Ventilation Pattern for Non-Invasive Determination of ELV, EPBF, Cardiac Output and/or CO2 Content in Venous Blood

Abstract

The present invention relates to non-invasive determination of the effective lung volume [ELV], cardiac output, effective pulmonary blood flow [EPBF] and/or the carbon dioxide content of venous blood of a mechanically ventilated subject (3). The subject (3) is ventilated using a ventilation pattern comprising at least one phase of decreased ventilation and at least one phase of increased ventilation, wherein each of said phases comprises at least two breaths during which a level of CO2 expired by said subject assumes a substantially steady state (SS1, SS2). At least one of said phases of decreased and increased ventilation comprises at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than said first breath, for causing the level of expired CO2 to assume said substantially steady state (SS1, SS2).

Claims

1-33. (canceled)

34. A method for enabling a non-invasive determination of at least one physiological parameter related to an effective lung volume (ELV), a cardiac output, an effective pulmonary blood flow (EPBF) and/or a carbon dioxide (CO2) content of venous blood of a mechanically ventilated subject from flow or volume and CO2 measurements, comprising the step of: ventilating the subject using a ventilation pattern comprising at least one phase of decreased ventilation and at least one phase of increased ventilation, wherein each of the phase of decreased ventilation and the phase of increased ventilation comprises at least two breaths during which a level of CO2 expired by the subject assumes a substantially steady state, and wherein at least one of the phases of decreased and increased ventilation comprises at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than the first breath, for causing the level of expired CO2 to assume the substantially steady state.

35. The method of claim 34, wherein both the phases of decreased and increased ventilation comprise at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than the first breath, for causing the level of expired CO2 to assume the substantially steady state.

36. The method of claim 34, wherein the at least first breath for generating the substantial change in the level of expired CO2 is one single breath.

37. The method of claim 34, wherein the at least second breath has a duration and/or a volume adapted to cause the level of expired CO2 to assume a substantially steady state during at least two consecutive breaths in the phase of decreased and/or increased ventilation.

38. The method of claim 34, wherein the at least second breath has a duration and/or a volume adapted to cause the level of expired CO2 to assume a substantially steady state during at least two consecutive breaths in the phase of decreased and/or increased ventilation during a first and a second breath of the phase of decreased and/or increased ventilation.

39. The method of claim 34, wherein the at least first and the at least second breath differ from a respective preceding breath in at least one of a duration of a pre-inspiratory pause, a duration of an end-inspiratory pause, and a tidal volume.

40. The method of claim 34, wherein the at least first breath in the phase of decreased ventilation comprises a pre-inspiratory pause which is prolonged compared to any pre-inspiratory pause of the preceding breath, and/or a post-inspiratory pause which is prolonged compared to any post-inspiratory pause of the preceding breath, in order to effectuate the substantial change in the level of expired CO2.

41. The method of claim 34, wherein the at least second breath in the phase of decreased ventilation comprises a pre-inspiratory pause which is shorter than the pre-inspiratory pause of the at least first breath in the phase of decreased ventilation.

42. The method of claim 34, wherein the at least first breath in the phase of increased ventilation comprises a pre-inspiratory pause which is shortened compared to any pre-inspiratory pause of the preceding breath, in order to effectuate the substantial change in the level of expired CO2.

43. The method of claim 34, wherein the at least second breath in the phase of increased ventilation is a breath of decreased tidal volume compared to the at least first breath in the phase of increased ventilation and/or wherein the at least second breath in the phase of increased ventilation comprises a pre-inspiratory pause which is prolonged compared to any pre-inspiratory pause of the at least first breath in the phase of increased ventilation.

44. The method of claim 34, further comprising the steps of: measuring expired CO2 in expiration gases expired by the subject, and using expired CO2 as control parameter, controlling the duration and/or volume of the at least second breath so as to obtain the substantially steady state level of expired CO2.

45. The method of claim 34, further comprising the step of: determining EPBF, cardiac output and/or the CO2 content of venous blood from a sequence of breaths comprising at least two breaths of substantially steady state within a phase of decreased ventilation and at least two breaths of substantially steady state within a phase of increased ventilation.

46. The method of claim 34, further comprising the step of: determining ELV from a sequence of breaths comprising at least two transient breaths between a phase of increased ventilation and a phase of decreased ventilation, or vice versa.

47. The method of claim 45, wherein EPBF, the cardiac output and/or the CO2 content of venous blood is determined only from breaths during which the level of expired CO2 assumes a substantially steady state, or from a sequence of breaths in which breaths of substantially steady state are weighted more heavily than breaths of non-steady state.

48. The method of claim 46, wherein ELV is determined only from breaths during which the levels of expired CO2 differ substantially, or from a sequence of breaths in which transient breaths are weighted more heavily than breaths of steady state.

49. A computer program for enabling determination of at least one physiological parameter related to an effective lung volume (ELV), a cardiac output, an effective pulmonary blood flow (EPBF) and/or a carbon dioxide (CO2) content of venous blood of a subject from flow and CO2 measurements obtained during mechanical ventilation of the subject using a breathing apparatus, the computer program comprising: computer readable code which, when executed by a processing unit of the breathing apparatus, causes the breathing apparatus to ventilate the subject using a ventilation pattern comprising at least one phase of decreased ventilation and at least one phase of increased ventilation, wherein each of the phase of decreased ventilation and the phase of increased ventilation comprises at least two breaths during which a level of CO2 expired by the subject assumes a substantially steady state, and wherein the code, when executed by the processing unit, causes at least one of the phases of decreased and increased ventilation to comprise at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than the first breath, for causing the level of expired CO2 to assume the substantially steady state.

50. A breathing apparatus for enabling determination of at least one physiological parameter related to an effective lung volume (ELV), a cardiac output, an effective pulmonary blood flow (EPBF) and/or a carbon dioxide (CO2) content of venous blood of a subject from flow and CO2 measurements obtained during mechanical ventilation of the subject using of the breathing apparatus, comprising: a control unit configured to control an operation of the breathing apparatus such that the subject is ventilated using a ventilation pattern comprising at least one phase of decreased ventilation and at least one phase of increased ventilation, each of the phase of decreased ventilation and the phase of increased ventilation comprising at least two breaths during which a level of CO2 expired by the subject assumes a substantially steady state, wherein the control unit is configured to cause at least one of the phases of decreased and increased ventilation to comprise at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than the first breath, for causing the level of expired CO2 to assume the substantially steady state.

51. The breathing apparatus of claim 50, wherein the control unit is configured to cause both of the phases of decreased and increased ventilation to comprise at least a first breath for generating a substantial change in the level of expired CO2 compared to a preceding breath, and at least a second breath being different in duration and/or volume than the first breath, for causing the level of expired CO2 to assume the substantially steady state.

52. The breathing apparatus of claim 50, wherein the control unit is configured to cause the at least first breath to be one single breath.

53. The breathing apparatus of claim 50, wherein the control unit is configured to cause the at least second breath to have a duration and/or volume adapted to cause the level of expired CO2 to assume a substantially steady state during at least two consecutive breaths in the phase of decreased and/or increased ventilation, and preferably during a first and a second breath in the phase of decreased and/or increased ventilation.

54. The breathing apparatus of claim 50, wherein the control unit is configured to cause the at least first and the at least second breath to differ from a respective preceding breath in at least one of a duration of a pre-inspiratory pause, a duration of an end-inspiratory pause, and a tidal volume.

55. The breathing apparatus of claim 50, further comprising: a CO2 sensor measuring expired CO2 in expiration gas expired by the subject, wherein the control unit is configured to use expired CO2 as control parameter for controlling the duration and/or volume of the at least second breath so obtain the substantially steady state level of expired CO2.

56. The breathing apparatus of claim 55, wherein the control unit, in the phase of decreased and/or increased ventilation, is configured to: compare the level of expired CO2 in the at least first breath with the level of expired CO2 in the at least second breath, and if the level of expired CO2 in the at least second breath deviates from the level of expired CO2 in the at least first breath by more than a predetermined amount, delivering at least a third breath being different in duration and/or volume than the at least first breath and the at least second breath, which third breath is adapted to cause the level of expired CO2 to assume a substantially steady state.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] The present invention will become more fully understood from the detailed description provided hereinafter and the accompanying drawings which are given by way of illustration only. In the different drawings, same reference numerals correspond to the same element.

[0063] FIG. 1 illustrates a breathing apparatus according to an exemplary embodiment of the invention;

[0064] FIGS. 2A-2E illustrate a ventilation pattern according to an exemplary embodiment of the invention;

[0065] FIGS. 3A-3D illustrate a ventilation pattern according to another exemplary embodiment of the invention;

[0066] FIGS. 4A-4B illustrate a ventilation pattern according to another exemplary embodiment of the invention, and

[0067] FIGS. 5A-5E illustrate a ventilation pattern according to yet another exemplary embodiment of the invention.

DETAILED DESCRIPTION

[0068] FIG. 1 illustrates a breathing apparatus 1 for enabling continuous and non-invasive determination of one or more physiological parameters related to the effective lung volume (ELV), the cardiac output, the effective pulmonary blood flow (EPBF) and/or the carbon dioxide content of venous blood of a subject 3, according to an exemplary embodiment of the invention.

[0069] In this embodiment, the breathing apparatus 1 is a ventilator for providing ventilatory treatment to a subject 3 (herein sometimes referred to as the patient). The ventilator is connected to the patient 3 via an inspiratory line 5 for supplying breathing gas to the patient 3, and an expiratory line 7 for conveying expiration gas away from the patient 3. The inspiratory line 5 and the expiratory line 7 are connected to a common line 9, via a so called Y-piece 11, which common line is connected to the patient 3 via a patient connector, such as an endotracheal tube.

[0070] The breathing apparatus 1 further comprises a control unit 13 for controlling the ventilation of the patient 3 based on preset parameters and/or measurements obtained by various sensors of the breathing apparatus. The control unit 13 controls the ventilation of the patient 3 by controlling a pneumatic unit 15 of the breathing apparatus 1, which pneumatic unit 15 is connected at one hand to one or more gas sources 17, 19 and at the other hand to the inspiratory line 5 for regulating a flow and/or pressure of breathing gas delivered to the patient 3. To this end, the pneumatic unit 15 may comprise various gas mixing and regulating means, such as mixing chambers, controllable gas mixing valves and one or more controllable inspiration valves.

[0071] The control unit 5 comprises a processing unit 21 and a non-volatile memory 23 storing a computer program which, when executed by the processing unit 21, causes the control unit to control the ventilation of the patient 3 as described hereinafter. Unless stated otherwise, actions and method steps described hereinafter are performed by, or caused by, the control unit 21 upon execution of different code segments of the computer program stored in the memory 23.

[0072] The control unit 5 is configured to enable accurate, continuous and non-invasive determination of one or more physiological parameters related to the ELV, the cardiac output, the EPBF and/or the CO2 content of venous blood of the patient 3 by causing the breathing apparatus 1 to ventilate the patient 3 using a ventilation pattern allowing one or more of the cardiac output, the EPBF and/or the CO2 content of venous blood of the patient 3 to be determined substantially independently of ELV, and allowing ELV to be determined from transient breaths during which changes in ELV are caused mainly by changes in the duration of the breathing cycle (t) or VCO2 rather than changes in EPBF and the CO2 content of venous blood.

[0073] The ventilation pattern is a cyclic ventilation pattern comprising alternating phases of decreased and increased ventilation. Each phase of decreased ventilation comprises at least a first breath for generating a substantial change in the level of CO2 expired by the patient 3, and at least a second breath, following said at least first breath, for causing said level of expired CO2 to assume a substantially steady state level within the phase of decreased ventilation, i.e. during at least two breaths in said phase of decreased ventilation. Each phase of increased ventilation comprises at least a first breath for generating a substantial and opposite change in the level of CO2 expired by the patient 3, and at least a second breath, following said at least first breath, for causing the level of expired CO2 to assume a new substantially steady state level within the phase of decreased ventilation (i.e. during at least two breaths in the phase of decreased ventilation). The control unit 5 is configured to cause the level of expired CO2 to assume said steady states in the phases of decreased and increased ventilation by changing the duration and/or volume of said at least one second breath with respect to the duration and/or volume of said at least one first breath. Also, the control unit 5 is typically configured to cause said substantial change in the level of expired CO2 by changing the duration and/or volume of said at least one first breath with respect to a breath directly preceding said at least one first breath.

[0074] That the level of expired CO2 assumes a substantially steady state during at least two breaths herein means that a measure of expired CO2 obtained during a first breath is substantially equal to a corresponding measure of expired CO2 obtained during a second breath. Said measure of expired CO2 may be any measure indicative of alveolar CO2 of the ventilated patient 3, e.g. a measure of the fraction of alveolar CO2 (FACO2) or a measure of the partial pressure of alveolar CO2 (PACO2), including but not limited to end-tidal fraction of alveolar CO2 (FetCO2) and end-tidal partial pressure of CO2 (PetCO2).

[0075] The at least two breaths of the same phase of decreased or increased ventilation during which the level of expired CO2 assumes a substantially steady state will hereinafter be referred to as breaths of steady state. Preferably but not necessarily, the at least two breaths of steady state in the phase of decreased and increased ventilation, respectively, are two or more consecutive breaths within said phase.

[0076] FIGS. 2-5 illustrate some examples of cyclic ventilation patterns which, in accordance with the principles described above, may be applied to the patient 3 by the breathing apparatus 1 in order to enable non-invasive determination of one or more of said physiological parameters from flow and CO2 measurements.

[0077] FIGS. 2A-2E illustrate a ventilation pattern caused by applying the technique of forced steady state only within phases of decreased ventilation while, in phases of increased ventilation, the level of expired CO2 is allowed to passively and gradually reach a substantially steady state. Each cycle of the illustrated ventilation pattern comprises a total of nine breaths B1-B9.

[0078] With reference now made to FIG. 2A illustrating the airway pressure of the ventilated patient, e.g. as measured by a pressure sensor (not shown) located in or close to the Y-piece 11 of the breathing apparatus in FIG. 1, a phase of decreased ventilation is initiated by delivering a first breath B1 having a pre-inspiratory pause A which is prolonged compared to any pre-inspiratory pause of a preceding breath (not shown), which preceding breath is the last breath of a preceding phase of increased ventilation.

[0079] In FIG. 2B, the solid curve illustrates the variation in CO2 level over time, as measured by a sensor for measuring CO2 content of inspiration and expiration gases inhaled and exhaled by patient being ventilated with the ventilation pattern in FIG. 2A, such as a CO2 sensor 29 of the breathing apparatus 1 in FIG. 1, as will be described in more detail below. The CO2 level may for example be measured as the fraction of CO2 (FCO2) in the gas measured upon during expiration, corresponding to the alveolar fraction of CO2 (FACO2) of the ventilated patient 3. The data points connected by the dashed line 25A represent an end-tidal level of CO2 expired in each breath, in this case corresponding to the end-tidal fraction of CO2 (FetCO2) of each breath. Accordingly, the dashed line 25A illustrates a variation in end-tidal level of expired CO2 over time.

[0080] As shown in FIG. 2B, said first breath B1 causes a substantial change in the end-tidal level of CO2 expired by the patient. In a second breath B2, immediately following said first breath, the pre-inspiratory pause B is shortened compared to the pre-inspiratory pause A of the first breath. This shortening of the pre-inspiratory pause prevents further increase in the end-tidal level of expired CO2 and causes the end-tidal level of CO2 expired during said second breath B2 to substantially correspond to the end-tidal level of CO2 expired during the first breath Bl. Consequently, the end-tidal level of expired CO2 assumes a substantially steady state, denoted SS1, during said first and second breaths. In this exemplary ventilation pattern, a third breath B3 having a pre-inspiratory pause C corresponding in duration to the pre-inspiratory pause B of the second breath is delivered to the patient following said second breath. This third breath causes the end-tidal level of expired CO2 to remain substantially constant at said level SS1 of steady state. Thus, in this example, the first, second and third breaths in the phase of decreased ventilation are all breaths of steady state as the level of expired CO2 remains substantially constant during said breaths.

[0081] After the third breath, a phase of increased ventilation is initiated by delivering a fourth breath B4 having no or only a very short pre-inspiratory pause compared to the preceding breath B3. As mentioned above, the proposed technique of forced steady state is not applied within phases of increased ventilation in this embodiment. This means that after delivery of the fourth breath B4 initiating the phase of increased ventilation, no further changes in effective ventilation are made within said phase of increased ventilation. As illustrated in FIG. 2B, this causes the end-tidal level of expired CO2 to gradually approach a new and lower steady state level SS2. This exemplary ventilation pattern comprises six identical breaths B4-B9 of increased ventilation, which is often sufficient for the end-tidal level of expired CO2 to passively reach a new level of substantially steady state.

[0082] FIGS. 2C-2E illustrate simulation data from a simulation in which a patient is ventilated by means of a breathing apparatus corresponding to the breathing apparatus 1 in FIG. 1, using a cyclic ventilation pattern in which each cycle corresponds to the ventilation pattern illustrated in FIG. 2A. The simulation data is obtained during a sequence of 30 breaths.

[0083] FIG. 2C illustrates the end-tidal fraction of CO2 (FetCO2) for each breath in said sequence of breaths, as measured e.g. by said CO2 sensor 29 of the breathing apparatus 1. As expected, the FetCO2 curve in FIG. 2C resembles the dashed curve 25A illustrating the end-tidal level of expired CO2 in FIG. 2A.

[0084] FIG. 2D illustrates the minute elimination (MVCO2) and mean minute elimination (MVCO2 mean) of CO2 of the patient for the same sequence of breaths. The ventilation pattern is preferably adapted such that the mean minute elimination of CO2 is substantially constant. To this end, the breaths of increased ventilation are preferably hyperventilated breaths and the breaths of decreased ventilation are preferably hypoventilated breaths.

[0085] FIG. 2E visualizes the changes in effective ventilation of the proposed ventilation pattern and indicates the duration in seconds, t, of each breath in the sequence of breaths, and the duration in seconds, tpause, of the pre-inspiratory pause of each breath in the sequence of breaths. In this exemplary embodiment, the first breath of decreased ventilation comprises a pre-inspiratory pause of approximately eight seconds, the second and third breath of decreased ventilation comprise a pre-inspiratory pause of approximately four seconds, whereas the fourth to ninth breath in each cycle of the cyclic ventilation pattern, corresponding to breaths of increased ventilation, comprises no or only a very short pre-inspiratory pause. The total duration of each cycle of the cyclic ventilation pattern is 52 seconds.

[0086] FIGS. 3A-3B illustrate an embodiment of a ventilation pattern caused by applying the technique of forced steady state both in phases of decreased ventilation and phases of increased ventilation. In this embodiment, each cycle of the ventilation pattern comprises a total of six breaths B1-B6, three of which are breaths of decreased ventilation and three of which are breaths of increased ventilation. The total duration of each cycle of the cyclic ventilation pattern is 40 seconds.

[0087] With reference now made to FIG. 3A, the first three breaths B1-B3 in the phase of decreased ventilation are identical to the first three breaths B1-B3 in FIG. 2A, thus causing a substantial increase in the level of expired 002 to a first substantially steady state level SS1. In this embodiment, the fourth breath B4 initiating the phase of increased ventilation differs from the preceding breath B3 in both duration and volume. Besides the pre-inspiratory pause of the fourth breath B4 being removed or at least substantially shortened with respect to the pre-inspiratory pause of the preceding breath B3, the tidal volume of the fourth breath B4 is increased compared to the tidal volume of said preceding breath B3. This effectively causes wash-out of CO2 from the lungs of the patient, causing a substantial decrease in the level of CO2 expired by the patient, as shown in FIG. 3B. The first breath of increased ventilation B4 is adapted in duration and volume so as to bring the level of expired CO2 to a level at which it can be maintained for at least one more breath in the same phase of increased ventilation, which level corresponds to the second substantially steady state level SS2.

[0088] Preferably, the first breath of increased ventilation B4 should be adapted in duration and/or volume to fully compensate for the substantial increase in the level of expired CO2 caused by the first breath B1 in the phase of decreased ventilation, meaning that said first breath of increased ventilation B4 should bring the level of expired CO2 back to the level of expired CO2 prior to delivery of said first breath of decreased ventilation B1. To maintain the level of expired CO2 at said second substantially steady state level SS2, the fifth breath B5 differ from said fourth breath B4 in duration and/or volume so as to prevent further decrease in the level of expired CO2, and to cause the level of CO2 expired during said fifth breath B5 to substantially correspond to the level of CO2 expired during the preceding fourth breath B4. in this embodiment, the fifth breath B5 differ from the fourth breath B4 in that the temporary change in tidal volume is removed, meaning that the tidal volume of the fifth breath B5 is set to a value substantially corresponding to the tidal volume of the breaths preceding said fourth breath B4. The change in duration of the pre-inspiratory pause of the fourth breath B4 is maintained also for the fifth breath B5, meaning that the fifth breath contains no or only a short pre-inspiratory pause substantially corresponding to the pre-inspiratory pause of the fourth breath B4. After said fifth breath, a sixth breath B6 being identical in duration and volume to the fifth breath is delivered to the patient. This sixth breath causes the level of expired CO2 to remain substantially constant and equal to the second level SS2 of substantially steady state. Thus, in this exemplary ventilation pattern, all breaths of decreased ventilation B1-B3 and all breaths of decreased ventilation B4-B6 are breaths of steady state as the level of expired CO2 remains substantially constant during said breaths.

[0089] FIGS. 3C-3D illustrate simulation data from a simulation in which a patient is ventilated by means of a breathing apparatus corresponding to the breathing apparatus 1 in FIG. 1, using a cyclic ventilation pattern in which each cycle corresponds to the ventilation pattern illustrated in FIG. 3A. The simulation data is obtained during a sequence of 30 breaths.

[0090] FIG. 3C illustrates FetCO2 for each breath in said sequence of breaths, as measured e.g. by said CO2 sensor 29 of the breathing apparatus 1. As expected, the FetCO2 curve in FIG. 3C resembles the dashed curve 25B illustrating variations in the end-tidal levels of CO2 in FIG. 3B.

[0091] FIG. 3D illustrates the minute elimination (MVCO2) and mean minute elimination (MVCO2 mean) of CO2 of the patient for the same sequence of breaths. In this embodiment too, the breaths of increased ventilation are hyperventilated breaths and the breaths of decreased ventilation are hypoventilated breaths, which prevents drifting of the mean minute elimination of CO2 and so keeps said mean minute elimination of CO2 substantially constant during ventilation with the proposed ventilation pattern.

[0092] In the exemplary ventilation pattern illustrated in FIGS. 3A-3D, the tidal volume of the fourth breath B4 may be increased by approximately 55% compared to the tidal volume of the preceding breath B3. According to another exemplary ventilation pattern (not illustrated), the substantial decrease in the level of expired CO2 from the first substantially steady state level SS1 to the second substantially steady state level SS2 may be caused by two consecutive breaths of increased tidal volume, i.e. by two breaths both having a tidal volume that is larger than the breaths preceding said two breaths of increased tidal volume. In one embodiment, said two breaths of increased tidal volume have no pre-inspiratory pauses and tidal volumes that are substantially equal to each other and increased by approximately 19% compared to the tidal volumes of the breaths preceding said two breaths of increased tidal volume. In one embodiment, the fourth breath B4 in FIG. 3A is replaced by said two consecutive breaths of increased tidal volume, resulting in a ventilation pattern comprising seven breaths of which three are breaths of decreased ventilation and four are breaths of increased ventilation, wherein the first breath 1B of decreased ventilation alone is adapted to cause the substantial increase in the level of expired CO2 in the transition between phases of increased ventilation and phases of decreased ventilation, and wherein said two consecutive breaths of increased tidal volume are adapted to cause the substantial decrease in the level of expired CO2 in the transition between phases of decreased ventilation and phases of increased ventilation.

[0093] FIGS. 4A-4B illustrate another exemplary ventilation pattern in which the proposed technique of forced steady state is applied both in phases of decreased ventilation and phases of increased ventilation. In this embodiment, each cycle of the ventilation pattern comprises a total of six breaths B1-B6, three of which are breaths of decreased ventilation and three of which are breaths of increased ventilation.

[0094] With reference now made to FIG. 4A illustrating the airway pressure of the ventilated patient, a phase of decreased ventilation is initiated by delivering a first breath B1 having an end-inspiratory pause A (sometimes referred to as post-inspiratory pause) which is prolonged compared to any end-inspiratory pause of a preceding breath (not shown), which preceding breath is the last breath of a preceding phase of increased ventilation.

[0095] As shown in FIG. 4B, said first breath B1 causes a substantial change (increase) in the level of CO2 expired by the patient. In a second breath B2, immediately following said first breath, the end-inspiratory pause is removed or substantially shortened compared to the end-inspiratory pause A of the first breath B1, and a pre-inspiratory pause B is added or substantially prolonged compared to any pre-inspiratory pause of the first breath B1. The removal or shortening of the end-inspiratory pause in the second breath B2 prevents further increase in the level of expired CO2 and causes the level of CO2 expired during said second breath B2 to substantially correspond to the level of CO2 expired during the first breath B1. Consequently, the level of expired CO2 assumes a substantially steady state SS1 during said first and second breaths. In this exemplary ventilation pattern, a third breath B3 having a pre-inspiratory pause C corresponding in duration to the pre-inspiratory pause B of the second breath B2 is delivered to the patient following said second breath. This third breath B3 causes the level of expired CO2 to remain substantially constant at said steady state level SS1. Thus, in this example too, the first, second and third breaths in the phase of decreased ventilation are all breaths of steady state as the level of expired CO2 remains substantially constant during said breaths.

[0096] The fourth to sixth breath B4-B6 are identical to the fourth to six breaths B4-B6 in the ventilation pattern illustrated in FIG. 3A. This means that a fourth breath B4 differing from the preceding third breath B3 in both duration (no or substantially shortened pre-inspiratory pause) and volume (increased tidal volume) is delivered to the patient to initiate the phase of increased ventilation through forced wash-out of CO2 from the lungs of the patient, abruptly bringing the level of expired CO2 from the first substantially steady state level SS1 to a new substantially lower level SS2. Said fourth breath B4 is immediately followed by a fifth breath B5 differing from said fourth breath B4 in that the temporary change in tidal volume is removed to prevent further decrease in the expired level of CO2 and force the level of CO2 expired during the fifth breath B5 to remain at or near said new and lower level SS2, which level thus constitutes a substantially steady state level of CO2 expired during the fourth and fifth breath. The sixth breath B6 is identical to the fifth breath B5 and serves to maintain the level of CO2 expired during the sixth breath B6 at said second and substantially steady state level SS2.

[0097] FIGS. 5A-5E illustrate yet another exemplary ventilation pattern in which the proposed technique of forced steady state is applied both in phases of decreased ventilation and phases of increased ventilation. In this embodiment, each cycle of the ventilation pattern comprises a total of seven breaths B1-B7, three of which are breaths of decreased ventilation and four of which are breaths of increased ventilation. All breaths in the cycles of the cyclic ventilation pattern are identical in volume and differ from each other only in duration, in a manner causing the level of expired CO2 to assume substantially steady states both in phases of decreased ventilation and phases of increased ventilation.

[0098] The first three breaths B1-B3 of decreased ventilation are identical to the breaths B1-B3 in FIG. 4A. In the fourth breath B4, the pre-inspiratory pause C that was present in the third breath B3 is removed, thereby initiating the phase of increased ventilation by causing a decrease in the level of expired CO2. In this scenario, the fourth breath B4 alone is not sufficient to cause the desired change in the level of expired CO2 and, therefore, a fifth breath B5 being identical to the fourth breath B4 is delivered immediately following said fourth breath. The fifth breath B5, in combination with said fourth breath B4, generates said substantial change in the level of expired CO2. After the fifth breath, a sixth and a seventh breath B6-B7 having pre-inspiratory pauses D and E which are prolonged compared to the (non-existing) pre-inspiratory pause of the fifth breath B5 are delivered to the patient to prevent further decrease in the level of expired CO2, and to cause the level of expired CO2 to remain a the substantially constant steady state level SS2.

[0099] The variation in the level of expired CO2 is illustrated by the dashed line 25D in FIG. 5B, and further in FIG. 5C showing the FetCO2 curve obtained during a simulation in which a patient was ventilated using a cyclic ventilation pattern in which each cycle corresponds to the ventilation pattern in FIG. 5A. Simulation data is shown for a sequence of 30 breaths. FIG. 5D illustrates the minute elimination (MVCO2) and mean minute elimination (MVCO2 mean) of CO2 of the patient during said sequence of breaths.

[0100] FIG. 5E visualizes the changes in effective ventilation of the exemplary ventilation pattern of FIG. 5A and indicates the duration in seconds, t, of each breath in the sequence of breaths, and the total duration in seconds, tpause, of the inspiratory pause (including both end-inspiratory and pre-inspiratory pauses) of each breath in the sequence of breaths. In this exemplary embodiment, the first breath B1 of decreased ventilation comprises no pre-inspiratory pause and an end-inspiratory pause of approximately nine seconds, the second and third breaths B2-B3 of decreased ventilation comprise a pre-inspiratory pause of approximately five seconds and no end-inspiratory pause, the fourth and fifth breaths B4-B5 causing the transition from decreased to increased ventilation comprise no pre-inspiratory pause and no end-expiratory pause, whereas the sixth and seventh breaths B6-B7, constituting the last breaths in the phase of increased ventilation, comprises a pre-inspiratory pause of approximately one second and no end-expiratory pause. The total duration of each cycle of the cyclic ventilation pattern is 42 seconds.

[0101] Above it has been described that the breathing apparatus 1 (FIG. 1) is configured to ventilate the patient 3 in a manner that enables the at least one physiological parameter related to the ELV, cardiac output, EPBF and/or the CO2 content of venous blood of the ventilated patient to be accurately and reliably determined. Determination may be made by external units, e.g. by an external computer or a monitoring system configured to obtain flow and CO2 measurements related to the ongoing ventilation of the patient. Preferably, the breathing apparatus 1 is configured to determine the at least one physiological parameter itself. The above described ventilation pattern allows said at least one physiological parameter to be non-invasively determined by the breathing apparatus 1 in a continuous manner, e.g. on a breath-by-breath basis.

[0102] With reference again made to FIG. 1, the breathing apparatus 1 may comprise at least one flow sensor 27 for measuring at least an expiratory flow of expiration gas exhaled by the subject, and at least one CO2 sensor 29 for measuring the CO2 content of at least the expiration gas exhaled by the subject. The control unit may be configured to determine said at least one physiological parameter from flow and CO2 measurements obtained during an analysed sequence of breaths during which the subject is ventilated using said ventilation pattern. Preferably, the flow and CO2 sensors 27, 29 are configured to measure also inspiratory flow and CO2 content.

[0103] In the illustrated embodiment, the flow sensor 27 and the CO2 sensor 29 form parts of a capnograph 31 configured for volumetric capnography measurements. The capnograph 31 is arranged in the proximity of the airways opening of the patient 3, namely in the common line 9 of the breathing circuit in which it is exposed to all gas exhaled and inhaled by the patient 3. The capnograph 31 is connected to the breathing apparatus 1 via a wired or wireless connection 33, and configured to transmit the flow and CO2 measurements to the ventilator for further processing by the processing unit 21 of the breathing apparatus. The breathing apparatus 1 is preferably configured to generate a volumetric capnogram 35 from the flow and CO2 measurements received from the capnograph 31, and, additionally, to display the volumetric capnogram 35 on a display 37 of the ventilator.

[0104] In one embodiment, the control unit 5 of the breathing apparatus 1 is configured to determine the at least one physiological parameter based on said flow and CO2 measurements using the following capnodynamic equation for a single-chamber lung model, which describes how the fraction of alveolar carbon dioxide (F.sub.ACO2) varies from one breath to another:

ELV.Math.(F.sub.ACO2.sup.nF.sub.ACO2.sup.n1)=t.sup.n.Math.EPBF.Math.(C.sub.VCO2C.sub.ACO2.sup.n)VTCO2.sup.n(eq. 3)

where ELV is the effective lung volume for CO2 storage at end of expiration, F.sub.ACO2.sup.n is the alveolar CO2 fraction in the lung at end of expiration n, t.sup.n is the duration of breath n, EPBF is the effective pulmonary blood flow, CvCO2 is the CO2 concentration in mixed venous blood (volume of CO2 gas per volume blood), C.sub.ACO2.sup.n is the CO2 concentration in alveolar capillaries during breath n, and VTCO2.sup.n is the tidal elimination of CO2 in breath n.

[0105] F.sub.ACO2.sup.n may be measured by the CO2 sensor 29 while C.sub.ACO2.sup.n and VTCO2 may be directly calculated from F.sub.ACO2.sup.n, the tidal volume of breath n (VT.sup.n), and a known deadspace volume, as well known in the art, leaving EPBF, CvCO2 and ELV as unknown physiological parameters to be determined.

[0106] During steady state of expired CO2, the factor (F.sub.ACO2.sup.n-F.sub.ACO2.sup.n1) in equation 3 becomes zero, allowing EPBF and CvCO2 to be determined independently of ELV in accordance with the principles described herein.

[0107] Equation 3 is analogous to equation 1 in WO2013/141766, disclosing a non-invasive and continuous method for simultaneous determination of ELV, cardiac output and CvCO2. Preferably, the control unit 5 of the breathing apparatus 1 is configured to use the method disclosed in WO2013/141766 to determine the parameter triplet {ELV, EPBF, CvCO2} from an analysed sequence of breaths, based on the correlation between the directly measureable or derivable parameters F.sub.ACO2 (=F.sub.ACO2.sup.nF.sub.ACO2.sup.n1), C.sub.ACO2 and VTCO2 in said analysed sequence of breaths. Of course, in exact correspondence with the method disclosed in WO2013/141766, the control unit 5 may also be configured to determine the parameter triplet {ELV, Q, CvCO2} based on the correlation between the directly measureable or derivable parameters F.sub.ACO2, CaCO2 and VTCO2 in said analysed sequence of breaths. Here Q is the cardiac output, F.sub.ACO2 is the change in volume fraction of alveolar CO2 between breath n and n1, CaCO2 is the CO2 content of arterial blood, and VTCO2 is the tidal elimination of CO2. As mentioned in the background portion, EBPF is directly derivable from cardiac output, and vice versa (see eq. 2).

[0108] Introducing an index n indicating the number of the breath in the analysed sequence of breaths, and rearranging equation 3 such that the unknown parameters are gathered on the left-hand side of the equation yields:

ELV.Math.F.sub.ACO.sub.2.sup.nEPBF.Math.C.sub.VCO.sub.2.Math.t.sup.n+EPBF.Math.C.sub.ACO.sub.2.sup.n.Math.t.sup.n=VTCO.sub.2.sup.n(eq. 4)

[0109] Writing this equation in matrix form for the breaths n=1, 2, . . . , N in the analysed sequence of breaths:

[00002]$.Math.\left(\mathrm{eq}..Math.5\right).Math.[.Math.\begin{array}{ccc}.Math.F_A.Math.C.Math.O_2^1& -.Math..Math.t^1& C_A.Math.C.Math.O_2^1.Math..Math..Math.t^1\\ \mathrm{.Math.}& \mathrm{.Math.}& \mathrm{.Math.}\\ .Math.F_A.Math.C.Math.O_2^n& -.Math..Math.t^n& C_A.Math.C.Math.O_2^n.Math..Math..Math.t^n\\ \mathrm{.Math.}& \mathrm{.Math.}& \mathrm{.Math.}\\ .Math.F_A.Math.C.Math.O_2^N& -.Math..Math.t^N& C_A.Math.C.Math.O_2^N.Math..Math..Math.t^N\end{array}].Math.[.Math.\begin{array}{c}\mathrm{ELV}\\ \mathrm{EPBF}.Math.{\mathrm{CvCO}}_2\\ \mathrm{EPBF}\end{array}]=[.Math.\begin{array}{c}-{\mathrm{VTCO}}_2^1\\ \mathrm{.Math.}\\ -{\mathrm{VTCO}}_2^n\\ \mathrm{.Math.}\\ -{\mathrm{VTCO}}_2^N\end{array}]$

[0110] When the analysed sequence of breaths N comprises more than three breaths (i.e. when N>3), this becomes an overdetermined system of equations and the unknown parameter triplet {ELV, EPBF.Math.CvCO.sub.2, EPBF} and hence the physiological parameters ELV, EPBF, and CvCO.sub.2 can be determined by finding an approximate solution to the overdetermined system of equation. As well known in the art, the approximate solution to an overdetermined system of equations can be calculated in different ways, e.g. using the method of least squares. The solution to the overdetermined system of equations will depend on the correlation of the parameters F.sub.ACO2, C.sub.ACO2 and VTCO2 in the respiratory cycles of the analyses sequence of respiratory cycles.

[0111] This system of equations (eq. 5) may be rewritten as A.Math.x.sub.A=a, where

[00003]$A=\left[\begin{array}{ccc}.Math.F_A.Math.C.Math.O_2^1& -.Math..Math.t^1& C_A.Math.C.Math.O_2^1.Math..Math..Math.t^1\\ \mathrm{.Math.}& \mathrm{.Math.}& \mathrm{.Math.}\\ .Math.F_A.Math.C.Math.O_2^n& -.Math..Math.t^n& C_A.Math.C.Math.O_2^n.Math..Math..Math.t^n\\ \mathrm{.Math.}& \mathrm{.Math.}& \mathrm{.Math.}\\ .Math.F_A.Math.C.Math.O_2^N& -.Math..Math.t^N& C_A.Math.C.Math.O_2^N.Math..Math..Math.t^N\end{array}\right],.Math.X_A=\left[\begin{array}{c}\mathrm{ELV}\\ \mathrm{EPBF}.Math.{\mathrm{CvCO}}_2\\ \mathrm{EPBF}\end{array}\right],\mathrm{and}.Math..Math.a=\left[\begin{array}{c}-{\mathrm{VTCO}}_2^1\\ \mathrm{.Math.}\\ -{\mathrm{VTCO}}_2^n\\ \mathrm{.Math.}\\ -{\mathrm{VTCO}}_2^N\end{array}\right]$

[0112] The control unit 5 of the breathing apparatus 5 may for example be configured to calculate an approximate solution for the parameter triplet {ELV, EPBF.Math.CvCO.sub.2, EBBF} by minimizing the error |A.Math.x.sub.Aa|. Using the method of least squares, the solution may be calculated as:

x.sub.A=(A.sup.T.Math.A).sup.1.Math.A.sup.T.Math.a(eq. 6)

[0113] Consequently, the control unit 5 may determine approximate values of ELV, EPBF, CvCO2, and cardiac output from flow and CO2 measurements obtained for an analysed sequence of breaths during which the patient 3 is ventilated using a ventilation pattern causing the level of expired CO2 to vary during said analysed sequence of breaths. For continuous monitoring of ELV, EPBF, cardiac output and/or CvCO2, the ventilation pattern is preferably a cyclic ventilation pattern and the parameters are preferably determined by the control unit 5 on a breath-by-breath basis. Preferably but not necessarily, the number of breaths in said analysed sequence of breaths corresponds to the number of breaths in each cycle of the cyclic ventilation pattern.

[0114] Preferably, to allow EPBF, cardiac output and CvCO2 to be determined independently of ELV in accordance with the principles of the present invention, the breathing apparatus 1 is configured to ventilate the patient 3 using any of the above described ventilation patterns, and the control unit 5 is configured to determine EPBF, cardiac output and/or CvCO2 only from breaths during which the level of expired CO2 assumes a substantially steady state, or to determine EPBF, cardiac output and/or CvCO2 from a sequence of breaths in which breaths of substantially steady state are weighted more heavily than breaths of non-steady state. Once EPBF, cardiac output and/or CvCO2 has been determined, the control unit 5 may determine ELV only from transient breaths in said sequence of analysed breaths, or from a sequence of breaths in which transient breaths are weighted more heavily than breaths of steady state, preferably using the determined values of EPBF, cardiac output and/or CvCO2.

[0115] For example, the breathing apparatus 1 may be configured to ventilate the patient 3 using a cyclic ventilation pattern in which each cycle corresponds to the ventilation pattern shown in FIG. 3A, i.e. a cyclic ventilation pattern comprising alternating phases of three breaths of decreased ventilation (B1-B3 in FIG. 3A) and three breaths of increased ventilation (B4-B6 in FIG. 3A). For each breath n, the control unit 5 determines F.sub.ACO2 (F.sub.ACO2.sup.n-F.sub.ACO2.sup.n1, C.sub.ACO2 and VTCO2 from known and measured parameters, and inserts the values of F.sub.ACO2, t, C.sub.ACO2 and VTCO2 into equation 5. After one cycle of the cyclic ventilation pattern, the following system of six equations is obtained, wherein equation 1 and 4 (n=1, 4) originate from transient breaths and equations 2-3 and 5-6 (n=2, 3, 5, 6) originate from breaths of substantially steady state.

[00004]$.Math.\left(\mathrm{eq}..Math.7\right).Math.\left[\begin{array}{ccc}.Math.F_A.Math.C.Math.O_2^1& -.Math..Math.t^1& C_A.Math.C.Math.O_2^1.Math..Math..Math.t^1\\ .Math.F_A.Math.C.Math.O_2^2& -.Math..Math.t^2& C_A.Math.C.Math.O_2^2.Math..Math..Math.t^2\\ .Math.F_A.Math.C.Math.O_2^3& -.Math..Math.t^3& C_A.Math.C.Math.O_2^3.Math..Math..Math.t^3\\ .Math.F_A.Math.C.Math.O_2^4& -.Math..Math.t^4& C_A.Math.C.Math.O_2^4.Math..Math..Math.t^4\\ .Math.F_A.Math.C.Math.O_2^5& -.Math..Math.t^5& C_A.Math.C.Math.O_2^5.Math..Math..Math.t^5\\ .Math.F_A.Math.C.Math.O_2^6& -.Math..Math.t^6& C_A.Math.C.Math.O_2^6.Math.t^6\end{array}\right].Math.\left[\begin{array}{c}\mathrm{ELV}\\ \mathrm{EPBF}.Math.{\mathrm{CvCO}}_2\\ \mathrm{EPBF}\end{array}\right]=\left[\begin{array}{c}-{\mathrm{VTCO}}_2^1\\ -{\mathrm{VTCO}}_2^2\\ -{\mathrm{VTCO}}_2^3\\ -{\mathrm{VTCO}}_2^4\\ -{\mathrm{VTCO}}_2^5\\ -{\mathrm{VTCO}}_2^6\end{array}\right]$

[0116] The control unit 5 may, in this scenario, be configured to determine EPBF and CvCO2 independently of ELV by calculating EPBF and CvCO2 only from equations 2, 3, 5 and 6 originating from breaths of steady state. The thus determined values of EPBF and CvCO2 may then be inserted into the system of equations, whereupon said system of equations can be solved by the control unit 5 with regard to ELV.

[0117] For each breath, the equation originating from the oldest breath in the analysed sequence of breath may be replaced by an equation originating from the most recent breath, whereby ELV, EPBF, cardiac output and CvCO2 can be monitored continuously by performing the above calculations on a breath-by-breath basis.

[0118] The ventilation pattern described herein may be predetermined, meaning that the ventilation pattern is determined prior to application thereof to the ventilated patient and does not alter or change in response to measured parameters. In other embodiments, the ventilation pattern may be an adaptive ventilation pattern which is automatically adapted based on measured parameters indicative of the response from the patient to the currently applied ventilation pattern. For example, the control unit 5 of the breathing apparatus 1 may be configured to use a measure of expired CO2, e.g. measured by the CO2 sensor 29, as control parameter for feedback control of the duration and/or volume of the breaths of the ventilation pattern. Thus, the control unit 5 may be configured to use expired CO2 for feedback control of the duration of the inspiratory pause (end-inspiratory and/or pre-inspiratory pauses) and/or the tidal volume of breaths in the ventilation pattern in order to effectuate the substantial change in the level of expired CO2 in the transition between phases of increased ventilation and decreased ventilation, and/or to cause the level of expired CO2 to assume a substantially steady state within the phase of increased and/or decreased ventilation. To this end, the control unit 5 may for example be configured to compare the level of expired CO2 in said at least first breath with the level of expired CO2 in said at least second breath, and, if the level of expired CO2 in said at least second breath deviates from the level of expired CO2 in said at least first breath by more than a predetermined amount, cause delivery of at least a third breath being different in duration and/or volume than said at least first breath and said at least second breath, which third breath is adapted to cause the level of expired CO2 to assume a substantially steady state during at least two breaths of the current phase, e.g. during said second and third breath.

[0119] Preferably, expired CO2 is measured even if not used as control parameter or for calculation of the at least one physiological parameter. This allows the breathing apparatus 1 to verify that a substantially steady state of expired CO2 is reached within the phases of increased and/or decreased ventilation, and thus to verify that the currently applied ventilation pattern really allows EPBF, cardiac output and/or CvCO2 to be determined independently of ELV. The control unit 5 of the breathing apparatus 1 may be configured to establish whether or not a substantially steady state is reached within a phase of increased or decreased ventilation by comparing CO2 measurements obtained during breaths of said phase of increased or decreased ventilation. If a substantially steady state is not reached, the control unit 5 may be configured to switch to another ventilation pattern hopefully capable of causing the level of expired CO2 to reach a steady state, and/or to trigger an alarm to an operator of the breathing apparatus. Furthermore, the control unit 5 may be configured to cause display of a curve illustrating variations in the level of expired CO2 over time on the display 37 of the breathing apparatus, for example a FetCO2 curve derivable from measurements obtained by the capnograph 31.