and wherein the measurement system includes a gas X analyzer positioned to measure the gas X concentration exiting the one expiratory valve.

13. A system as claimed in any of the preceding claims, wherein the breathing circuit is a SGD circuit.

14. A system as claimed in any of the preceding claims wherein the control system implements a virtual SGD circuit.

15. A system as claimed in any of the preceding claims wherein gas X is carbon dioxide .

16. A system as claimed in any of the preceding claims wherein the control system is adapted to target end tidal concentrations of a first gas X and at least a second gas Y contemporaneously.

17. A system as claimed in claim 16, wherein gas X is carbon dioxide and gas Y is oxygen.

18. A system as claimed in any of the preceding claims wherein a transition to a different targeted end tidal concentration of at least one gas X is attained in 10 to 25 seconds.

19. A system as claimed in any of the preceding claims wherein the subject is hyperventilating.

20. The use of a system as claimed in any one of claims 1 to 18, to target an end tidal concentration of gas X in a hyperventilating subject.

21. The use of a system as claimed in claim 17, as a preliminary step in a non- therapeutic diagnostic procedure in aid of diagnosing a medical condition associated with vascular stenosis or altered vascular reactivity.

22. The use as claimed in claim 21 , wherein the subject is hyperventilating.

23. The use as claimed in any of one of claim 20 to 22, wherein the subject is undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the heart.

24. The use as claimed in any of one of claims 20 to 22, wherein the subject is undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the heart.

25. The use as claimed in any of one of claims 20 to 22, wherein the subject is undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the brain.

26. The use as claimed in any of one of claims 24 to 25, wherein the subject is undergoing an MRI procedure.

27. A method for controlling an amount of at least one gas X in a subject's lung to target at least one end tidal partial pressure of at least one gas X (PetX^T), the method comprising:

Using a control system to control a gas delivery device (optionally a gas blender, optionally a real time gas blender) operatively connected to a breathing circuit, the control system configured (e.g. programmed) to make available for inspiration for at least one of a series of respective intervals defined by a series of respective inspiratory cycles of variable size or a length of time including a series of respective inspiratory cycles of variable size a first inspired gas of a first composition determined to target at least one end tidal partial pressure of at least one gas X (PetX^T) for a first portion of the inspiratory cycle of a respective breathfi], wherein the control system or a breathing circuit operatively connected to the gas delivery device is configured such when the subject's ventilation in a respective breath [ij exceeds the first inspired available for a breath (e.g. a gas reservoir of a selected volume is emptied or a selected volume of the gas of first composition has been delivered for the respective breath), a second inspired gas of second composition having a partial pressure of gas X (PX) selected from a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i-1], or a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i], wherein the control system implements a feedback algorithm which compares a PetX^T for a respective breath [i] of variable size and preferably a respective current PetX value measured by a measurement system operatively associated with the breathing circuit, to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

28. A method as claimed in claim 27, wherein:

(1) the breathing circuit is configured to connect the gas delivery device to a patient airway interface;

(2) the measurement system is configured for measuring the concentration of the at least one gas X in a subject's end tidal expired gas;

(3) the control system is configured to target a PetX^T for at least one in a series of respective intervals, the respective intervals defined by a series of respective inspiratory cycles of variable size or a length of time including a series of respective inspiratory cycles of variable size, the control system including a processor configured to, for a respective breath [i]:

A. obtain input of at least one logistically attainable PetX^T value for the respective interval; B. obtain input from the measurement system of at least one measured PetX value attained as a result of gas exchange in a previous interval, preferably in an immediately preceding respective breath [i-1];

D. Controlling the amount of gas X in a volume of gas delivered to the subject in a first portion of the inspiratory cycle of a respective breath [i] and in a second remaining portion of that inspiratory cycle, to target the PetX^T for the interval, the breathing circuit or the control system configured to make available to a subject, for inspiration:

(b) when the subject's ventilation in a respective breath [i] exceeds the first inspired available for a breath, a second inspired gas of second composition having a partial pressure of gas X (PX) selected from a PX approximating the PX in the subject's arterial blood after a previous breath, preferably a respective breath [i-1], or a PetX^T targeted in the respective breath [i], the gas of second composition available for inspiration for the second remaining portion of the inspiratory cycle of a respective breath [i].

29. A method as claimed in claim 28, wherein the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively based on a predictive algorithm, and wherein a feedback control signal is added to the control signal generated as a result of the prospective determination.

30. A system as claimed in claim 29, wherein the amount of gas X required to be inspired by the subject in at least a first portion of a respective breath [i] to target the PetX^T for a respective interval is determined prospectively on a breath by breath basis, and wherein the feedback control signal is generated using a feedback control algorithm selected from a group comprising a PD, a PI and a PID control algorithm.

31. A system as claimed in claim 30, wherein the predictive algorithm comprises:

a. obtaining input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (( W);

c. obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C VXP], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

32. A method as claimed in claim 31 , wherein the mass balance equation is computed based on a tidal model of the lung.

33. A method as claimed in claim 32, wherein the mass balance equation is computed based on a tidal model of the lung.

34. A method according to claim 33, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes comprising or corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [ij.

35. A method according as claimed in claim 34, wherein a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [i],

36. A method as claimed in claim 35, wherein the mass balance equation is solved for F,X.

37. A method as claimed in any one of claims 28 to 36, comprising obtaining inputs required to compute an F|X to target PetX[i]^T for a respective breath [i], wherein F|X is computed prospectively using a mass balance equation which comprises terms corresponding to all or an application-specific subset of the terms in:

eq. 1

or

38. A method according any of the preceding claims, wherein the control system is implemented by a computer, the computer configured to provide output signals to one or more rapid flow controllers.

39. A method according to any of the preceding claims, wherein the gas delivery device is a gas blender and wherein the measurement system includes at least one flow sensor positioned to measure flow of an inspiratory gas stream to a subject and wherein the gas blender is controlled to add a variable amount of a gas containing a gas X to the inspiratory gas stream based on measurements obtained from the flow sensor to deliver an amount of gas X required to be inspired by the subject to target the PetX^T for a respective interval.

40. A method as claimed in any one of the preceding claims wherein the breathing circuit includes a patient airway interface, a distally located one way inspiratory valve and a distally located one way expiratory valve and wherein the measurement system includes a gas X analyzer positioned to measure the gas X concentration exiting the one expiratory valve.

41. A method as claimed in any of the preceding claims, wherein the breathing circuit is a SGD circuit.

42. A method as claimed in any of the preceding claims wherein the control system implements a virtual SGD circuit.

43. A method as claimed in any of the preceding claims wherein gas X is carbon dioxide.

44. A method as claimed in any of the preceding claims wherein the control system is adapted to target end tidal concentrations of a first gas X and at least a second gas Y contemporaneously.

45. A method as claimed in claim 44, wherein gas X is carbon dioxide and gas Y is oxygen.

46. A method as claimed in any of the preceding claims wherein a transition to a different targeted end tidal concentration of at least one gas X is attained in 10 to 25 seconds.

47. A method as claimed in any of the preceding claims wherein the subject is hyperventilating.

48. The use of a method as claimed in any one of claims 27 to 47, to target an end tidal concentration of gas X in a hyperventilating subject.

49. The use of a method as a method as claimed in any of the preceding claims as a preliminary step in a non-therapeutic diagnostic procedure in aid of diagnosing a medical condition associated with vascular stenosis or altered vascular reactivity.

50. The use as claimed in claim 49, wherein the subject is hyperventilating.

51. The use as claimed in any of the preceding claims, wherein the subject is

undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the heart.

52. The use as claimed in any of one of the preceding claims, wherein the subject is undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the heart.

53. The use as claimed in any of one of the preceding claims, wherein the subject is undergoing a diagnostic imaging procedure to assess vascular occlusion or vascular reactivity in the brain, optionally by BOLD-MRI.

54. The use as claimed in any of one of the preceding claims, wherein the subject is undergoing an RI procedure.

55. A system for controlling an amount of at least one gas X in a subject's lung to target at least one end tidal partial pressure of at least one gas X (PetX^T), the system uses a control system for controlling the gas delivery device, wherein the control system implements a sequential gas delivery system and a feedback algorithm which compares a PetX¹ for a respective breath [i] of variable size and preferably a respective current PetX value measured by a measurement system, to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval.

56. A computer program product or programmed IC chip for use in conjunction with a gas delivery device, a breathing circuit and a measurement system operatively connected to the breathing circuit, to control an amount of at least one gas X in a subject's lung to attain a target end tidal partial pressure of a gas X in the subject's lung, comprising program code sufficient for implementing a sequential gas delivery system and a feedback algorithm which compares a PetX^T for a respective breath [ij of variable size and preferably a respective current PetX value measured by the measurement system operatively associated with the breathing circuit, to obtain an error signal, the feedback algorithm adapted for generating a control signal based on the error signal, the control signal determining the amount of gas X to be inspired by the subject in at least a first portion of a respective ensuing respective inspiratory cycle to target PetX^T for the respective interval, wherein the sequential gas delivery system comprises one of:

(a) breathing circuit that is a sequential gas delivery circuit; and

(b) program code for implementing a virtual sequential gas delivery algorithm.

57. A computer program product or programmed IC chip as claimed in claim 56, wherein the program code is adapted for controlling a system or use as claimed in any of claims 1-26 or implementing a system, method or use as claimed in any of claims 27- 55.

58. A method for targeting at least one partial pressure of at least one gas X (PetX^T) in a subject, optionally in a spontaneously breathing mammal's blood, comprising, with respect to a series of respective breaths [i]:

(A) making available to a subject a first gas in the first part of a respective breath [i] and a neutral second gas (e.g. a gas having a partial pressure of gas X which equals the measured end tidal concentration of gas X in an immediately preceding breath or equals PetX^T targeted in the current respective breath [i]), in the second part of a respective breath [i], wherein the amount of neutral gas received in a respective breath [i] at least equals or preferably exceeds the dead space volume of the subject's lung; and

(B) using a feedback control algorithm to:

59. A computer program product for targeting at least one partial pressure of at least one gas X (PetX^T) in a subject, optionally in a spontaneously breathing mammal's blood, comprising, with respect to a series of respective breaths [i], machine readable code for:

(B) using a feedback control algorithm to:

(iii) generate a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in the first gas to target PetX^T for the respective breath [(].

60. A method of controlling a gas delivery device adapted for delivering a respiratory gas to a mammal, comprising: a) measuring (or otherwise obtaining input of) for a respective breath [i] the concentration of the at least one gas X in a subject's expired gas in a previous breath; b) making available to a subject, for inspiration in a respective breath [i], a first gas and a neutral second gas which is preferably one of the end tidal partial pressure of gas X measured for or computed for a previous breath, preferably an immediately preceding breath [i-1] and a gas having a partial pressure of gas X which equals PetX^T targeted in the respective breath [i], such that when the subject's minute ventilation exceeds the fresh gas available for a breath, the second gas is delivered for the remainder of the breath; c) computing (or otherwise obtaining input of) an error signal based on PetX^T for the respective breath [i] and a measured value of the concentration of gas X in the subject's end tidal expired gas for the previous breath [i-1];

d) generating a control signal based on the error signal that determines the amount of gas X needed to be inspired by the subject in the first gas to target PetX^T for the respective breath [i].

61. An apparatus for targeting a partial pressure of at least one gas X (PetX^T), preferably in a spontaneously breathing mammal's blood, comprising:

(1) a gas delivery device configured for connection to a breathing circuit;

(2) a control system;

(3) a measurement system configured to obtain a value which represents an

approximation of the partial pressure of the at least one gas X in the subject's arterial blood after gas exchange in a previous breath, optionally the concentration of the at least one gas X in a subject's end tidal expired gas after gas exchange in breath [i-1]; wherein the control system is configured, with respect to a series of respective breaths [i]: (A) to make available to a subject a first gas in the first part of a respective breath [i] and a neutral second gas (preferably which is one of the end tidal partial pressure of gas X measured for or computed for a previous breath, preferably an immediately preceding breath and a gas having a partial pressure of gas X which equals PetX^T targeted in the respective breath [i]) in the second part of a respective breath [i], such that the amount of neutral gas received in a respective breath [i] at least equals and preferably exceeds the dead space volume;

(B) to use a feedback control algorithm to:

62. A system for targeting an end partial pressure of at least one gas X (PetX^T) using a gas delivery device, optionally in a spontaneously breathing mammal's expired gas, comprising: .

(1) a control system;

(2) a measurement system configured to obtain a value which represents an

approximation of the partial pressure of the at least one gas X in the subject's arterial blood after gas exchange in a previous breath, optionally the concentration of the at least one gas X in a subject's end tidal expired gas after gas exchange in breath [i-1]; wherein the control system is configured, with respect to a series of respective breaths [i]:

(A) to control the gas delivery device to provide to a subject a first gas in the first part of a respective breath [i] and a neutral second gas (preferably a gas which is one of the end tidal partial pressure of gas X measured for or computed for a previous breath, preferably an immediately preceding breath [i-1] and a gas having a partial pressure of gas X which equals PetX^T targeted in the respective breath [i]) in the second part of a respective breath [i], such that the amount of neutral gas received in a respective breath [i] at least equals and preferably exceeds the dead space volume;

(B) to use a feedback control algorithm to:

(iii) generate a control signal for controlling the gas delivery device based on the error signal that determines the amount of gas X needed to be inspired by the subject in the first gas to target PetX^T for the respective breath [i].

Claims Relevant to Section B VSGD Invention

1A. A respiratory gas delivery system adapted to deliver an inspiratory gas of variable composition comprising:

A. a gas delivery apparatus operatively connected to a processor;

B. a flow sensor adapted to monitor in real time the rate of inspiration of a gas;

wherein, for a plurality of respective inspiratory cycles [i]1 to [i]n and a plurality of time points [t]1 to [t]n over the course of a respective inspiratory cycle [i], the processor is configured to:

(a) use output from the flow sensor to monitor the cumulative volume of gas inspired in the respective inspiratory cycle at any given time point [t]i to [t]_n;

(b) execute an algorithm to determine a desired composition of the inspired gas based on whether or not at least one threshold cumulative volume of a desired gas composition has been inspired in the respective inspiratory cycle, the desired composition including a composition selected from a first composition selected for delivery for a first portion of an inspiratory cycle and at least one alternate nth composition selected for delivery during the course of the inspiratory cycle; and

(c) generate a control signal effective to signal the gas delivery apparatus to deliver the first composition in the first part of an inspiratory cycle and then the nth composition during the course of the inspiratory cycle based on whether or not the at least one threshold cumulative volume has been reached. 2A. A respiratory gas delivery system as claimed in claim 1A, wherein the composition corresponding to a first portion of an inspiratory cycle is determined using at least one first criterion and wherein the at least one alternate composition is determined using at least one different criterion.

3A. A respiratory gas delivery system as claimed in any one of claims 1A and 2A, wherein the at least one cumulative volume is set to be less than a subject's tidal volume minus anatomic dead space volume such that the entire volume of the composition corresponding to a first portion of an inspiratory cycle is destined to enter a subject's alveolar space.

4A. A respiratory gas delivery system according to any one of claims 1A, 2A and 3A, wherein the alternate composition is a neutral gas.

5A. A respiratory gas delivery system according to any one of claims 1A, 2A and 3A, wherein the alternate composition is a percentage composition of a constituent gas as low as 0%, wherein the constituent gas is of a type determined by a user to warrant conservation by reducing delivery to the anatomical dead space.

6A. A system as claimed in claim 1A, wherein the processor is configured to simulate gas delivery from at least a virtual first gas reservoir and a virtual second gas reservoir, wherein:

(b) at least the first gas reservoir is assumed to contain a gas corresponding to a first portion of an inspiratory cycle, the processor configured to send a control signal to signal to the gas delivery apparatus to deliver a gas of a specified composition of the first gas reservoir for the first part of a respective inspiratory cycle [i], the first gas reservoir set to contain a volume of gas adapted to be depleted in each inspiratory cycle at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor;

(c) the processor generates a control signal effective to signal the gas delivery apparatus to deliver a gas of composition substantially equal to the specifiable or specified composition of the at least second gas reservoir for a second part of a respective inspiratory cycle [i] when the first gas reservoir is depleted.

7A. A system as claimed in any one of the preceding claims, wherein the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is continually filled with a gas of the specified composition at a specifiable or specified reservoir-specific fill rate which is less than the reservoir specific depletion rate.

8A. A system as claimed in any one of the preceding claims, wherein the volume of the at least first gas reservoir is set based on an assumption that the first gas reservoir is full at the start of an inspiratory cycle, the volume selected to be a volume that can be predicted to be depleted at a reservoir specific depletion rate which tracks the inspiratory flow rate measured by the flow sensor.

9A. A system as claimed in any one of the preceding claims, wherein the apparatus is configured to deliver a first gas of a first composition for a first part of each inspiratory cycle [i] and a second gas of a second composition for a second part of each inspiratory cycle [i].

10A. A system as claimed in claim 9A, wherein the apparatus is configured to simulate gas delivery from at least two gas reservoirs, wherein the first reservoir is exclusively depleted in a first part of a each inspiratory cycle [i], and the second reservoir is exclusively delivered in a second part of each inspiratory cycle [i]. 1A. A system as claimed in claim 7A, wherein the fill rate of the first reservoir is less than the subject's total inspired volume minus the total volume of gas inspired into the anatomic dead space volume over a measurement interval. 12A. A system as claimed in claim 11 , wherein the measurement interval is one minute. 13A- A system as claimed in any one of the preceding claims, wherein the composition of gas delivered in the second part of each inspiratory cycle [i] is neutral with respect to at least one gas X in the inspiratory gas.

14A. A respiratory gas delivery system adapted for use with a first breathing circuit having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes gas delivery characteristics of a reference respiratory gas delivery system that is adapted to be used in conjunction with a reference second breathing circuit, the gas delivery characteristics of the reference respiratory gas system dictated at least in part by at least one structural component of the reference second breathing circuit, the respiratory gas delivery system including: a) a flow sensor positioned for determining at least an inspiratory flow rate;

b) a gas delivery apparatus adapted to deliver a gas comprising a plurality of component gases through the patient airway interface, the gas delivery apparatus operatively connected to a computer, the computer configured to supplant at least one structural component of the reference second breathing circuit by using a mathematical model or algorithmic model of the at least one supplanted structural component to generate gas delivery characteristics that are functionally equivalent to those generated by the at least one supplanted structural component.

15A. A system as claim in claim 14A, wherein the computer is configured to simulate structural features defined by at least one component of a sequential gas delivery circuit.

16A. A respiratory gas delivery system according to claim 14A, wherein the reference breathing circuit is a re-breathing circuit which organizes the delivery of a first component gas of selected first composition and a second component gas comprising exhaled gas and wherein the computer is configured to signal the gas delivery apparatus to deliver a component gas of selected first composition and a component gas of second composition including a gas of composition which matches that of at least one component of an exhaled gas.

17A. A system as claimed in claim 15A, wherein the components gases are formulated for delivery by the gas delivery apparatus by blending requisite constituent gases.

18A. A system as claimed in any one of claims 15A, 16A and 17A, wherein the component gas of second composition has a percentage composition of at least one gas X which substantially matches the percentage composition of a gas X in a subject's last exhaled end tidal gas.

19A. A system as claimed in claim 18, further comprising a gas analyzer operatively connected to the computer to provide input of a value corresponding to an amount of the at least a gas X in the subject's last exhaled end tidal gas. 20A. A respiratory gas delivery system according to any one of claims 14A to 18A, wherein the reference breathing circuit is a sequential gas delivery circuit having a flow control system which alternately directs gas flow from: (a) a first circuit flow path organized to deliver a first gas component of the first gas composition; and (b) a second circuit flow path organized to deliver a second gas component of the second gas composition.

21 A. A respiratory gas delivery system according to claim 20A, wherein the at least one supplanted structural component of the reference breathing circuit comprises a component which arrests flow during the course of substantially each respective inspiratory cycle [i] from the first circuit flow path, and subsequently, in the same inspiratory cycle, initiates gas flow from the second circuit flow path and wherein flow from the first and second flow paths is substituted in the respiratory gas delivery system by controlling the gas delivery apparatus to alternately deliver a gas of first composition of a selected volume corresponding to that of the first gas component and a gas of second composition corresponding the second gas component.

22A. A respiratory gas system according to claim 21A, wherein the reference respiratory gas delivery system is adapted to deliver a component gas of first composition from a first circuit flow path leading from a first gas reservoir, and when the first gas reservoir is depleted, a component gas of second composition from a second circuit flow path.

23A. A respiratory gas system according to claim 22A, wherein the second flow path is a second gas reservoir, a gas output port operatively connected to a gas source or an ambient air inlet.

24A. A respiratory gas system according to claim 21A, wherein the gas delivery apparatus is controlled in part by modelling depletion of the first gas reservoir at a rate which tracks a subject's real time inspiratory rate, the first gas reservoir set to have a volume which is replenished in each inspiratory cycle and depleted in substantially each inspiratory cycle.

25A. A respiratory gas system according to claim 24A, wherein delivery of first gas composition virtualizes filling the first gas reservoir at a flow rate which matches the fill rate of first gas reservoir of the reference second breathing circuit and emptying of the first gas reservoir at a rate of inspiration monitored in real time, wherein the respiratory gas system is adapted to supplant the first gas reservoir and at least one structural component involved in cyclically arresting flow from the first circuit flow path and initiation of flow from the second circuit flow path.

26A. A respiratory gas system according to claim 25A, wherein the at least one structural component is a sequential gas delivery valve.

27A. A respiratory gas system according to claim 26A, wherein the first and second circuit flow paths are optionally replaced with a common circuit flow path leading from the gas delivery apparatus to the patient airway interface and wherein the gas delivery apparatus is configured to first deliver via the common circuit flow path a gas of first composition and then a gas of second composition.

28A. A respiratory gas system according to claim 27A, wherein the gas delivery apparatus is a gas blender and wherein the computer signals the gas delivery apparatus to alternately deliver, in a repeating cycle, a gas blend of a volume of the gas of first composition for the first portion of an inspiratory cycle and then a gas blend the gas of the second composition for the remainder of an inspiratory cycle.

29A. A respiratory gas system according to claim 28A, further comprising a pressure transducer to track the beginning and end of each inspiratory cycle.

30A. A respiratory gas system according to claim 14A, wherein the reference breathing circuit comprises a first gas reservoir and a second gas reservoir and wherein the first and second gas reservoirs are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first gas reservoir using at least one of an algorithmic and mathematical model (e.g. of replenishment and/or depletion) of the first gas reservoir by delivering a gas of the first composition corresponding to a full or selected partial volume of the first gas reservoir and subsequently a gas of the second composition upon simulated depletion or partial depletion of the gas of first composition in the first gas reservoir.

31A. A respiratory gas system according to claim 1A, wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation.

32A. A respiratory gas system according to claim 1 A, including a gas analyzer wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less than the subject's minute ventilation minus anatomic dead space ventilation and wherein the gas of second composition corresponds to that of subject's exhaled gas from a breath n-1 (the immediately previous expiratory cycle) as determined by the gas analyzer.

33A. A respiratory gas system according to claim 14A, wherein the reference respiratory gas delivery system is adapted to be used in conjunction with a reference sequential gas delivery circuit including an inlet port into a first gas reservoir operatively connected to a gas blender for receiving a blended component gas of first composition from, and when the first reservoir is depleted, a component gas of second composition from a second gas reservoir containing a subject's end tidal exhaled gas , and wherein at least the first gas reservoir and second gas reservoir are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first and second gas reservoirs using a mathematical model of replenishment and depletion of the first gas reservoir by delivering a gas of the first composition first and subsequently a gas of the second composition upon simulated depletion of the first gas reservoir.

34A. A respiratory gas system according to claim 33A, wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation.

35A. A respiratory gas system according to claim 34A, including a gas analyzer wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation and wherein the gas of second composition corresponds to that of subject's exhaled gas from a breath n-1.

36A. A respiratory gas delivery system adapted to be operatively connected to a first breathing circuit and virtualize, at least one structural feature of a reference second breathing circuit, the respiratory gas delivery system including:

a) at least one measurement device operatively connected to the first breathing circuit;

b) a gas delivery apparatus operatively connected to a computer for controlling the gas delivery apparatus; the computer configured to: (1) obtain input from the measurement device; (2) execute at least one of an algorithmic and mathematical model of the reference second breathing circuit; and (3) generate a control signal that signals the gas delivery apparatus to output at least one gas composition to the first breathing circuit such that the gas delivery characteristics of the respiratory gas delivery system simulate the at least one structural feature of the reference second breathing circuit.

37A, A respiratory gas system according to any one of claims 1A and 36A, wherein the reference respiratory gas delivery system is adapted to deliver a component gas of first composition from a first gas reservoir, and when the first reservoir is depleted, a component gas of second composition from an alternate flow path, and wherein at least the first gas reservoir and alternate flow path are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first gas reservoir and alternate flow path using at least one of a mathematical model and algorithmic model of depletion of the first gas reservoir by delivering a gas of the first composition first and subsequently a gas of the second composition upon simulated depletion of the first gas reservoir.

38A. A respiratory gas delivery system according to claim 37A, wherein the measurement device is a flow sensor positioned to monitor the inspiratory flow rate through the first breathing circuit and wherein the model depletes the first gas reservoir at the inspiratory flow rate.

39A. A system as claimed in any one of claims 1A to 13A, wherein the gas delivery apparatus includes a gas output port operatively connected to a breathing circuit including a gas delivery portion comprising a single gas conduit leading to a patient airway interface.

40A. A system as claimed in any one of claims 1A to 13A, wherein the gas delivery apparatus is operatively connected to a breathing circuit in which the gas delivery portion consists essentially of a gas conduit leading operatively connected to a patient airway interface.

41A. A respiratory gas delivery system adapted for use with a first breathing circuit including a patient airway interface, characterized in that the respiratory gas delivery system virtualizes at least one structural component of a reference, second breathing circuit, the respiratory gas delivery system including:

a) at least one device adapted for selecting a juncture during an inspiratory cycle for switching between a first gas composition and at least one alternate, nth gas composition,

b) a gas delivery apparatus for delivering a gas comprising a plurality of component gases into the patient airway interface, the gas delivery

apparatusoperatively connected to a computer;

wherein the computer is configured to supplant the at least structural component, by using at least one of an algorithmic and a mathematical model of the at least one structural component to generate gas delivery characteristics that simulate the functions of the at least one structural component.

42A. A system according to claim 41 A, where the juncture demarcates a point at which inspired gas has already filled the alveoli and begins to fill the anatomical dead space.

43A. A system according to claim 42A, wherein the juncture is identified by monitoring at least one parameter in real time.

44A. A system according to claim 43A, wherein the parameter is selected from at least one of volume, pressure and gas concentration.

45A. A system according to claim 44A, wherein the parameter is a gas flow rate or volume.

46A- A system according to any one of claims 41 A to 45A, wherein the device is a flow sensor, positioned in relation to the first breathing circuit, for at least determining the volume gas inhaled via the patient airway interface.

47A. A system according to any one of claims 41A to 46A, wherein the at least one structural component comprises or consists of at least one set of structural parts adapted to direct gas flow from a first circuit flow path to at least one alternate, nth circuit flow path during the course of a given inspiratory cycle.

48A. A system according to any one of claims 41A to 47A, wherein the first circuit flow path is adapted to provide a gas of a first gas composition and the at least one alternate flow path is adapted to provide gas of at least one alternate gas composition. 49A. A system according to any one of claims 41A to 48A, wherein the first circuit flow path is operatively connected to a first gas source and the respiratory gas delivery system simulates at least one gas flow characteristic of the first gas source selected from a maximum volume, a maximum rate of flow and the % composition or partial pressure of at least one gas in the second gas composition.

50A. A system according to any one of claims 41 A to 49A, wherein the at least one alternate nth circuit flow path of the reference breathing circuit is a second gas source and the respiratory gas delivery system simulates at least one gas flow characteristic of at least one second gas source selected from a maximum volume, a maximum rate of flow and the % composition or partial pressure of at least one gas in the second gas composition.

51A. A system according to any one of claims 41A to 50A, second gas source is a second gas reservoir adapted to receive a subject's exhaled gas.

52A. A system according to any one of claims 41A to 51A, the reference breathing circuit is adapted to deliver the subjects last expired gas from the immediately preceding breath first.

53A. A respiratory gas delivery system adapted to deliver a plurality of constituent gases comprising:

A. a gas delivery apparatus operatively connected to a processor;

B. a measurement device, optionally a flow sensor, adapted to monitor in real time a parameter correlated with a selected juncture in the inspiratory cycle, optionally the rate of inspiration of a gas; and optionally

C. an input device configured for obtaining input of at least of one subject specific parameter corresponding to or sufficient to determine a subject's minute ventilation;

wherein the processor is configured to:

(a) generate a control signal effective to signal the apparatus to output a first component gas of a first composition for a first portion of a plurality of respective inspiratory cycles [i]¹ to [i]ⁿ, optionally using input of the subject specific

parameter; (b) use output from the measurement device (optionally a flow sensor) to monitor in real time a selected juncture in the inspiratory cycle, optionally the rate of inspiration of the first gas during a first portion of a respective inspiratory cycle [i];

(c) generate a control signal effective to signal the apparatus to deliver a second component gas of a second composition corresponding to that of a neutral gas in a second portion of a respective inspiratory cycle [i];

(d) use output from the measurement device, optionally the flow sensor to signal the apparatus to deliver the first gas at a volume output or at a rate which is less than the subject's minute ventilation such that the apparatus is adapted to satisfy the subject's inspiratory requirement in cycles [ij'to [if by the first gas in a first portion of a respective inspiratory cycle [i] and by the second gas in a second portion of an inspiratory cycle [i].

54A. A system as claimed in claim 53A,wherein the entire volume of first gas delivered over the course of inspiratory cycles [i]¹to [if is less than the subject's minute volume minus anatomic dead space volume and wherein the entire volume of the first gas is organized to enter alveolar space of the subject.

55A. A system as claimed in any of the preceding claims, wherein the gas delivery apparatus is configured for use with a breathing circuit including a gas delivery portion, the gas delivery portion consisting essentially of a conduit operatively connected a patient airway interface, the gas delivery portion operatively connected to at least one measurement device selected from a flow sensor, a gas analyzer and a pressure transducer.

56A. A system as claimed in claim any of the preceding claims, wherein the processor is configured to simulate gas delivery from a first gas reservoir characterized in that:

(a) it is a reservoir for the first component gas;

(b) it is depleted in a first portion of a respective respiratory cycle at a rate which corresponds to the rate of inspiration of the first component gas as measured by the flow sensor;

(c) at least one of the parameter selected from parameters (i) and (ii) pertains to the first gas reservoir, as follows: (i) it is filled at a rate which is less than the patient's minute ventilation; (ii) it has a maximum volume capacity which is set to be less than the subject's tidal volume per breath minus the subject's anatomic dead space volume;

wherein the processor is configured to use at least one of an algorithmic and a mathematical model of replenishment (e.g. filling) and depletion of the first gas reservoir by delivering a gas of the first gas composition first and subsequently a gas of the second gas composition upon simulated depletion of the first gas reservoir.

57A. A respiratory gas delivery system adapted for use with a first breathing circuit having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes gas delivery characteristics of a reference respiratory gas delivery system that is adapted to be used in conjunction with a reference breathing circuit, the gas delivery characteristics of the reference respiratory gas system dictated at least in part by structural features, for example components such as tubing, valves and gas reservoirs, of the reference breathing circuit, the respiratory gas delivery system including:

a) a flow sensor, optionally positioned in or proximal to the patient airway

interface;

b) a gas delivery apparatus adapted to deliver a gas comprising a plurality of component or constituent gases into the patient airway interface, optionally into the gas conduit, the gas delivery apparatus controlled by an on-board computer, for example a microprocessor, or an external computer; and optionally

c) a gas analyzer, wherein the gas analyzer is optionally positioned in or

proximal to the patient airway interface;

wherein the computer is programmed to supplant structural features of the reference breathing circuit by using a mathematical model of the supplanted structural features to generate gas delivery characteristics that are functionally equivalent to those generated by the supplanted structural features, the supplanted structural features optionally defined by components of a sequential gas delivery circuit. 58A. A respiratory gas delivery system according to claim 57A, wherein the reference breathing circuit is a re-breathing circuit which organizes the delivery of a first component gas of selected first composition and a second component gas comprising exhaled gas and wherein the computer is programmed to deliver, for example by blending requisite constituent gases, a component gas of selected first composition and a component gas of second composition which matches that of an exhaled gas, optionally the subject's last exhaled end tidal gas.

59A. A respiratory gas delivery system according to claim 57A or 58A, wherein the reference breathing circuit is a sequential gas delivery circuit having a flow control system which alternately directs gas flow from: (a) a first circuit flow path organized to deliver a first gas component, optionally of selected volume; and (b) a second circuit flow path organized to deliver a second gas component; optionally, one or more structural components of the reference breathing circuit arresting flow from the first circuit flow path, for example a first valve, and subsequently initiating gas flow from the second circuit flow path, for example via a second valve, optionally in each inspiratory cycle; and wherein flow from the first and second flow paths is substituted in the respiratory gas delivery system by controlling the gas delivery apparatus to alternately deliver (e.g. by controlling flow of a blended gas or blending gases under computer control), optionally in a repeating cycle, optionally within each inspiratory cycle, a gas of first composition of the selected volume corresponding to the first gas component and a gas of second composition corresponding the second gas component.

60A. A respiratory gas system according to claim 59A, wherein the reference respiratory gas delivery system is adapted to deliver a component gas of first composition from a first circuit flow path leading from a first gas reservoir, and when the first gas reservoir is depleted, a component gas of second composition from a second circuit flow path, optionally an ambient air port or second gas reservoir and wherein the gas delivery apparatus is controlled in part by modelling filling and depletion of the first gas reservoir (the delivered composition and volume virtualizes filling and emptying of the first gas reservoir) to supplant the first gas reservoir, and wherein the first and second circuit flow path are optionally replaced with a common circuit flow path leading from the gas delivery apparatus to the patient airway interface which delivers a gas of first composition and a gas of second composition, optionally the gas delivery apparatus alternately, optionally in a repeating cycle, blending a volume of the gas of first composition and blending the gas of second composition which is available for the remainder of the breath (optionally, a pressure transducer repeatedly tracks the beginning and end of each inspiratory cycle).

61A. A respiratory gas system according to claim 57A, wherein the reference breathing circuit comprises a first and a second gas reservoir and wherein the first and second gas reservoirs are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first gas reservoir using a mathematical model of filling and depletion of the first gas reservoir by delivering a gas of the first composition corresponding to a full or selected partial volume of the first gas reservoir and subsequently a gas of the second composition upon simulated depletion of the gas of first composition in the first gas reservoir.

62A. A respiratory gas system according to claim 57A, wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation.

63A. A respiratory gas system according to any of preceding claims, including a gas analyzer wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is optionally less that the subject's minute ventilation minus anatomic dead space ventilation and wherein the gas of second composition corresponds to that of subject's exhaled gas from a breath n-1 as determined by the gas analyzer.

64A. A respiratory gas system according to any of the preceding claims, wherein the reference respiratory gas delivery system is adapted to be used in conjunction with a reference sequential gas delivery circuit including an inlet port into a first gas reservoir operatively connected to a gas blender for receiving a blended component gas of first composition from, and when the first reservoir is depleted, a component gas of second composition from a second gas reservoir containing a subject's end tidal exhaled gas , and wherein at least the first gas reservoir and second gas reservoir are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first and second gas reservoirs using a mathematical model of filling and depletion of the first gas reservoir by delivering a gas of the first composition first and subsequently a gas of the second composition upon simulated depletion of the first gas reservoir.

65A. A respiratory gas delivery system according to any of the preceding claims, wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation.

66A. A respiratory gas system according to any of the preceding claims, including a gas analyzer wherein the computer simulates filling of an inspiratory gas reservoir at a rate of flow that is less that the subject's minute ventilation minus anatomic dead space ventilation and wherein the gas of second composition corresponds to that of subject's exhaled gas from a breath n-1.

67A. A respiratory gas delivery system including or adapted for use with a first breathing circuit having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system is adapted to virtualize, for example, simulate the function, for example selected gas delivery characteristics, of a reference respiratory gas delivery system which includes or is adapted for use with a second, reference breathing circuit, that is structurally different (e.g. less wasteful of gas and/or less complex (e.g. fewer parts or parts more easy to assemble, integrate or coordinate) and/or less bulky, and/or less expensive and/or less prone to failure or physical limitations), the respiratory gas delivery system including:

a) a flow sensor, optionally positioned in or proximal to the patient airway

interface;

b) a gas delivery apparatus adapted to deliver a gas comprising a plurality of component or constituent gases into the patient airway interface, optionally into the gas conduit ( the gas delivery apparatus may include an on-board computer for controlling the gas delivery apparatus or may adapted to receive input from an external computer); and optionally

c) a gas analyzer, wherein the gas analyzer is optionally positioned in or

proximal to the patient airway interface; wherein control of the gas delivery apparatus simulates selected gas delivery characteristics of the reference gas respiratory gas delivery system that are defined at least in part by structural features, for example, structural parts of the reference breathing circuit and optionally define: (1) the source and/or order of delivery of one or more component gases; and/or (2) the composition and volume of the gas or a component or constituent of the gas made available for inspiration in a breath, series of breaths, breath segment or series of breath segments, or time period;

and wherein the computer is programmed provide inputs to the gas delivery apparatus to:

(1) control the gas delivery apparatus by executing an algorithm that employs as inputs data obtained from the flow sensor (and optionally the gas analyzer) and at least a mathematical model of at least a portion of the second, reference breathing circuit, including parameters that describe supplanted structural features e.g. structural parts of the second, reference breathing circuit, the supplanted features e.g. structural parts:

a. defining at least in part the selected gas delivery characteristics;

b. absent in the first breathing circuit; and

(2) generate an output signal to the gas delivery apparatus that simulates the supplanted structural features of the second, reference breathing circuit, such that when the respiratory gas delivery system outputs gas to the first breathing circuit the selected gas delivery characteristics of the respiratory gas delivery system simulate portions of the reference respiratory gas delivery system defined by the supplanted parts of the second reference breathing circuit.

68A. A respiratory gas system according to claim 67A, wherein the reference respiratory gas delivery system is adapted to deliver a component gas of first composition from a first gas reservoir, and when the first reservoir is depleted, a component gas of second composition from a second gas reservoir, and wherein at least the first gas reservoir and second gas reservoir are absent from the first breathing circuit and wherein the gas delivery apparatus is programmed to simulate gas delivery from the first and second gas reservoirs using a mathematical model of filling and depletion of the first gas reservoir by delivering a gas of the first composition first and subsequently a gas of the second composition upon simulated depletion of the first gas reservoir.

69A. A respiratory gas delivery system adapted for use with a first breathing circuit having at least one gas conduit leading to a patient airway interface, characterized in that the respiratory gas delivery system virtualizes structural components a reference breathing circuit, the respiratory gas delivery system including:

a) a flow sensor, positioned for at least determining the volume gas inhaled via the patient airway interface;

b) a gas delivery apparatus including or controlled by a computer for delivering a gas comprising a plurality of component or constituent gases into the patient airway interface;

wherein the computer is programmed to supplant one or more structural components of the reference breathing circuit by using a mathematical model of the structural component(s) to be supplanted to generate gas delivery characteristics that supplant it/them.

Claims Sets Relevant to Section C Inventions

1 B. An apparatus for controlling an amount of at least one gas X in a subject's lung to attain a series of targeted end tidal partial pressures of at least one gas X (PetX^T), the series of targeted end tidal partial pressures of at least one gas X (PetX^T) adapted to stimulate a physiological response comprising:

(1) a gas delivery device;

(2) a control system for controlling the gas delivery device, wherein the control system is adapted to target a series of PetX^T values for a series of respective intervals, the series of PetX^T values comprising at least one of a set of PetX^T increments and a set of PetX^T decrements, the control system including means for:

a. Obtaining input of a series of logistically attainable PetX^T values for the series of respective intervals; and

b. Determining an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval; c. Controlling the amount of gas X in a volume of gas delivered to the subject in a respective interval to target the respective PetX^T for the interval.

2B. An apparatus as claimed in claim 1 B, wherein at least one of the size and the number of intervals is selected to show a pattern of a physiological response to a series of increments or decrements in PetX^T.

3B. An apparatus as claimed in claim 2B, wherein the pattern of a physiological response is obtained for a range of the stimulus for at least a range of the physiological response of interest, and wherein the series of intervals are selected to satisfy a condition, the condition defined by attainment or predicted attainment of a minimum increment or decrement in a physiologic response to a increment or decrement in a subject's end tidal partial pressure of gas X.

4B. An apparatus as claimed in claim 1B, 2B or 3B, wherein each interval is a respective breath [i] and wherein the control system Is configured to obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in a respective breath [i] (CMVX|J]), wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation based on the prospective computation.

5B. An apparatus as claimed in any one of claims 1B, 2B and 3B, wherein the prospective computation relies on a tidal mode! of the lung.

6B- An apparatus as claimed in claim 3B, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [ij.

7B. An apparatus as claimed in claim 3B, wherein the respective PetX[i]^T for the series of breaths [i] increases every Nth breath in respective selected increments ("Z") from the start of the series to the end of the series (from PetX[i¹]^T to PetX[iⁿ]^T), wherein either N equals 1 and Z is greater than 0 in each breath in the series, or N is greater than 1 and Z may be zero in breaths which are not the Nth breath and Z is greater than 0 in every Nth breath.

8B. An apparatus as claimed in any of the preceding claims, where the physiologic response over the time course of the response is exponential, and wherein the rate of change in PetX^T is selected such that two time constants in the progress of the response are achieved before a next interval.

9B. An apparatus as claimed in any of the preceding claims, where the physiologic response over its time course is exponential, and wherein the rate of change in PetX^T is selected such that three time constants in the progress of the response are achieved before a next interval (e.g. the next increment or decrement in stimulus is given in the inspiratory cycle immediately after the response is attained or projected to be attained). 10B. An apparatus as claimed in any one of the preceding claims, wherein the control system is implemented by a computer, the computer preferably providing output signals to one or more rapid flow controllers.

11 B. An apparatus as claimed in any one of the preceding claims, wherein a

concentration of gas X (F|X) is computed to target or attain PetXpf in a respective breath [ij.

12B. An apparatus as claimed in any one of the preceding claims, wherein, the mass balance equation is solved for F|X.

13B. An apparatus as claimed in any one of the preceding claims, wherein a

determination of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval is made prospectively and wherein the wherein the gas delivery device is a sequential gas delivery device.

14B. An apparatus as claimed in any one of the preceding claims, wherein a

determination of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval is made prospectively and wherein the wherein the apparatus is connected to a sequential gas delivery circuit.

15B. An apparatus as claimed in any one of the preceding claims, wherein the computer receives input from a gas analyzer and an input device adapted for providing input of one or more logistically attainable target end tidal partial pressureof gas X (PetX[i]^T) for a series of respective breaths [i].

16B. An apparatus as claimed in any one of the preceding claims, wherein the control system, in each respective breath [i], controls the delivery of at least a first inspired gas and wherein delivery of the first inspired gas is coordinated with delivery a second inspired neutral gas, wherein a selected volume of the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired neutral gas for the remainder of the respective breath [i], wherein volume of the first inspired gas is fixed or selected for one or more sequential breaths by way of user input so that intake of the second inspired neutral gas at least fill the entirety of the anatomic dead space.

17B. An apparatus as claimed in claim 16B wherein the apparatus is connected to a sequential gas delivery circuit.

18B. An apparatus as claimed in any one of the preceding claims, wherein the gas delivery device is a gas blender.

19B. An apparatus as claimed in any one of the preceding claims, wherein the control system implements program code stored in a computer readable memory or comprises a signal processor embodied in one or more programmable IC chips.

20B. A computer program product for use in conjunction with a gas delivery device to control an amount of at least one gas X in a subject's lung to attain a series of target end tidal partial pressureof a gas X in the subject's lung, comprising program code for: a. Obtaining input of a series of logistically attainable end tidal partial pressureof gas X (PetX¹) for a respective interval;

b. Obtaining input of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective interval; and

c. Controlling the amount in a volume of gas delivered to the subject in a respective interval to target the respective PetX[i]^T based on the input; wherein at least one of the size and the number of intervals is selected to disclose a pattern of a physiologic response to the series of targeted end tidal partial pressures of the at least one gas X.

21 B. A computer program product as claimed in claim 20B, wherein a concentration of gas X (F|X) is computed to target or attain PetX[i]^T in a respective breath [i].

22B. A computer program product as claimed in claim 21 B, wherein F_fX is computed prospectively using a mass balance equation preferably solved for F|X, .

23B, An apparatus as claimed in any one of claims 1B to 19B, wherein X is C0_2.

24B. An apparatus as claimed in claim 23B, wherein a series of PetC0₂ targets provide a series of controlled vasoactive stimuli for measurement of vascular reactivity.

25B. An apparatus as claimed in any of the preceding claims, wherein the series of PetC0₂ targets provide at least one of the following:

e) a controlled vasoactive stimulus for measurement of cerebrovascular reactivity; f) a controlled vasoactive stimulus for measurement of liver, kidney, heart or eye vascular reactivity; or

g) a simultaneous change the subject's end tidal partial pressuresof oxygen and carbon dioxide to selected values, for example to potentiate a diagnosis or treat cancer; and

h) a controlled vasoactive stimulus for diagnosing steno-occlusive-disease.

26B. A method for controlling an amount of at least one gas X in a subject's lung to attain a series of targeted end tidal partial pressures of at least one gas X (PetX^T), the method comprising:

a. Obtaining input of a series of logistically attainable PetX^T values for a series of respective intervals comprising at least one of a set of PetX^T increments and set of PetX^T decrements; and

b. Determining an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^Tfor a respective interval; c. Controlling a gas delivery device to deliver the amount of gas X in a volume of gas delivered to the subject in a respective interval to target the respective PetX^T for the interval.

wherein at least one of the size and the number of intervals is selected to disclose a pattern of a physiologic response to the series of targeted end tidal partial pressures of the at least one gas X.

27B. A method as claimed in claim 26B, wherein each interval is a respective breath [i] and wherein the control system is configured for obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in a respective breath [i] (CMVX[I^'])₍ wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation based on the prospective computation.

28B. A method as claimed in claim 27B, wherein the prospective computation relies on a tidal model of the lung.

29B. A method claimed in claim 28B, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

30B. A method as claimed in claim 27B, wherein the respective PetX[i]^T for the series of breaths [i] increases every Nth breath in respective selected increments ("Z") from the start of the series to the end of the series (from PetX[i¹]^T to PetX[iⁿ]^T), wherein either N equals 1 and 2 is greater than 0 in each breath in the series, or N is greater than 1 and Z may be zero in breaths which are not the Nth breath and Z is greater than 0 in every Nth breath.

31 B. A method as claimed in any of claims 26B to 30B, wherein the physiologic response over the time course of the is exponential, and wherein the rate of change in PetX^T is selected such that two time constants in the progress of the response are achieved before a next interval.

32B- A method as claimed in any of claims 26B to 30B, wherein the physiologic response over the time course of the response is exponential, and wherein the rate of change in PetX^T is selected such that three time constants in the progress of the response are achieved before a next interval (e.g. the next increment or decrement in stimulus is given in the inspiratory cycle immediately after the response is attained or projected to be attained).

33B. A method as claimed in any one claims 26B to 32B, wherein the control system is implemented by a computer, the computer preferably providing output signals to one or more rapid flow controllers.

34B. A method as claimed in any one claim 26B to 33B, wherein a concentration of gas X (F|X) is computed to target or attain PetX[i]^T in a respective breath [i].

35B. A method as claimed in any one of claims 26B to 34B, wherein, the mass balance equation is solved for FiX.

36B. A method as claimed in any one of claims 26B to 35B, wherein a determination of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval is prospectively made and wherein the wherein the gas delivery device is a sequential gas delivery device.

37B. A method as claimed in any one of claims 26B to 36B, wherein a determination of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX^T for a respective interval is prospectively made and wherein the wherein the apparatus is connected to a sequential gas delivery circuit.

38B. A method as claimed in any one of claims 26B to 37B, wherein the computer receives input from a gas analyzer and an input device adapted for providing input of one or more logistically attainable target end tidal partial pressureof gas X (PetX[i]^T) for a series of respective breaths [i]. 39B. A method as claimed in any one of claims 26B to 38B, wherein the control system, in each respective breath [i], controls the delivery of at least a first inspired gas and wherein delivery of the first inspired gas is coordinated with delivery a second inspired neutral gas, wherein a selected volume of the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired neutral gas for the remainder of the respective breath [i], wherein volume of the first inspired gas is fixed or selected for one or more sequential breaths by way of user input so that intake of the second inspired neutral gas at least fill the entirety of the anatomic dead space.

40B. A method as claimed in any one of claims 26B to 39B, wherein the gas delivery device is a gas blender.

41 B. A method as claimed in any one of claims 26B to 40B, wherein the control system implements program code stored in a computer readable memory or comprises a signal processor embodied in one or more programmable IC chips.

42B. An apparatus as claimed in any one of claims 1B to 19B, wherein X is C0₂.

43B. A method as claimed in claim 42B, wherein a series of PetC0₂ targets provide a series of controlled vasoactive stimuli for measurement of vascular reactivity.

44B. A method as claimed in claim 42B, wherein the series of PetC0₂ targets provide at least one of the following:

a) a controlled vasoactive stimulus for measurement of cerebrovascular reactivity; b) a controlled vasoactive stimulus for measurement of liver, kidney, heart or eye vascular reactivity; or

c) a simultaneous change the subject's end tidal partial pressuresof oxygen and carbon dioxide to selected values, for example to potentiate a diagnosis or treat cancer; and d) a controlled vasoactive stimulus for diagnosing steno-occlusive-disease.

45B. A method of controlling a gas delivery device to target or attain a target end tidal partial pressureof gas X in a subject, wherein a signal processor operatively associated with (e.g. via one or more flow controllers) a gas delivery device controls the amount of gas X contained in a volume of inspiratory gas delivered to a subject in a respective breath [i], using inputs and outputs processed by the signal processor for a respective breath [i], the method comprising:

(a) Obtaining input of one or more values sufficient to compute the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C_MvX[i]);

(b) Obtaining input of a logistically attainable end tidal partial pressureof gas X (Pe†X[i]^T) for a respective breath [i];

(c) Utilizing a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject to target the PetX[i]^T for a respective breath [i] (in the "inspired gas" in a respective breath [i]), the prospective computation using inputs sufficient to compute a mass balance equation for a respective breath [i], the inputs including values , for a respective breath [i], from which CMVXIJ] and the concentration of gas X in the subject's lung affecting mass transfer can be determined, wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Outputting control signals to the gas delivery device (e.g. the flow controller(s)) to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

46B. A method according to claim 45B, wherein the mass balance equation is formulated in terms of discrete respective breaths [i] taking into account one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i]. 47B. A method according to claim 45B or 46B, wherein the inspired gas comprises a first inspired gas and a second inspired gas, wherein the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired gas for the remainder of the respective breath [i], the volume of the first inspired gas preferably selected so that intake of the second inspired gas at least fills the entirety of the anatomic dead space.

48B. A method according to any of the preceding claims, comprising tuning one or more parameters required for computation of FjX.

49B. A method according to claim 1B or 45B, wherein a target end tidal concentration of gas X and a target end tidal concentration of a gas Y are selected for a respective breath [i], and wherein F|X and F|Y are determined using a mass balance equation comprising all or a functional subset of the terms in equation 1 or 2, independently of each other, and, if present, independently of the concentration of any other component Z of the inspiratory gas.

50B. A method according to claim 1B or 45B, wherein one or more diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is/are not logistically attainable in one breath and wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is obtained in a predetermined number of breaths greater than 1.

51 B. A method according to any of the preceding claims, wherein a selected PetX[i]^T is re-targeted repeatedly for a series of tuning breaths and wherein a measured steady state value for an end tidal concentration of gas X is used to compute F|X for a first breath in the series of tuning breaths.

52B. A method according to any of the preceding claims, wherein gas X is carbon dioxide.

53B. A method according to any of the preceding claims, wherein gas X is oxygen.

54B. An apparatus for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising:

(1) a gas delivery device;

(2) a control system for controlling the gas delivery device including means for: (a) Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVX[G);

(b) Obtaining input of a logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

(c) Obtaining input of a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX.I., wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Controlling the amount of gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation

55B. An apparatus according to claim 54B, wherein the mass balance equation is computed based on a tidal model of the lung.

56B. An apparatus according to claim 54B, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes comprising or corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i].

57B. An apparatus according to claim 54B to 56B, wherein the inspired gas comprises a first inspired gas and a second inspired gas, wherein the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired gas for the remainder of the respective breath [i], the volume of the first inspired gas selected so that intake of the second inspired gas at least fills the entirety of the anatomic dead space; and wherein, optionally, for a respective breath [i], the volume of the first inspired gas and the concentration of gas X in the second inspired gas are selected to attain PetX[i]^T; and wherein, optionally, for a respective breath [i], the concentration of gas X in the second inspired gas corresponds to PetX[i]^T for a respective breath [i]. 58B. An apparatus according to claim 54B, wherein a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [i].

59B. An apparatus according to claim 54B, wherein the mass balance equation is solved for F|X.

60B. An apparatus or method according to any of the preceding claims, comprising the step of obtaining inputs required to compute an F|X to target PetX[i]^T for a respective breath [i], wherein F|X is computed prospectively using a mass balance equation which comprises terms corresponding to all or an application-specific subset of the terms in:

eq. 1

or

61 B. An apparatus according any of the preceding claims, wherein the control system is implemented by a computer, the computer optionally providing output signals to one or more rapid flow controllers.

62B. An apparatus according to claim 61 B, wherein the computer receives input from a gas analyzer and an input device adapted for providing input of one or more logistically attainable target end tidal concentration of gas X (PetX[i]^T) for a series of respective breaths [i], optionally wherein the control system, in each respective breath [i], controls the delivery of at least a first inspired gas and wherein delivery of the first inspired gas is coordinated with delivery a second inspired neutral gas, wherein a selected volume of the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired neutral gas for the remainder of the respective breath [i], wherein the volume of the first inspired gas is standardized for a series of breaths [i...i+η], and/or selected for a respective breath [i] to target or attain PetX[i]^T, optionally by way of ongoing user input spanning one or breaths [i], and wherein intake of the second inspired neutral gas at least fill the entirety of the anatomic dead space; wherein F|X is computed using equation 1 , optionally wherein the control system requires input of the volume of inspired gas entering the subject's alveoli, and wherein said volume if computed by fixing a tidal volume of an inspired gas containing gas X using a ventilator and subtracting a volume of gas corresponding to an estimated or measured value for the subject's anatomic dead space volume.

63B. An apparatus according to any of the preceding claims, wherein said computer is programmed to tune or receive inputs for tuning one or more parameters required for computation of F|X.

64B. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of vascular reactivity.

65B. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of cerebrovascular reactivity. 66B. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of liver, kidney, heart or eye vascular reactivity.

67B. The use of a method or apparatus according to any of the preceding claims, to simultaneously change the subject's end tidal concentrations of oxygen and carbon dioxide to selected values.

68B. The use of a method or apparatus according to claim 67B, to treat cancer.

69B. A method or apparatus according to any of the preceding claims, wherein the mass balance equation optionally does not account for re-inspiration in a respective breath [ij of a mass of gas X left in the subject's dead space volume after exhalation in a previous breath

70B. A method or apparatus according to any of the preceding claims, wherein the mass balance equation (optionally written in terms of one or more concentration of gas X in one or more discrete volumes of gas):

(a) Preferably accounts for the total amount of gas X in the lung following inhalation of the inspired gas in a respective breath [ij (M_LX[i]) including transfer of gas X between the lung and the pulmonary circulation; (b) Assumes distribution of M_LX[i] into compartments including the subject's FRC (MLXDJFRC). a fixed or spontaneously inspired tidal volume (Μι.Χ[ί]ντ) and preferably the subject's anatomic dead space volume (MLX[I]VD);

(c) Assumes uniform distribution of the _LX[i]FRc a and Μι_Χ[ϊ]ντ in the cumulative volume FRC+V_T;

(d) Preferably includes a term that accounts for re-inspiration in a respective breath [i] of an amount of gas X left in the dead space volume after exhalation in a previous breath [i-1].

71 B. A method or apparatus according to any of the preceding claims, wherein the concentration of gas X in the second inspired gas corresponds to PetX[i]^T for a respective breath [i].

72B. A programmable IC chip for use in conjunction with a gas delivery device for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising program code for:

(a) Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CM X[i]);

(b) Obtaining input of a series of logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

(c) Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX.^'I], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation. A method of controlling a gas delivery device to control an amount of at least one gas X in a subject's lung, the method adapted to target one or more end tidal partial pressuresof the at least one gas X, the method comprising:

73B. The use of a signal processor operatively associated with a gas delivery device to control the amount of gas X contained in one or more respective volumes of gas delivered to a subject in one or more respective breaths [i] using inputs processed by the signal processor for respective breaths [i], wherein the signal processor: (a) Processes input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVXW);

(b) Processes input of a logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

(c) Uses a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMVX[I], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Outputs control signals to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

74B. A use according to claim 70B, wherein gas delivery device is a gas blender comprising one or more flow controllers, a respective flow controller operatively associated with a respective gas source of differing percentage composition of gas X ranging from 0-100%, wherein the signal processor outputs control signals to at least one flow controller to control the amount of gas X in a volume of gas delivered to the subject.

75B. A use according to claim 70B, wherein the signal processor controls the amount of carbon dioxide and oxygen in each respective breath [i] to target a logistically attainable end tidal partial pressure of carbon dioxide and a logistically attainable end tidal partial pressure of oxygen for a respective breath [i].

76B. A method, apparatus or use according to any of the preceding claims wherein any one of the features described in any of claims 1B to 75B, are individually, or in any combination, implemented in the method.

77B. A gas delivery device comprising one or more flow controllers for controlling the end tidal partial pressure of a gas X in a subject, wherein a signal processor operatively associated with the flow controller(s): (a) Obtains input of one or more values sufficient to compute the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMWXPD;

(b) Obtains input of a logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

(c) Uses a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject to target the PetX[i]^T for a respective breath [i], the prospective computation using inputs sufficient to compute a mass balance equation for a respective breath [i], the inputs including values, for a respective breath [i], from which C_MVX[i] and the concentration of gas X in the subject's lung affecting mass transfer can be determined, for example C_MvX[ij and the concentration or partial pressure of gas X in the subject's lung as a result of inspiration in a breath [i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Outputting control signals to the flow controller(s) to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

78B. A gas delivery device according to claim 76B, wherein any one of the features described in any of claims 2B to 76B, are individually, or in any plausible combination, implemented using signals input to or output by the signal processor.

79B. A method of controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising the steps of:

a. Obtaining input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C_MvX[i]);

b. Obtaining input of a logistically attainable end tidal partial pressureof gas X (PetX[i^']^T) for a respective breath [i]; c. Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C_MvX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

d. Controlling the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

1C. A method of controlling a gas delivery device to target or attain a target end tidal partial pressureof gas X in a subject, wherein a signal processor operatively associated with (e.g. via one or more flow controllers) a gas delivery device controls the amount of gas X contained in a volume of inspiratory gas delivered to a subject in a respective breath [i], using inputs and outputs processed by the signal processor for a respective breath [i], the method comprising:

(a) Obtaining input of one or more values sufficient to compute the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVX[I^']);

(c) Utilizing a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject to target the PetX[i]^T for a respective breath [i] (in the "inspired gas" in a respective breath [i]), the prospective computation using inputs sufficient to compute a mass balance equation for a respective breath [i], the inputs including values , for a respective breath [i], from which C_MVX[i] and the concentration of gas X in the subject's lung affecting mass transfer can be determined, wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and (d) Outputting control signals to the gas delivery device (e.g. the flow controller(s)) to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation,

2C. A method according to claim 1C, whereinthe mass balance equation is formulatedin terms of discrete respective breaths [i] taking into account one or more discrete volumes corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i],

3C. A method according to claim 1C or 2C, wherein the inspired gas comprises a first inspired gas and a second inspired gas, wherein the first inspired gas is delivered in the first part of a respective breath [i] followed by the second inspired gas for the remainder of the respective breath [i], the volume of the first inspired gas preferably selected so that intake of the second inspired gas at least fills the entirety of the anatomic dead space.

4C. A method according to claim 1C or 2C, wherein a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [i].

5C. A method according to claim 1C or 2C where, the mass balance equation is solved for F|X.

6c . A method according to claim 1C or 2C, comprising the step of obtaining inputs required to compute F|X to target PetX[i]^T for a respective breath [i], wherein F,X is computed prospectively using a mass balance equation which comprises terms corresponding to all or an application-specific subset of the terms in:

or

A method according to claim 6C, wherein F|X is computed prospectively from a balance equation expressed in terms which correspond to all or an application- specific subset of the terms in equation 1 and the first inspired gas has a concentration of gas X which corresponds to F|X for the respective breath [i].

8C. A method according to claim 1C, wherein the gas inspired by the subject in each respective breath [i] comprises a first inspired gas and a second inspired neutral gas, wherein the first inspired gas is delivered in the first part of a respective breath [i] followed by a second inspired neutral gas for the remainder of the respective breath [i], the volume of the first inspired gas selected so that intake of the second inspired neutral gas at least fills the entirety of the anatomic dead space; wherein F|X is computed prospectively using a mass balance equation which comprises all or a functional subset of the terms in equation 1 and wherein the first inspired gas has a concentration of gas X which corresponds to F|X for the respective breath [i].

9C. A method according to any of claims 1C to 4C, comprising ascertaining the volume of inspired gas entering the subject's alveoli by fixing a tidal volume of an inspired gas containing gas X using a ventilator and subtracting a volume of gas corresponding to an estimated or measured value for the subject's anatomic dead space volume.

10C. A method according to any of the preceding claims, wherein the gas inspired by the subject is inspired via a sequential gas delivery circuit; and wherein the rate of flow of gas into the sequential gas delivery circuit is optionally used to compute the volume of inspired gas entering the subject's alveoli in a respective breath [i].

11 C. A method according to any of the preceding claims, comprising tuning one or more parameters required for computation of F|X.

12C. A method according to claim 11C, wherein an estimated or measured value for the subject's functional residual capacity (FRC) is tuned.

13C. A method according to any of claims 1C, 11C or 12C, comprising tuning an estimated or measured value of the subject's total metabolic production or consumption of gas X.

14C. A method according to claim 11C or 13C, wherein FRC is tuned in a series of tuning breaths by:

(a) changing the targeted end tidal concentration of gas X between a tuning breath [i+x] and a previous tuning breath [i +x -1]; (b) comparing the magnitude of the difference between the targeted end tidal concentration of gas X for said tuning breaths [i+x] and [i+x-1]with the magnitude of the difference between the measured end tidal concentration of gas X for the same tuning breaths to quantify any discrepancy in relative magnitude; and

(c) adjusting the value of FRC in proportion to the discrepancy to reduce the discrepancy in any subsequent prospective computation of F|X.

15C. A method according to claim 11C or 12C, wherein the total metabolic production or consumption of gas X is tuned in a series of tuning breaths by comparing a targeted end tidal concentration of gas X (PetX[i+x]^T) for the at least one tuning breath [i+x] with a corresponding measured end tidal concentration of gas X for the corresponding breath [i+x] to quantify any discrepancy and adjusting the value of the total metabolic production or consumption of gas X in proportion to any discrepancy to reduce the discrepancy in any subsequent prospective computation of F[X.

16C. A method according to claim 11C or 13C, wherein FRC is tuned in a series of tuning breaths in which a sequence of end tidal concentrations of gas X is targeted at least once by:

(b) selecting a target end tidal concentration of gas X (PetX[i]^T) for at least one tuning breath [i+x] wherein PetX[i+x]^T differs from PetX[i+x-1]^T; and

(c) comparing the magnitude of the difference between the targeted end tidal concentration of gas X for said tuning breaths [i+x] and [i+x-1] with the magnitude of the difference between the measured end tidal concentration of gas X for the same tuning breaths to quantify any discrepancy in relative magnitude;

(d) adjusting the value of FRC in proportion to any discrepancy in magnitude to reduce the discrepancy in a subsequent prospective computation of F[X including in any subsequent corresponding tuning breaths[i+x-1] and [i+x] forming part of an iteration of the sequence. 17C. A method according to claim 11C or 12C, wherein the total metabolic consumption or production of gas X is tuned in a series of tuning breaths in which a sequence of end tidal concentrations of gas X is targeted at least once by:

(a) obtaining input of a measured baseline steady state value for PetX{i] for computing F|X at start of a sequence;

(b) targeting a selected target end tidal concentration of gas X (PetX[i]^T) for each of a series of tuning breaths [i+1...i+n], wherein PetX[i]^T differs from the baseline steady state value for PetX[i];

(c) comparing the targeted end tidal concentration of gas X (PetX[i+x]^T) for at least one tuning breath [i+x] in which the targeted end tidal gas concentration of gas X has been achieved without drift in a plurality of prior breaths [1+x-1, 1+x- 2...] with a corresponding measured end tidal concentration of gas X for a corresponding breath [i+xj to quantify any discrepancy and adjusting the value of the total metabolic consumption or production of gas X in proportion to the discrepancy to reduce the discrepancy in a subsequent prospective computation of F|X including in any subsequent corresponding tuning breath [i+x] forming part of an iteration of the sequence.

18C. A method according to any of the preceding claims, wherein input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in a respective breath [i] (CiwX[i]) is determined by a compartmental model of gas dynamics.

19C- A method according to any of the preceding claims, wherein the compartmental model of gas dynamics accounts for the total and compartmental metabolic production or consumption of gas X, the total and compartmental storage capacity for gas X and the total cardiac output and compartmental contribution to total cardiac output.

20C. A method according to claim 18C, wherein the compartmental model is a one compartment model.

21 C. A method according to any of the preceding claims, wherein the compartmental model is a five compartment model.

22C. A method according to any of claims 1C to 21 C, wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X is not logistically attainable in one breath and wherein the diagnostically or therapeutically relevant target end tidal concentration of gas X is obtained in a predetermined number of breaths greater than 1.

23C. A method according to claim 1C, wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X is not logistically attainable in one breath and wherein the diagnostically or therapeutically relevant target end tidal concentration of gas X is obtained in a logistically minimized number of breaths of predetermined number greater than 1.

24C. A method according to claim 1C, wherein a target end tidal concentration of gas X and a target end tidal concentration of a gas Y are selected for a respective breath [i], and wherein F|X and F|Y are determined using a mass balance equation comprising all or a functional subset of the terms in equation 1 or 2, independently of each other, and, if present, independently of the concentration of any other component Z of the inspiratory gas.

25C. A method according to claim 1C, wherein one or more diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is/are not logistically attainable in one breath and wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is obtained in a predetermined number of breaths greater than 1.

26C. A method according to claim 1C, wherein one or more diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is not logistically attainable in one breath and wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is obtained in a logistically minimized number of breaths of predetermined number greater than 1.

27C. A method according to claim 1C, wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X is logistically attainable in one breath and wherein the diagnostically or therapeutically relevant target end tidal concentration of gas X is obtained in a number of breaths greater than 1.

28C. A method according to claim 1C, wherein one or more diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is/are logistically attainable in one breath and wherein a diagnostically or therapeutically relevant target end tidal concentration of gas X and/or gas Y is obtained in a number of breaths greater than 1.

29C. A method according to any of the preceding claims, wherein a selected PetX[i]^T is re-targeted repeatedly for a series of tuning breaths and wherein a measured steady state value for an end tidal concentration of gas X is used to compute F|X for a first breath in the series of tuning breaths.

30C. A method according to any of the preceding claims, wherein gas X is carbon dioxide.

31C. method according to any of the preceding claims, wherein gas X is oxygen.

32C. A method according to any of the preceding claims, wherein gas X is an anesthetic gas optionally isoflurane.

33C. An apparatus for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising:

(1) agas delivery device;

(2) a control system for controlling the gas delivery device including means for:

(a) Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMVX['J);

(c) Obtaining input of a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C_MvX[i], wherein one or more values required to control the amount of gas X in the volume of gas delivered to the subject is output from the mass balance equation; and

(d) Controlling the amount of gas X in the volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[iJ^T based on the prospective computation

34C. An apparatus according to claim 33C, wherein the mass balance equation is computed based on a tidal model of the lung. 35C. An apparatus according to claim 33C, wherein the mass balance equation is computed in terms of discrete respective breaths [i] including one or more discrete volumes comprising or corresponding to a subject's FRC, anatomic dead space, a volume of gas transferred between the subject's lung and pulmonary circulation in the respective breath [i] and an individual tidal volume of the respective breath [i],

36C. An apparatus according to claim 33C or 35C, wherein the inspired gas comprises a first inspired gas and a second inspired gas, wherein the first inspired gas is delivered in a first part of a respective breath [i] followed by the second inspired gas for aremainder of the respective breath [i], avolume of the first inspired gas selected so that intake of the second inspired gas at least fills the entirety of the anatomic dead space; and wherein, optionally, for a respective breath [i], the volume of the first inspired gas and aconcentration of gas X in the second inspired gas are selected to attain PetX[i]^T; and wherein, optionally, for a respective breath [i], the concentration of gas X in the second inspired gas corresponds to PetX[i]^T for a respective breath [i].

37C. An apparatus according to claim 36C, wherein a concentration of gas X (F|X) in the first inspired gas is computed from the mass balance equation to target or attain a PetX[i]^T in a respective breath [i].

38C. An apparatus according to claim 37C, wherein the mass balance equation is solved for F|X.

39C. An apparatus according to any of claims 33C to 38C, comprising the step of obtaining inputs required to compute an F_tX to target PetX[i]^T for a respective breath [i], wherein F|X is computed prospectively using a mass balance equation which comprises terms corresponding to all or an application-specific subset of the terms in:

F_{iX ]} ______ _ eq. 1

or

Fx i]- ^PetX^^T ·&χε^{+ ν}τ)- _σχ[^ί-ιΥ iFRC+v_D)-PB-Q. (\-s).T_s .(c^ ]-c, 1)

' ^l?J~ (V_T -V_D)-P3

eq. 2

40C. An apparatus according to claim 33C, wherein the gas delivery device is a sequential gas delivery device. 41 C. An apparatus according to any one of claims 33C to 39C, wherein the control system is implemented by a computer.

42C. An apparatus according to claim 41 C, wherein the computer provides output signals to one or more rapid flow controllers.

43C. An apparatus according to claim 41 C or 42C, wherein the computer receives input from a gas analyzer and an input device adapted for providing input of one or more logistically attainable target end tidal concentration of gas X (PetX[i]^T) for a series of respective breaths [i].

44C. An apparatus according to claim 39C, wherein the control system, in each respective breath [i], controls the delivery of at least a first inspired gas and wherein delivery of the first inspired gas is coordinated with delivery a second inspired neutral gas, wherein a selected volume of the first inspired gas is delivered in afirst part of a respective breath [i] followed by the second inspired neutral gas for aremainder of the respective breath [i], wherein the volume of the first inspired gas is standardized for a series of breaths [i...i+n], and/or selected for a respective breath [i] to target or attain PetX[i]^T, optionally by way of ongoing user input spanning one or breaths p], and wherein intake of the second inspired neutral gas at least fill the entirety of the anatomic dead space; wherein F|X is computed using equation 1.

45C. An apparatus according to claim 33C, wherein the control system requires input of a volume of inspired gas entering the subject's alveoli, and wherein said volume if computed by fixing a tidal volume of an inspired gas containing gas X using a ventilator and subtracting a volume of gas corresponding to an estimated or measured value for the subject's anatomic dead space volume.

46C. An apparatus according to any of claims 33C to 45C, wherein the apparatus is connected to a sequential gas delivery circuit.

47C. An apparatus according to claim 46C, wherein the control system requires user input of a rate of flow of gas into the sequential gas delivery circuit and wherein said rate is used to compute the volume of inspired gas entering the subject's alveoli in a respective breath [i]. 48C- An apparatus according to claim 41 C, wherein said computer is programmed to tune or receive inputs for tuning one or more parameters required for computation of F,X.

49C. An apparatus according to claim 33C or 48C, wherein an estimated or measured value for asubject's FRC is tuned.

50C. An apparatus according to any one of claims 4BC or 49C, wherein said computer is programmed to tune an estimated or measured value of a subject's total metabolic production or consumption of gas X is tuned.

51 C. An apparatus according to any of claims 49C or 50C, wherein said computer is programmed to tune FRC in a series of tuning breaths by: a. computing or obtaining user input of a change in the targeted end tidal partial pressure of gas X between a tuning breath [i+x] and a previous tuning breath [i +x -11;

b. computing or obtaining user input of a comparison between the magnitude of the difference between the targeted end tidal partial pressure of gas X for said tuning breaths [i+x] and [i+x-1] with the magnitude of the difference between the measured end tidal partial pressure of gas X for the same breaths to quantify any discrepancy in relative magnitude; and c. computing or obtaining user input of an adjusted value of FRC in proportion to the discrepancy to reduce the discrepancy in any subsequent prospective computation of F|X.

52C. An apparatus according to any one of claims 48C to 51 C, wherein an estimated or measured value of total metabolic production or consumption of gas X is tuned in a series of tuning breaths by comparing a targeted end tidal partial pressureof gas X (PetXfi+x]¹^ for the at least one tuning breath [i+x] with a corresponding measured end tidal partial pressureof gas X for the corresponding breath [i+x] to quantify any discrepancy and adjusting the value of the total metabolic production or consumption of gas X in proportion to the discrepancy to reduce the discrepancy in any subsequent prospective computation of F|X. 53C- An apparatus according to claim 48C, wherein FRC is tuned in a series of tuning breaths in which a sequence of end tidal concentrations of gas X is targeted at least once by:

(b) selecting a target end tidal partial pressure of gas X (PetX[i]^T) for at least one tuning breath [i+x] wherein PetX[i+x]^T differs from PetX[i+x 1];

(c) comparing the magnitude of the difference between the targeted end tidal partial pressure of gas X for said tuning breaths [i+x] and [i+x-1] with the magnitude of the difference between the measured end tidal partial pressure of gas X for the same breaths to quantify any discrepancy in relative magnitude;

(d) adjusting the value of FRC in proportion to the discrepancy in magnitude to reduce the discrepancy in a subsequent prospective computation of F|X including in any subsequent corresponding tuning breaths[i+x-1] and [i+x] forming part of an iteration of the sequence.

54C. An apparatus according to claim 48C, 50C or 53C, wherein an estimated or measured value of the total metabolic consumption or production of gas X is tuned in a series of tuning breaths in which a sequence of end tidal partial pressure of gas X is targeted at least once by:

(b) targeting a selected target end tidal partial pressure of gas X (PetX[i]^T) for each of a series of tuning breaths [i+1...i+n], wherein PetX[i]^T differs from the baseline steady state value for PetXfl];

(c) comparing the targeted end tidal partial pressure of gas X (PetXfi+x]^"0 for at least one tuning breath [i+x] in which the targeted end tidal gas concentration of gas X has been achieved without drift in a plurality of prior breaths [1 +x-1 , 1+x- 2...] with a corresponding measured end tidal partial pressure of gas X for a corresponding breath [i+x] to quantify any discrepancy and adjusting the value of the total metabolic consumption or production of gas X in proportion to the discrepancy to reduce the discrepancy in a subsequent prospective computation of F| including in any subsequent corresponding tuning breath [i+x] forming part of an iteration of the sequence.

55C. An apparatus according any of the preceding claims, wherein the control system is adapted to compute the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in a respective breath [i] (C vX[i]), wherein CMVXM) is determined by a compartmental model of gas dynamics.

56C. An apparatus according to claim 55C, wherein the compartmental model of gas dynamics accounts for a total and compartmental metabolic production or consumption of gas X, a total and compartmental storage capacity for gas X and a total cardiac output and compartmental contribution to total cardiac output.

57C. An apparatus according to claim 56C, wherein the compartmental model is a one compartment model.

58C. An apparatus according to claim 56C, wherein the compartmental model is a five compartment model.

59C. An apparatus according to claim 33C, wherein a computer provides output signals to one or more rapid flow controllers.

60C. An apparatus according to claim 33C, wherein a computer receives input from a gas analyzer, and an input device adapted for providing input of one or more logistically attainable target end tidal concentration of gas X (PetX[i]^T) for a series of respective breaths [i]; and optionally input from a pressure transducer and/or a flow transducer. 61 C. An apparatus according to claim 39C, wherein the means for:

(a) obtaining input of a logistically attainable target end tidal concentration of gas X (PetX[i]^T) for one or more ensuing respective breaths [i];

(b) obtaining input of a concentration of gas X (CMVX[I]) in the mixed venous blood entering the subject's lung for gas exchange in a respective breath [i]; and

(c) prospectively computing F|X using equation 1 or 2;

is program code stored in a computer readable memory or is a signal processor embodied in one or more programmable IC chips.

62C. An apparatus according to claim 61 C, wherein the program code is embodied in a computer program product. 63C. An apparatus according to any one of ciaims 33C to 62C, wherein the gas delivery device is a gas blender.

64C. An apparatus according to claim 41 C, wherein the computer is programmed to target one or more target end tidal concentrations of oxygen, carbon dioxide and/or anesthetic.

65C. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of vascular reactivity, 66C. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of cerebrovascular reactivity. 67C. The use of a method or apparatus according to any of the preceding claims to provide a controlled vasoactive stimulus for measurement of liver, kidney, heart or eye vascular reactivity.

68C. The use of a method or apparatus according to any of the preceding claims, to simultaneously change the subject's end tidal concentrations of oxygen and carbon dioxide to selected values.

69C. The use of a method or apparatus according to claim 68C, to treat cancer.

70C. A method according to any of claims 1C to 32C, wherein the mass balance equation optionally does not account for re-inspiration in a respective breath [i] of a mass of gas X left in the subject's dead space volume after exhalation in a previous breath [i-1].

71 C. A method according to any one of claims 1C to 32C, wherein the mass balance equation (optionally written in terms of one or more concentration of gas X in one or more discrete volumes of gas);

(a) Preferably accounts for the total amount of gas X in the lung following inhalation of the inspired gas in a respective breath [i] ( [ X[i]) including transfer of gas X between the lung and the pulmonary circulation;

(b) Assumes distribution of M_LX[i] into compartments including the subject's FRC ( LX[I]FRC)_I a fixed or spontaneously inspired tidal volume (Μ|_Χ[ι^"]ντ) and preferably the subject's anatomic dead space volume (M_LX|1]VD);

(c) Assumes uniform distribution of the MiJX[i]FRc a and M_LX[i]vT in the cumulative volume FRC+V_T; (d) Preferably includes a term that accounts for re-inspiration in a respective breath [i] of an amount of gas X left in the dead space volume after exhalation in a previous breath [i-1].

72C. A method according to any one of claims 3C to 32C or 70C to 71 C, the concentration of gas X in the second inspired gas corresponds to PetX[i]^T for a respective breath [i].

73C. A method any one of claims 3C to 32C or 70C to 72C, wherein for a respective breath [i], the volume of the first inspired gas and the concentration of gas X in the second inspired gas are selected to attain PetX[i]^T.

74C. An apparatus according to any of claims 36C, the concentration of gas X in the second inspired gas corresponds to PetX[i]^T for a respective breath [i].

75C. An apparatus according to claim 36C or 74C, wherein for a respective breath [i], the volume of the first inspired gas and the concentration of gas X in the second inspired gas are selected to attain PetX[i]^T.

76C. A computer program product for use in conjunction with a gas delivery device for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising program code for:

(a) Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C VX.I]);

(c) Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including C_MVX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

77C. A computer program product according to claim 76C, comprising program code for implementing a method as defined in any of claims 2C to 32C. 78C. A computer program product according to claim 76C, comprising program code for controlling an apparatus as defined in any of the preceding claims.

79C. A programmable IC chip for use in conjunction with a gas delivery device for controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressure of the at least one gas X, comprising program code for:

(a) Obtaining input of a concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (CMV P]);

(c) Obtaining input of a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[iJ^T for a respective breath [i] using inputs required to compute a mass balance equation including CM XII], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

80C. A programmable IC chip according to claim 79C, comprising program code for implementing a method as defined in any of claims 2C to 32C or for controlling an apparatus as defined in any of the preceding claims.

81 C. A preparatory method for using a gas delivery device to control an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressureof the at least one gas X, comprising the step of executing a sequence of tuning breaths for tuning one or more inputs into a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target a PetX[i]^T for a respective breath [i], said inputs required to compute a mass balance equation, wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation.

82C. A method of controlling a gas delivery device to control an amount of at least one gas X in a subject's lung, the method adapted to target one or more end tidal partial pressuresof the at least one gas X, the method comprising: Using a signal processor operatively associated with a gas delivery device to control the amount of gas X contained in one or more respective volumes of gas delivered to a subject in one or more respective breaths [i] using inputs processed by the signal processor for respective breaths [i], wherein the signal processor:

(a) Processes input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C_MvX[i]);

(c) Uses a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CMvXfi], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

83C. A method according to claim 82C, wherein gas delivery device is a gas blender comprising one or more flow controllers, a respective flow controller operatively associated with a respective gas source of differing percentage composition of gas X ranging from 0-100%, wherein the signal processor outputs control signals to at least one flow controller to control the amount of gas X in a volume of gas delivered to the subject.

84C. A method according to claim 83C, wherein the signal processor controls the amount of carbon dioxide and oxygen in each respective breath [i] to target a logistically attainable end tidal partial pressure of carbon dioxide and a logistically attainable end tidal partial pressure of oxygen for a respective breath [i].

85C. A method according to any of claims 81 C to 83C wherein any one of the features described in any of claims 2C to 32C, are individually, or in any combination, implemented in the method. 86C. An automated method of controlling an amount of at least one gas X in a subject's lung to attain a targeted end tidal partial pressure of the at least one gas X, the method comprising the steps of:

(a) Processing input of the concentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C VX[I^']);

(b) Processing input of a logistically attainable end tidal partial pressureof gas X (PetX[i]^T) for a respective breath [i];

(c) Utilizing a prospective computation of an amount of gas X required to be inspired by the subject in an inspired gas to target the PetX[i]^T for a respective breath [i] using inputs required to compute a mass balance equation including CwivX[i], wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Outputting control signals to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

87C. A method according to any of claims 86C, wherein any one of the features described in any of claims 2C to 32C, are individually, or in any combination, implemented in the method.

88C. A gas delivery device comprising one or more flow controllers for controlling an end tidal partial pressure of a gas X in a subject, wherein a signal processor operatively associated with the flow controller(s):

(a) Obtains input of one or more values sufficient to compute aconcentration of gas X in the mixed venous blood entering the subject's pulmonary circulation for gas exchange in one or more respective breaths [i] (C_MvX[ij);

(b) Obtains input of a logistically attainable end tidal partial pressureof gas X (PetX[i)^T) for a respective breath [i];

(c) Uses a prospective computation sufficient to determine an amount of gas X required to be inspired by the subject to target the PetXfj]^T for a respective breath [i], the prospective computation using inputs sufficient to compute a mass balance equation for a respective breath [i], the inputs including values, for a respective breath [i], from which CMVX[I] and the concentration of gas X in the subject's lung affecting mass transfer can be determined, for example CMVXD] and a concentration or partial pressure of gas X in the subject's lung as a result of inspiration in a breath [i],wherein one or more values required to control the amount of gas X in a volume of gas delivered to the subject is output from the mass balance equation; and

(d) Outputting control signals to the flow controllers) to control the amount gas X in a volume of gas delivered to the subject in a respective breath [i] to target the respective PetX[i]^T based on the prospective computation.

89C. A gas delivery device according to claim 88C, wherein any one of the features described in any of claims 2C to 87C, are individually, or in any plausible combination, implemented using signals input to or output by the signal processor.