WO2020208258A1 - Method, device and computer program for estimating a pulmonary blood flow of a subject - Google Patents

Method, device and computer program for estimating a pulmonary blood flow of a subject Download PDF

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Publication number
WO2020208258A1
WO2020208258A1 PCT/EP2020/060428 EP2020060428W WO2020208258A1 WO 2020208258 A1 WO2020208258 A1 WO 2020208258A1 EP 2020060428 W EP2020060428 W EP 2020060428W WO 2020208258 A1 WO2020208258 A1 WO 2020208258A1
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Prior art keywords
lung
ecmo
gas
blood flow
flow
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PCT/EP2020/060428
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French (fr)
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Kaspar BACHMANN
David BERGER
Luciano Gattinoni
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Universität Bern
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1698—Blood oxygenators with or without heat-exchangers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3666—Cardiac or cardiopulmonary bypass, e.g. heart-lung machines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/40—Respiratory characteristics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/40—Respiratory characteristics
    • A61M2230/43—Composition of exhalation

Definitions

  • the invention relates to a method, a device and a computer program for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly an extracorporeal membrane oxygenation device (ECMO).
  • an extracorporeal oxygenation device particularly an extracorporeal membrane oxygenation device (ECMO).
  • ECMO extracorporeal membrane oxygenation device
  • Extracorporeal oxygenation in particular extracorporeal membrane oxygenation (ECMO) is increasingly used as rescue therapy for severe cardiopulmonary failure.
  • ECO extracorporeal oxygenation
  • ECMO extracorporeal membrane oxygenation
  • two large blood vessels of the subject are typically cannulated and connected to an external blood oxygenation device, such as a membrane oxygenator, to assist native lung function.
  • an external blood oxygenation device such as a membrane oxygenator
  • blood drained from the venous system is oxygenated outside of the body, and then reintroduced either to the venous system (veno-venous extracorporeal oxygenation) or to the arterial system (veno-arterial extracorporeal oxygenation).
  • Veno-venous extracorporeal oxygenation is typically used for patients with respiratory failure, while veno-arterial extracorporeal oxygenation can also be applied for patients suffering from cardiac and/or respiratory failure.
  • Pulmonary blood flow can be measured directly in a clinical setting i.e. by echocardiography or a pulmonary catheter.
  • echocardiography is assessor dependent and not standardized, and measurement by a pulmonary catheter is difficult during ECO treatment.
  • pulmonary blood flow can also be measured by an ultrasound flow probe on the pulmonary artery main trunk.
  • VA veno-arterial
  • the native heart and lung work in parallel with the extracorporeal circuit and the assessment of native cardiac output (i. e. blood flow through the lungs) is difficult.
  • the ongoing unloading of the right ventricle even at low ECO blood flow makes assessment of cardiac function during ECO weaning challenging.
  • a first aspect of the invention relates to a method for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, in particular an extracorporeal membrane oxygenation device (ECMO), wherein
  • ECMO extracorporeal membrane oxygenation device
  • a first gas flow of a gas exhaled by the subject is determined, wherein the gas is soluble in blood
  • an external blood flow through the extracorporeal oxygenation device is determined, - a pulmonary blood flow of the subject is estimated from the first gas flow, the second gas flow and the external blood flow.
  • the gas may be any gas, which is at least in part soluble in blood and may be exhaled by the subject.
  • the term“soluble” may relate to a solution mechanism of the gas involving or not involving a chemical reaction of the gas, such as i.e. the reaction CO 2 + H2O « HCO3- + H + of CO 2 .
  • the gas exhaled by the subject is CO 2 , O 2 or an anesthetic gas, particularly CO 2 .
  • the gas exhaled by the subject is CO 2 or O 2 .
  • anesthesia gas refers to a gas used in anesthesia of a patient, such as i.e. sevoflurane or desflurane.
  • CO 2 as the exhaled gas is advantageous, because CO 2 concentration or partial pressure is especially easy to detect.
  • the gas exhaled by the subject is CO 2 . Therefore, this embodiment relates to a method for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, in particular an extracorporeal membrane oxygenation device (ECMO), wherein
  • ECMO extracorporeal membrane oxygenation device
  • a second CO 2 flow released from the extracorporeal oxygenation device is determined
  • an external blood flow through the extracorporeal oxygenation device is determined
  • - a pulmonary blood flow of the subject is estimated from the first CO 2 flow, the second CO 2 flow and the external blood flow.
  • the method according to the invention provides a sufficiently accurate and reliable estimation of the pulmonary blood flow in a non-invasive manner from data which are readily available and easy to obtain.
  • gas exchange during ECO reflects the combined effect of ventilation and perfusion of the native lung and those of the ECO circuit is used for estimation of the pulmonary blood flow.
  • pulmonary blood flow means a blood flow rate (in units of volume per time) of blood flowing through a blood vessel of the lung or leading to the lung, in particular through the pulmonary artery.
  • external blood flow refers to a blood flow rate (in units of volume per time) of blood flowing through the extracorporeal oxygenation device.
  • the expression“external” is used to clarify that said blood flow is external from the subject body.
  • the pulmonary blood flow is estimated, in other words not directly measured, but indirectly determined with a certain accuracy from other measured or known values.
  • the pulmonary blood flow is estimated automatically.
  • the term subject means a living or non-living human or animal, in particular a patient.
  • the subject is connected to an extracorporeal oxygenation device.
  • venous system i.e. from the Vena femoralis or the Vena jugularis interna
  • oxygenated in the external oxygenation device and reintroduced into a vein (in case of veno-venous
  • the method according to the present invention and its scope of protection are not meant to include the step of connecting the subject to the extracorporeal oxygenation device, in other words cannulating the subject.
  • the method described herein is to be performed on a subject which is already connected to an extracorporeal oxygenation device and is thus non-invasive.
  • the extracorporeal oxygenation device may be any suitable oxygenation device known in the art, such as for example a membrane oxygenation device. Such devices remove carbon dioxide from and introduce oxygen into blood flowing through the device.
  • gas flow designates a flow rate (in units of volume per time) of the gas.
  • the first gas flow is determined by measuring the end-tidal gas partial pressure (petG) of the subject, particularly during exhalation, calculating the fraction of end-tidal gas (FeG) by dividing the end-tidal gas partial pressure by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject.
  • the barometric pressure and the lung volume may be measured during the method or previously obtained.
  • the gas partial pressure of the inspired gas (also termed FiO 2 when the gas is O 2 ) must be known to determine the first gas flow. This is particularly relevant for patients who are artificially ventilated with O 2 concentrations higher than that of the surrounding air.
  • the total amount of the gas in the expired air may also be directly measured. For example, this is possible with certain mainstream capnographs in case the exhaled gas is CO 2 .
  • the first gas flow is determined by measuring the end-tidal gas partial pressure (petG) of the subject, particularly during exhalation, determining the mean pulmonary expired gas (pEG) by averaging the measured end-tidal gas partial pressure or end-tidal gas curve over the respiratory cycle, in particular with correction for the inspiratory to expiratory (I:E) ratio, more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume, calculating the fraction of end-tidal gas (FeG) by dividing the mean pulmonary expired gas (pEG) by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation (V LUNG ) of the subject.
  • pEG and the first gas flow (VG LUNG ) is calculated as follows:
  • Mean pulmonary expired gas may also be determined by integration of the expiratory partial pressure curve of the gas.
  • any suitable means of gas detection known in the art may be used, for example in case of CO 2 a side stream or main stream capnograph placed near the mouth of the subject. Therein, in particular, the subject is mechanically ventilated by means of a tracheal tube.
  • the second gas flow reflects gas released at the extracorporeal oxygenation device per unit of time, which is equivalent to gas removed from the blood flowing through the extracorporeal oxygenation device.
  • the second gas flow is determined by measuring expiratory gas partial pressure at an exhaust of the extracorporeal oxygenation device, calculating the fraction of end-tidal gas by dividing the expiratory gas partial pressure by the barometric pressure, and multiplying the fraction of end-tidal gas with the ventilation rate V ECMO (also designated as sweep gas flow) of the extracorporeal oxygenation device, in particular as follows:
  • the amount of the released gas may also be measured directly.
  • the external blood flow through the extracorporeal oxygenation device may be determined for example by measurement of the flow rate using a flow meter.
  • the external blood flow may be a parameter which is set at a pump of the extracorporeal oxygenation device.
  • the ventilation rate (sweep gas flow) of the ECO device is measured.
  • the pulmonary blood flow of the subject may be estimated from the first gas flow, the second gas flow and the external blood flow by means of a computing unit.
  • this unit may be connected to sensors for measuring the expiratory gas partial pressure of the subject, the ventilation rate (sweep gas flow) of the ECO, the expiratory partial pressure of the ECO and/or the blood flow through the ECO device, such that the computing unit receives data from these sensors and computes the estimated pulmonary blood flow.
  • This computing unit may also calculate the first and/or second gas flow from the measured gas partial pressures, in particular as described above, or at least one further computing unit (i.e. as part of a sensor unit) may be provided to implement this function.
  • equation (5) By implementing equations (4) and (6) into equation (5), the following equation can be derived:
  • Equation (8) can be modified with the following assumptions, wherein the sign indicates “approximately equal to”:
  • Equation (5) simplifies (12) to:
  • the sign of the first gas flow VG LUNG depends on the direction of the gas flow. For instance, for CO 2 , which is eliminated at the lung, the sign of VG LUNG is opposite to the VG LUNG for O 2 , which is taken up by the lung.
  • the external blood flow through the extracorporeal oxygenation device and/or a ventilation rate (also called sweep gas flow) of the blood flowing through the extracorporeal oxygenation device is changed, particularly reduced, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow and/or ventilation rate is estimated.
  • the method according to the invention allows the accurate and reliable estimation of the pulmonary blood flow during a weaning trial, when external blood flow and/or ventilation are reduced.
  • the external blood flow through the extracorporeal oxygenation device is changed, particularly reduced, wherein the ventilation rate of the blood flowing through the extracorporeal oxygenation device is kept constant, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow is estimated.
  • the ventilation rate of the blood flowing through the extracorporeal oxygenation device is changed, particularly reduced, wherein the external blood flow through the extracorporeal oxygenation device is kept constant, wherein a change of the pulmonary blood flow of the subject in response to the changed ventilation rate is estimated.
  • the external blood flow through the extracorporeal oxygenation device and the ventilation rate of the blood flowing through the extracorporeal oxygenation device are changed, particularly reduced, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow and the changed ventilation rate is estimated.
  • the external blood flow through the extracorporeal oxygenation device and the ventilation rate of the blood flowing through the extracorporeal oxygenation device are changed, particularly reduced, wherein the ratio between the external blood flow and the ventilation rate stays constant, wherein particularly the ratio between the external blood flow and the ventilation rate equals 1.
  • the external blood flow and ventilation rate are changed concurrently.
  • DVG ECMO determines the amount of the gas transported towards the membrane lung, while V ECMO determines the amount of the gas eliminated over the membrane lung with a major impact on DVGECMO.
  • DVGECMO does therefore not necessarily represent DQ ECMO , when V/Q ECMO differs from 1.
  • VG may decouple from Q ECMO . Accordingly, the ratio DVG ECMO /DVG LUNG is affected by V ECMO despite unchanged blood flows.
  • DVG ECMO In order to correct for a ratio between the ventilation rate and the external blood flow (V/Q) unequal to 1, DVG ECMO can be normalized into a new variable, DVG ECMONORM , only dependent on Q ECMO and independent of V ECMO with formula (15).
  • VG ECMONORM may also be designated “normalized second gas flow throughout this specification.
  • the estimated pulmonary blood flow is more accurate also when the ratio between external blood flow and ventilation changes, in particular during weaning of the subject.
  • the normalization factor and/or the constant is determined from a curve fitting function using pulmonary blood flow data measured at different ventilation-to- perfusion ratios (V/Q).
  • the normalization factor and/or the constant is directly determined from parameters obtained by a blood gas analysis.
  • V/Q ventilation/perfusion
  • sG is the solubility of the gas in blood
  • R is the gas constant
  • T is temperature
  • PvG venous partial pressure
  • PPMG is the post membrane partial pressure of the gas.
  • Kc indicates the solubility equilibration constant of the gas in blood, particularly of the CO 2 + H 2 O « HCO3- + H + reaction at a given pH. It describes the additional liberation of gaseous carbon dioxide from bicarbonate during the passage through the membrane lung.
  • pK is the acid dissociation constant.
  • Equation (16) can be solved for PPMG.
  • the next step is to calculate VGECMO. It should be noted that the factor 1000 is needed to convert the results in ml/min.
  • VG NORM can be calculated using equations (18) and (20).
  • anesthetic gases also exhibit a very low solubility in blood, such that no normalization is necessary when these gases are used to determine the pulmonary blood flow according to the present invention.
  • the normalization factor f’ is calculated according to the formula wherein c is a constant.
  • the V/Q ratio (at the lung) is estimated according to the formula wherein c a,02 is an O 2 concentration of arterial blood of the subject, c v,02 is
  • the O 2 concentration of the venous blood is determined according to the formula , wherein s is the O 2 saturation of the venous blood in per cent, and wherein Hb is the hemoglobin value of the venous blood.
  • the O 2 saturation of the venous blood is determined by blood gas analysis or by a sensor, more particularly a sensor comprised in a pulmonary catheter.
  • the O 2 concentration of the arterial blood is determined according to the formula , wherein s is the O 2 saturation of the arterial blood in per
  • Hb is the hemoglobin value of the arterial blood.
  • O 2 saturation of the arterial blood is assumed to be 100 per cent.
  • the extracorporeal oxygenation device is connected to the subject in parallel to the lung of the subject, wherein particularly the extracorporeal oxygenation device is connected to the subject by means of a first port to a vein of the subject and a second port to an artery of the subject, such that blood is able to flow from the vein through the first port into the extracorporeal oxygenation device, and blood oxygenated by the extracorporeal oxygenation device is able to flow through the second port into the artery.
  • Pulmonary blood flow is especially difficult to measure during veno-arterial extracorporeal oxygenation, particularly ECMO.
  • the method according to the invention is especially advantageous in this context.
  • a second aspect of the invention relates to a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly by means of the method according to the first aspect of the invention, comprising at least the following components:
  • a first unit adapted to determine a first gas flow of a gas exhaled by a subject, wherein the gas is soluble in blood
  • a second unit adapted to determine a second gas flow of the gas released from an extracorporeal oxygenation device to which the subject is connected
  • a third unit adapted to determine an external blood flow through said extracorporeal oxygenation device
  • a computing unit adapted to estimate a pulmonary blood flow of said subject from said first gas flow, said second gas flow and said external blood flow.
  • the gas is CO 2 , O 2 or an anesthetic gas, particularly CO 2 .
  • anesthesia gas refers to a gas used in anesthesia of a patient, such as i.e. sevoflurane or desflurane.
  • the gas is CO 2 or O 2 .
  • the gas is CO 2 .
  • CO 2 as the exhaled gas is advantageous, because CO 2 concentration or partial pressure is especially easy to detect.
  • this embodiment relates to a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly by means of the method according to the first aspect of the invention, comprising at least the following components:
  • a computing unit adapted to estimate a pulmonary blood flow of the subject from the first CO 2 flow, the second CO 2 flow and the external blood flow.
  • This device provides a sufficiently accurate and reliable estimation of the pulmonary blood flow in a non-invasive manner from data which are readily available and easy to obtain.
  • gas exchange during ECO reflects the combined effect of ventilation and perfusion of the native lung and those of the ECO circuit is used for estimation of the pulmonary blood flow.
  • the first unit of the device may be a first sensor or comprise a first sensor for measuring a partial pressure, amount or concentration of the gas exhaled by the subject, particularly a capnograph.
  • the first unit may comprise means for computation of values measured by the first sensor.
  • the values measured by the first sensor may be transmitted to the computing unit and computation may take place in the computing unit.
  • the first unit or the first sensor is adapted to be placed near a mouth of the subject, such that the partial pressure, amount or concentration of the gas exhaled by the subject can be measured by means of the first unit or the first sensor.
  • the second unit of the device may be a second sensor or comprise a second sensor for measuring a partial pressure, amount or concentration of the gas released or exhausted by the extracorporeal oxygenation device, particularly a capnograph.
  • the second unit may comprise means for computation of values measured by the second sensor.
  • the values measured by the second sensor may be transmitted to the computing unit and computation may take place in the computing unit.
  • the second unit or the second sensor is adapted to be placed near an exhaust of the extracorporeal oxygenation device, such that the partial pressure, amount or concentration of the gas released by the extracorporeal oxygenation device can be measured by means of the second unit or the second sensor.
  • the third unit may be a third sensor or comprise a third sensor for measuring a flow rate of the blood flowing through the extracorporeal oxygenation device, particularly a flow meter or flow probe, such as an ultrasonic flow probe.
  • the third unit may be a data processing unit adapted to obtain a flow rate value from a pump transporting the blood through the extracorporeal oxygenation device, wherein the flow rate value reflects the current flow rate provided by the pump. The flow rate values measured or obtained by the third unit may then be transmitted to the computing unit for performing further computing steps.
  • the first unit or the first sensor is adapted to measure the end-tidal partial pressure of the gas (petG) of the subject, particularly during exhalation, and the first unit and/or the computing unit is adapted to determine the first gas flow by calculating the fraction of end-tidal gas (FeG) by dividing the end-tidal partial pressure of the gas by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject.
  • the barometric pressure and the lung volume may be measured during the method or previously obtained.
  • the first unit or the first sensor is adapted to measure the end-tidal partial pressure of the gas (petG) of the subject, particularly during exhalation, and the first unit and/or the computing unit is adapted to determine the first gas flow by determining the mean pulmonary expired gas (pEG) by averaging the measured end-tidal partial pressure of the gas or end-tidal gas curve over the respiratory cycle, in particular with correction for the inspiratory to expiratory (I:E) ratio, more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume, calculating the fraction of end-tidal gas (FeG) by dividing the mean pulmonary expired gas (pEG) by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject.
  • Mean pulmonary expired gas may also be determined by integration of the expiratory pG curve.
  • the second gas flow reflects the gas released at the extracorporeal oxygenation device per unit of time, which is equivalent to the gas removed from the blood flowing through the extracorporeal oxygenation device.
  • the second unit or the second sensor is adapted to measure an expiratory partial pressure of the gas at an exhaust of the extracorporeal oxygenation device
  • the second unit or the computing unit is adapted to determine the second gas flow by calculating the fraction of end-tidal gas by dividing the expiratory partial pressure of the gas by the barometric pressure, and multiplying the fraction of end-tidal gas with the ventilation rate V ECMO (also designated as sweep gas flow) of the extracorporeal oxygenation device.
  • the device for estimating a pulmonary blood flow of a subject comprises a fourth sensor for measuring a ventilation rate (sweep gas flow) of the ECO device.
  • Q ECMO is the external blood flow through the extracorporeal oxygenation device
  • VG LUNG is the first gas flow
  • VG ECMO is the second gas flow.
  • the computing unit is adapted to estimate a change of the pulmonary blood flow of the subject in response to a change, particularly reduction, of the external blood flow and/or a ventilation rate of the blood flowing through the extracorporeal oxygenation device.
  • this formula may be applied if the ratio between ventilation (sweep gas flow) and blood flow through the extracorporeal oxygenation device is constant, more particularly equal to 1.
  • VG ECMO is the second gas flow at any ratio between the ventilation rate and the external blood flow.
  • this formula may be applied if the ratio between ventilation (sweep gas flow) and blood flow through the extracorporeal oxygenation device is not constant, more particularly not equal to 1.
  • the computing unit is adapted to calculate the normalization factor (f) according to the formula wherein c is a constant.
  • the normalization factor reflects the quotient
  • 1N is the first gas flow (VG LUNG ) when the ratio between the ventilation rate (VLUNG) of the lung and the blood flow through the lung (Q LUNG ) equals 1.
  • the computing unit is adapted to estimate the V/Q ratio (at the lung) according to the formula wherein c a,02 is an O 2 concentration of arterial
  • the computing unit is adapted to determine the O 2 concentration of the venous blood according to the formula wherein s is the O 2
  • the O 2 saturation of the venous blood can be determined by blood gas analysis or by a sensor, more particularly a sensor comprised in a pulmonary catheter.
  • the computing unit is adapted to determine the O 2 concentration of the arterial blood according to the formula , wherein s is the O 2
  • Hb is the hemoglobin value of the arterial blood.
  • O 2 saturation of the arterial blood can be assumed to be 100 per cent.
  • the extracorporeal oxygenation device is an extracorporeal membrane oxygenation device (ECMO).
  • ECMO extracorporeal membrane oxygenation device
  • the first unit and/or the second unit comprises a capnograph or is a capnograph, particularly a side stream capnograph or a main stream capnograph.
  • the third unit comprises a flow meter or is a flow meter.
  • a third aspect of the invention relates to a system comprising a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device according to the second aspect of the invention and an extracorporeal oxygenation device, particularly an extracorporeal membrane oxygenation device (ECMO device), wherein the second unit is adapted to determine a second gas flow released from the extracorporeal oxygenation device of the system, and the third unit is adapted to determine an external blood flow through the extracorporeal oxygenation device of the system.
  • ECMO device extracorporeal membrane oxygenation device
  • a fourth aspect of the invention relates to a computer program comprising computer program code for performing at least the following step of the method according to the first aspect of the invention when the computer program is executed on a computer: estimating a pulmonary blood flow of the subject from the first gas flow, the second gas flow and the external blood flow, in particular automatically.
  • a fifth aspect of the invention relates to a computer program comprising computer program code for performing at least the following step when the computer program is executed on a computer: estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device from a first gas flow of a gas exhaled by the subject, wherein the gas is soluble in blood, a second gas flow of the gas released from the extracorporeal oxygenation device and an external blood flow through the extracorporeal oxygenation device, in particular automatically.
  • the computer program according to the fourth or fifth aspect is further adapted to perform any further step of embodiments of the first aspect of the invention, in particular automatically.
  • the computer program according to the fourth or fifth aspect is further adapted to perform at least one of the following steps, in particular automatically:
  • - determining an external blood flow through the extracorporeal oxygenation device - determining the mean pulmonary expired gas (pEG), particularly by averaging the measured end-tidal partial pressure of the gas or end-tidal gas curve over the respiratory cycle, more particularly with correction for the inspiratory to expiratory (I:E) ratio, even more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume;
  • pEG mean pulmonary expired gas
  • V LUNG ventilation rate of the lung and the blood flow through the lung (Q LUNG ) equals 1,
  • c a,02 is an O 2 concentration of arterial blood of the subject
  • c v,02 is an O 2 concentration of venous blood of the subject
  • F i,02 is an inspiratory O 2 fraction
  • F e,02 is an expiratory O 2 fraction.
  • s is an oxygen saturation of the arterial blood.
  • Fig.1 shows a schematic flow diagram illustrating an extracorporeal oxygenation device connected to a subject and a device for estimating a pulmonary blood flow according to the present invention
  • Fig.2 illustrates an experimental ECMO weaning protocol with stepwise reduction of
  • V ECMO and/or Q ECMO V ECMO and/or Q ECMO ;
  • Fig.3 shows a plot of post membrane CO 2 partial pressure at the extracorporeal oxygenation device as a function of ventilation/blood flow ratio from a simulation
  • Fig.4 shows a 3D-surface plot of post membrane CO 2 partial pressure at the extracorporeal oxygenation device as a function of ventilation and blood flow from a simulation
  • Fig.5 shows a 3D-surface plot of CO 2 flow at the ECO device as a function of ventilation and blood flow from a simulation
  • Fig.6 shows the relationship between the ventilation/blood flow ratio at the ECO device and the normalization factor f
  • Fig.7 shows a 3D-surface plot of the normalized CO 2 flow at the ECO device as a function of ventilation and blood flow from a simulation
  • Fig.8 shows the relationship between the ventilation/blood flow ratio at the ECO device and an experimentally determined correction factor c.
  • Fig.9 shows a scatter plot of measured pulmonary blood flow (Q LUNG ) against the first CO 2 flow (VCO2 LUNG ) in animals subjected to ECMO;
  • Fig.10 shows a scatter plot of external blood flow (Q ECMO ) against normalized second
  • VCO2 ECMONORM CO 2 flow in animals subjected to ECMO
  • Fig.11 shows a scatter plot comparing measured change in pulmonary blood flow
  • Fig.12 shows a scatter plot of measured pulmonary blood flow (Q LUNG ) against the first CO 2 flow (VCO2 LUNG ) (A) and the normalized first CO 2 flow (VCO2 LUNGNORM ) (B) in animals subjected to ECMO;
  • Fig 13 shows a scatter plot of external blood flow (Q ECMO ) against second CO 2 flow
  • VCO2 ECMO VCO2 ECMO
  • Fig.14 shows the correlation between measured and calculated pulmonary blood flow
  • Fig.15 schematically depicts an simulator device for in-vitro lung / ECMO simulation comprising two parallel circuits (ECMO circuit, lung circuit) with the ability to shunt the oxygenator of the lung circuit.
  • Blood samples could be drawn after the oxygenator of the ECMO circuit (post membrane), after the oxygenator of the lung circuit (post lung), from the left atrium, the aorta and the right atrium;
  • Fig.16 shows a schematic plot of flow rate vs. time for the experimental setups of the simulator depicted in Fig. 15 under constant V/Q ratio (A) and varying V/Q ratio (B);
  • Fig.17 shows a schematic plot of flow rate vs. time for the experimental setups of the simulator depicted in Fig. 15 under limited venous return (A) and cardiac limitation (B) conditions;
  • Fig.18 shows the true shunt vs. calculated shunt from O 2 and CO 2 content [%] using the simulator device shown in Fig. 15.
  • B: Linear regression showed y 0.76*x + 8.03;
  • Fig.19 shows VCO2 and VO2 [ml/min] measured at the lung circuit and ECMO circuit of the simulator shown in Fig. 15 plotted against blood flow.
  • A VCO2 Gas vs. blood flow at the oxygenator of the lung circuit and the oxygenator of the ECMO circuit [ml/min].
  • B VCO2 Gas , normalized for a V/Q of 1 vs. blood flow.
  • C VCO2 Blood vs. blood flow.
  • D VO2 calculated from blood content vs. blood flow.
  • Fig.21 shows multiple linear regression for differences in CO2/O2 content, blood flow and VCO2/VO2 obtained by means of the simulator shown in Fig. 15. Blood flow is in [ml/min], VCO2 and VO2 are in [ml/min], difference in cCO2/cO2 is in [ml/100ml of blood]. Grids show the calculated model while dots represent actual data points.
  • C VCO2 Gas .
  • D Normalized VCO2 Gas ;
  • Fig.22 shows the relationship between V/Q and respiratory exchange ratio obtained by means of the simulator shown in Fig. 15.
  • A: Scatter plot between V/Q and R with y 1.01 * x + 1.0183.
  • Fig.24 shows bland-Altman plots of the data shown in Fig.23.
  • Fig. 1 is a schematic flow diagram illustrating an extracorporeal oxygenation device 10 connected to a subject and a device for estimating a pulmonary blood flow 20 according to the present invention.
  • the extracorporeal oxygenation device 10 is an extracorporeal membrane oxygenation device (ECMO) connected to the subject in parallel to the native lung L according to a veno-arterial setup, wherein the gas exhaled by the subject is CO 2 .
  • ECMO extracorporeal membrane oxygenation device
  • Body parts of the subject as well as components of the extracorporeal oxygenation device 10 and the device for estimating a pulmonary blood flow 20 are schematically depicted as boxes.
  • the blood vessels connecting the body parts of the subject and the tubings connecting parts of the extracorporeal oxygenation device 10 are shown as lines.
  • Blood flow B and CO 2 flow VCO2 LUNG , VCO2ECMO are indicated as arrows.
  • Blood flow in the subject occurs from the right heart RH via the native lung L, the left heart LA the arterial system A to the organs O and back to the right heart RH via the venous system V.
  • the extracorporeal oxygenation device 10 is connected to the subject via a first port 11 introduced into the venous system V and a second port 12 introduced into the arterial system A. Blood flow through the extracorporeal oxygenation device 10 is driven by a pump 13 and occurs from the first port 11 connected to the venous system V via a membrane 14, where the blood is oxygenated, and via a post membrane compartment PM to the second port 12 connected to the arterial system A.
  • the pulmonary blood flow rate is indicated by Q LUNG and the blood flow rate through the extracorporeal oxygenation device 10 is indicated by Q ECMO . Due to the parallel arrangement of the native lung L and the extracorporeal oxygenation device 10, the total blood flow rate Q total (not shown here) is equal to the sum Q LUNG + Q ECMO .
  • CO 2 partial pressures are indicated at different locations in the subject and the extracorporeal oxygenation device 10: c v CO2 indicates venous CO 2 partial pressure, c ao CO2 indicates arterial CO 2 partial pressure, particularly at the aorta, c LA CO2 indicates CO 2 partial pressure at the left heart LA, and c pm CO2 indicates CO 2 partial pressure at the post membrane compartment PM of the extracorporeal oxygenation device 10.
  • c v CO2 indicates venous CO 2 partial pressure
  • c ao CO2 indicates arterial CO 2 partial pressure, particularly at the aorta
  • c LA CO2 indicates CO 2 partial pressure at the left heart LA
  • c pm CO2 indicates CO 2 partial pressure at the post membrane compartment PM of the extracorporeal oxygenation device 10.
  • the CO 2 flow from the lung L is indicated by VCO2 LUNG and the CO 2 flow from the extracorp
  • FIG.1 components of the device for estimating a pulmonary blood flow 20 are depicted in Fig.1.
  • the device 20 comprises a first unit 21 for determining the first CO 2 flow released from the native lung L during gas exchange.
  • the first unit 21 may comprise a capnograph placed near the subject’s mouth to measure the CO 2 partial pressure in the exhaled air, and optionally a processing unit adapted to convert the measured CO 2 partial pressure to the first CO 2 flow.
  • a separate device i.e. the computing unit 24, may also be used to implement this conversion.
  • the calculation of the first CO 2 flow may take into account the current barometric pressure, the inspiration to expiration ratio and/or the lung ventilation rate (see equations (1) and (2) above).
  • the device 20 comprises a second unit 22 adapted to determine the second CO 2 flow released from the extracorporeal oxygenation device 10 during gas exchange at the membrane 14.
  • the second unit 22 may comprise a capnograph positioned near an exhaust of the extracorporeal oxygenation device 10 to measure the CO 2 partial pressure in the gas mixture released from the extracorporeal oxygenation device 10.
  • the CO 2 partial pressure may be mathematically converted into the second CO 2 flow by means of a processing unit of the second unit 22 or by a separate device, such as the computing unit 24.
  • the current barometric pressure as well as the ventilation of the extracorporeal oxygenation device 10 may be utilized, i.e. by equation (3) shown above.
  • a third unit 23 of the device 20 is configured to measure or otherwise obtain the blood flow rate through the extracorporeal oxygenation device 10, in other words the external blood flow Q ECMO .
  • the third unit 23 may be formed by or comprise a flow meter, such as i.e. an ultrasound flow meter attached to a tubing of the extracorporeal oxygenation device 10.
  • the third unit 23 may be the pump 13 or part of the pump 13, wherein the external blood flow is obtained from a pump setting, or the third unit 23 may be a processing unit adapted to receive a pump setting value from the pump 13 to determine the external blood flow.
  • the device 20 further comprises a computing unit 24 adapted to calculate the pulmonary blood flow Q LUNG of the subject from the first CO 2 flow VCO2 LUNG , the second CO 2 flow VCO2 ECMO and the external blood flow Q ECMO , in particular as described above (see equations (4) to (21) above).
  • the computing unit 24 is connected to the first unit 21, the second unit 22 and the third unit 23 by means of data connections 25 depicted by dashed lines in Fig. 1.
  • These data connections 25 may be realized by cable connections, wireless connections or any other suitable means of connection known in the art.
  • the device 20 shown in Fig.1 may be utilized to estimate the pulmonary blood flow Q LUNG in an easy and non-invasive manner, especially during weaning of the subject from the extracorporeal oxygenation device 10.
  • Example 1 Estimation of pulmonary blood flow during veno-arterial ECMO in a porcine model
  • Pulmonary blood flow i. e. cardiac output (Q LUNG ) and ECMO blood flow (Q ECMO ) were measured using ultrasound flow probes on the pulmonary artery main trunk and arterial ECMO tubing (Transonic PAU series, Ithaca, USA).
  • V/Q ventilation/perfusion
  • Q ECMO and V ECMO were set at 4 L/min each at baseline and afterward reduced– depending on the respective phase - to 75%, 50%, and 25% of baseline with an interval of one minute for each condition (Fig.2).
  • Expiratory concentration of CO 2 at the ECMO exhaust was calculated from the expiratory partial pressure of CO 2 at the ECMO exhaust, and used to calculate VCO2, assuming a barometric pressure of 760mmHg. Calculation of VCO2 for the lung
  • pECO2 Mean pulmonary expired carbon dioxide
  • VCO2 LUNG was calculated as follows:
  • Fig. 1 depicts the situation during VA-ECMO schematically.
  • Q is flow and D v-a CO2 is the inflow-outflow difference in blood CO 2 content in a given segment
  • D v-ao C02 is the difference between venous and aortal CO 2 content
  • D () ⁇ , ⁇ 2 is the difference between venous and left atrial CO 2 content
  • D v _ pm CO2 is the difference between venous and post membrane CO 2 content
  • Equation (E4) and (E6) are then implemented into equation (E5):
  • equation (E8) is modified with the following assumptions, wherein the sign“ ⁇ ” indicates“approximately equal to”:
  • Equation (E5) simplifies (E12) to:
  • VCO2 ECMO is influenced by V ECMO and Q ECMO .
  • Q ECMO determines the amount of CO 2 transported towards the membrane lung, while V ECMO determines the amount of CO 2 eliminated over the membrane lung with a major impact on DVCO2 ECMO .
  • DVCO2 ECMO does therefore not necessarily represent DQ ECMO , when V/Q ECMO differs from 1.
  • VCO2 may decouple from Q ECMO . Accordingly, the ratio DVCO2 ECMO /DVCO2 LUNG is affected by V ECMO despite unchanged blood flows.
  • sCO2 is the solubility of CO 2 in blood
  • R is the gas constant
  • T is temperature
  • PvCO2 is venous partial pressure
  • PPMCO2 is the post membrane CO 2 partial pressure. It is assumed that PPMCO 2 is equal to PeCO2ECMO, which is measured at the ECMO gas outlet.
  • Kc indicates the equilibration constant of the CO 2 + H2O « HCO3- + H + reaction at a given pH. It describes the additional liberation of gaseous carbon dioxide from bicarbonate during the passage through the membrane lung.
  • pK is the acid dissociation constant.
  • a plot of this function shows the known hyperbolic dependency of alveolar, i. e. postmembrane pCO2 from ventilation (Fig.3 and 4; V and Q values are assumed from 0 to 4 with an interval of 0.25 l/min).
  • the next step is to calculate VCO2ECMO and plot the function (Fig. 5). Note that the factor 1000 is needed to convert the results in ml/min.
  • the diverging effects of the ventilation on the ECMO on PCO 2 and VCO 2 become apparent.
  • the given VCO 2 is now normalized to a V/Q ratio of 1.
  • VCO2 NORM can be calculated using eq. (E19, E21).
  • This new function VCO 2NORM is independent of V or V/Q (Fig.7).
  • VCO2 NORM is dependent on Q and PvCO2, as well as the constant c which itself is dependent on temperature and pH.
  • VCO2ECMO was between 205 and 243 ml/min, while VCO2 LUNG was between 13 and 193 ml/min, corresponding to a measured Q LUNG of 10 to 964 mL/min (Table 1) and representing a normal VCO2 production for swine.
  • Q LUNG increased from its low baseline values to 928 - 1550 ml/min, and 328 - 1914 ml/min, respectively.
  • Q ECMO phase:“reduction of V”
  • Q LUNG increased from its low baseline values to 928 - 1550 ml/min, and 328 - 1914 ml/min, respectively.
  • Q ECMO phase:“reduction of V”
  • it remained close to baseline (2 - 980 ml/min).
  • VCO2 LUNG followed the changes in Q LUNG to 74.2– 232 ml/min (rise of 28– 57 ml/min from baseline) for“reduction of V&Q” and 39– 233 ml/min for“reduction of Q” (rise of 18– 45 ml/min from baseline), and remained steady at full Q ECMO (phase:“reduction of V”, 21– 188 ml/min, change of 7– 8 ml/min from baseline), with a high correlation between Q LUNG and VCO2 LUNG (Fig.9).
  • phase“reduction of V” 98.2 – 100.4 % of baseline or 3989 - 4186 l/min
  • phase“reduction of Q” reduction had to be stopped at 50% in one animal due to hemodynamic instability.
  • Q ECMO was reduced to approximately a quarter (25.4– 49.5% of baseline or 1048 -1994 ml/min).
  • the VCO2 ECMO values for phase:“reduction of V&Q” dropped to roughly a quarter from baseline (64 - 74 ml/min, 25.2– 33.6% of baseline) in parallel with reduced Q ECMO .
  • VCO2 ECMONORM In phase“reduction of V”, reducing V ECMO without any change in Q ECMO , VCO2 ECMONORM was 194– 249 ml/min or 93.3– 100.1 % of baseline. Without normalization, VCO2 ECMO decoupled from Q ECMO with a decrease from 205– 246 ml/min to 73– 96 ml/min in this phase. During phase:“reduction of Q”, VCO2 ECMONORM was 84– 156 ml/min or 38.3– 57.9 % of baseline. VCO2ECMONORM correlated highly with Q ECMO (Fig.10). Calculation of Q LUNG
  • the model presented herein for the estimation of Q LUNG using the change in VCO2 and change in Q ECMO predicts the directional change and absolute amount of pulmonary blood flow, i. e. cardiac output with acceptable accuracy.
  • the measurements needed are Q ECMO , V ECMO , V LUNG , peCO2 ECMO , etCO2 LUNG with standard side-stream capnographs, all of which are readily available in an ICU setting or an operating theater and require no specific training.
  • a closer look at formula (E8) as the background of the hypothesis shows an adaptation of the classic Berggren-shunt equation.
  • VA-ECMO is in concept an anatomical right-to-left shunt, where the ability to ventilate and oxygenate the shunted blood will clearly affect its functional influence (Fig. 1).
  • V ECMO 0 at any Q ECMO
  • Q ECMO 0 at any V ECMO
  • VCO2 ECMO only represents the shunt correctly, as long as V/Q on the ECMO are kept at a ratio of 1 (in phase“reduction of V&Q”).
  • V ECMO sweep gas flow
  • VQ, V and Q refers to the reduction in each phase.
  • DQ[real] is the measured delta in pulmonary blood flow
  • DQ[calculated] is the calculated delta in pulmonary blood flow
  • DQ[ECMO] is the change in ECMO flow [ml/min].
  • DVCO2[LUNG] and DVCO2[ECMONORM] are the changes in VCO2 [ml/min].
  • VCO2ECMO should increase simultaneously with the new steady state in order to fulfill formula (E5).
  • the short measurement periods did preclude a steady state for CO 2 elimination.
  • Q LUNG was calculated through a deliberate step change in VCO2, a steady state is not necessary, as there is no need for an absolute reference point.
  • VCO2 LUNG estimated from end-tidal pCO2 in healthy lungs - showed an acceptable relationship with Q LUNG , but stable minute ventilation on the lung was mandatory.
  • Q LUNG is the quantity to be calculated, a normalization procedure is not possible.
  • VCO2 LUNG can only represent blood flow that participates in gas exchange, shunt due to supine positioning of the animals could explain the bias of underestimation of pulmonary blood flow with the method presented herein.
  • blood flow estimation from exhaled CO 2 in a VA-ECMO setting is feasible with simple, non-invasive measurements and acceptable accuracy.
  • This concept can be derived from basic physiological equations and accuracy can be increased with normalizing the ECMO sweep gas flow and blood flow to a V/Q ratio of 1. This may be implemented to realize a simple, reproducible weaning procedure for the liberation from VA-ECMO devices.
  • Example 2 Cardiac output on veno arterial (VA) Extracorporeal membrane oxygenation (ECMO): Estimation by gas exchange
  • the animals (type: domestic pigs, weight approximately: 40-50 kg) were sedated with ketamine (15mg/kg), midazolam (0.5mg/kg) and methadone (0.2 mg/kg) administered intramuscular (IM) behind the ear. Fifteen minutes after the injection the sedation was evaluated and if deemed insufficient, further ketamine (up to 5 mg/kg) and midazolam (up to a maximum of 1 mg/kg) were administered. Once the sedation was judged adequate, the pigs were lifted on a table and supplemented with oxygen administered through a facial mask.
  • ketamine 15mg/kg
  • midazolam 0.5mg/kg
  • methadone 0.2 mg/kg
  • IM intramuscular
  • a central venous cannula was placed through the right jugular vein and after preparation of the surgical field, the induction of general anesthesia was provided through propofol to effect (1-4 mg/kg). Cefuroxime (1.5g) was given at induction of general anesthesia and 6 hours later. After intubation of the trachea, anesthesia was deepened and maintained with total intravenous anesthesia (TIVA) based on propofol (2- 8 mg ⁇ kg -1 ⁇ h -1 ) and fentanyl (5-30 mg ⁇ kg -1 ⁇ h -1 ). The doses of TIVA were titrated aiming at the absence of nociceptive autonomic responses and varied accordingly to the intensity of nociceptive stimuli.
  • TIVA total intravenous anesthesia
  • Additional boluses of fentanyl (100-200 mg) and/or increases of the rate infusions were provided in case an increase of 20% from the baseline of HR and blood pressure.
  • Positive pressure ventilation was started after tracheal intubation in a volume-controlled mode (Servo-I, Maquet Critical Care, Solna, Sweden) using PEEP of 5cmH2O, an FiO 2 of 0.30, and a tidal volume of 8- 12mL/kg body weight, targeting a PaCO 2 of 40-45 mmHg.
  • MAP mean arterial blood pressure
  • the depth of anesthesia and adequacy of nociception was continuously monitored by targeting a bispectral index ⁇ 60 (BIS Quatro, Covidien, Mansfield, MA, USA) and through tracking of nociceptive withdrawal reflexes (Pain tracker, Dolosys, GmBh, Germany). After 6-8 hours after the spinal injection, ropivacaine was repeated in case the analgesia was deemed insufficient.
  • tidal ventilation was continued with the respiratory rate fixed at 6-8/min and tidal volume of 10 ml/kg.
  • the flow rate of oxygenator sweep gas (60% O 2 , higher if needed) was initially adjusted to keep arterial pCO 2 in the normal range (ABL90Flex, Radiometer Medical Aps, Br ⁇ nsh ⁇ j, Denmark).
  • a left carotid artery catheter (5Fr introducer sheath) for arterial pressure measurement and blood sampling
  • a left atrial catheter was surgically placed for left atrial blood gas sampling.
  • a pulmonary artery catheter was placed through an introductory sheath in the right jugular vein for measurement of pulmonary artery pressure and mixed venous blood gas sampling.
  • the thoracic cavity was accessed via a sternotomy and the pericardium opened. After administration of 5000 U.I.
  • a bronchial blocker was introduced in the left lung (9.0FR, Uniblocker, Fuji Systems Corporation, Nishigo, Japan) and used to intermittently exclude the left lung from ventilation.
  • Disposable fiberoptics (Ambu aScope 3, Xiamen, China) were used to control bronchial blocker placement.
  • Ringer’s lactate was infused at a rate of 5 mL/kg/h, and thereafter reduced progressively of 25% each hour down to 3mL/kg/h, provided cardiovascular stability.
  • Hydroxyethyl starch HES; 6% Voluven; Fresenius Kabi, Bad Homburg, Germany
  • Intravascular and airway pressures were measured using transducers (xtrans®, Codan Medical, Germany) and a multi-modular monitor (S/5 Critical Care Monitor®; Datex-Ohmeda, GE Healthcare, Helsinki, Finland), including ECG and end-tidal CO 2 .
  • Output from pressure transducers and ultrasonic blood flow probes were recorded at 240 Hz in a data acquisition system (LabviewTM; National Instruments Corp., Austin, TX, USA), and processed off-line using a customized analysis software (Soleasy, Alea Solutions, Switzerland). Additionally a volumetric CO 2 measurement device was installed at the lung with dedicated data recording (Capnostat 5, Hamilton, Bonaduz, Switzerland). Dead space on a breath by breath analysis was recorded throughout the experiment.
  • a sidestream capnography was installed attached to the gas exhaust port.
  • the protocol consisted of weaning trials from VA-ECMO under different pulmonary conditions. Reductions in ECMO blood flow was stepwise. During the process of weaning, the function of RV and LV was supported with volume load, and once the preload was deemed adequate with perfusion of inotropes (dobutamine: 0.5-5 mcg/kg/min). In case of a major drop in blood pressure, the attempt was aborted and noradrenaline (0.1-1 mcg/kg/min) combined to dobutamine in order to restore hemodynamic stability.
  • mice were randomized into two experimental groups in which either dead space or shunt was induced.
  • group 1 first shunt was produced by temporarily inducing one lung ventilation by disconnecting the left lung from the respirator with a bronchial blocker. After measurements in this state, two-lung ventilation was initiated and the left pulmonary artery was temporarily clamped and measurements were redone. The animals in group 2 first had their pulmonary artery clamped, thus creating dead space before one-lung-ventilation was introduced. After measurements during each of these two experimental steps, two-lung-ventilation was reinitiated and the clamping was released.
  • Q ECMO blood flow was set to 4 liters per minute (l/min). If this could not be achieved, the maximum flow was defined as the highest Q ECMO possible without suctioning of the cannulae over the respiratory cycle, rounded down in steps of 500ml/min (e.g. maximum flow 3.2 liters, Q ECMO was set to 3 l/min). Sweep gas flow (V ECMO ) then was set to match half Q ECMO , which resulted in a V/Q ratio of 0.5.
  • the first step consisted of a consecutive, stepwise reduction in sweep gas flow of 500ml/min to zero, thus producing a diminishing V/Q ratio. Then sweep gas flow was increased in steps of 500ml/min up to 4l/min but not higher than Q ECMO , which resulted in a rising V/Q ratio. Q ECMO and ventilator settings were not changed. After each change in V ECMO , the settings remained this way for 2 minutes.
  • the second step then consisted of reducing Q ECMO in steps of 500ml/min as long as the RV and LV function could be supported enough with inotropes and vasopressors to produce a systemic mean arterial pressure of at least 40 mmHg.
  • the new flow settings were maintained until pulmonary blood flow remained unchanged. This time was limited to a maximum of 5 minutes, after which it was continued with the next reduction of blood flow by 500ml/min. If the cardiorespiratory system of the animal did not support the weaning, Q ECMO was set to initial values and the experimental step was redone once. V ECMO remained unchanged.
  • Step 3 consisted of the same ECMO flow changes as described in Step 2, but with a simultaneous reduction of V ECMO to produce a V/Q ratio of 1.
  • Blood gas analyses were drawn at the beginning of each step. Additionally there were blood gas analyses after each reduction of 1 l/min Q ECMO and/or V ECMO . This lead to precise information about the immediate changes in gas content and acid-base status and provided a comparison between gaseous measurements and blood measurements. The relationships between carbon dioxide elimination over the lung or membrane and the transported carbon dioxide could be investigated. Blood oxygen and blood carbon dioxide content was calculated according to the method of Dash RK, Bassingthwaighte JB. Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng.2010;38(4):1683-701).
  • ARDS acute respiratory distress syndrome
  • V/Q ECMO was corrected towards a value of 1, only depending on Q ECMO .
  • FIG. 12A there is a linear relationship between pulmonary blood flow (Q LUNG , Lung Blood Flow) calculated according to the method of the present invention and measured CO 2 elimination via the lung (VCO2 LUNG , Lung VCO2). This dependency is stronger when VCO2 LUNG is normalized to reflect the influence of the ventilation/perfusion ratio V/Q as shown in Fig.12B. For the normalization, V/Q was approximated by
  • c a,O2 is the arterial O 2 concentration
  • c v,O2 is the venous O 2 concentration
  • F i,O2 is the inspiratory O 2 fraction
  • F e,O2 is the expiratory O 2 fraction.
  • Fig. 14 A-D show correlation plots of measured pulmonary blood flow Q LUNG (abscissa) and pulmonary blood flow Q LUNG (ordinate) as calculated according to the method of the present invention.
  • Q LUNG was calculated from measured O 2 exchange at the lung and the ECMO (VO2 LUNG , VO2 ECMO ) and blood flow through the ECMO (Q ECMO ).
  • equation 13 was used to calculate Q LUNG , wherein G is molecular oxygen (O 2 ).
  • O 2 molecular oxygen
  • FIG. 14B Q LUNG was calculated from measured CO 2 exchange at the lung and the ECMO (VCO2 LUNG , VCO2 ECMO ) and blood flow through the ECMO (Q ECMO ).
  • Q LUNG was determined from equation 13, where G equals carbon dioxide (CO 2 ).
  • the oxygen concentration was estimated according to
  • s designates oxygen saturation in per cent
  • Hb designates the hemoglobin value or hemoglobin level in grams per deciliter.
  • the venous oxygen saturation was determined by direct measurement via a pulmonary catheter (Fig.14 C) or by blood gas analysis (Fig.14D). The arterial oxygen saturation was assumed to be 100 per cent. FiO2 was pre-set in the experiment and FeO2 was directly measured.
  • Example 3 Cardiac output estimations based on gas exchange during extracorporeal membrane oxygenation– an in vitro model
  • the simulation consisted of two parallel circuits - one representing the ECMO blood flow with extracorporeal gas exchange, the other lung and heart, merged into the systemic circulation (Fig. 15).
  • One circuit 31 represents the human heart and lung. It consisted of a micro- diagonal pump 40 (DeltaStream DP-II, Medos, Stolberg, Germany), generating non-pulsatile flow, as the heart and an oxygenator 37 (OxyLung QUADROX-i Pediatric Oxygenators; MAQUET, Hirrlingen, Germany) as the natural lung, including a blood flow bypass 43 around the OxyLUNG for the simulation of anatomical or functional right-to-left shunt.
  • the second circuit 30, consisting of the same type of pump 40 and oxygenators 37, represents the ECMO (OxyECMO). Both oxygenators 37 were operated at a fraction of inspired oxygen of 50% throughout the experiment. These two circuits 30, 31 (Lung and ECMO) were merged into one mixed flow, representing the Aorta and then guided into a simulated metabolic chamber 32. Here, over two oxygenators 37 (OxyVCO2/O2, Terumo Capiox RX25R, Ann Arbor, MI, USA) carbon dioxide was introduced into the system and oxygen washed out with a nitrogen/carbon dioxide gas blend to ensure venous pCO2 values between 50 and 80 mmHg and mixed venous saturations of 70– 90 %.
  • OxyVCO2/O2 Terumo Capiox RX25R
  • Gas flow was regulated with high precision flow control valves (Vögtlin RED-Y, Basel-Land, Switzerland). Blood was collected in a venous, air-free reservoir bag above the functional right atrium to ensure steady perfusate supply at different blood flow rates. Blood flow between the circuits 30,31 and the shunt 43 was regulated with simple flow restrictors 39.
  • Priming volume of the system was approximately 2.2 liters. It was filled with a mixture of discarded human red blood cells and lactated Ringer’s solution in a ratio of 3:1 to reach a hemoglobin value of 8 - 10 g/L. 50 - 100 mmol of Sodium Bicarbonate was added to reach physiological pH values between 7.3 -7.4. Glucose 20% was added to keep glucose level above 5 mmol/l. Boluses of 5000 I. E. Heparin were added every 2 to 3 hours to prevent clotting. The system was heated to 36.8°C using a temperature control system (HCV, Type 20–602, JostraFumedica, Muri/CH).
  • HCV temperature control system
  • Exhaust CO 2 at the ECMO was measured using a standard side-stream capnometer (Vamos, Dräger, Lübeck, Germany) with a constant 200 mL/min sidestream flow and a measurement accuracy of +/- 3.3 mmHg + 8% relative error.
  • a point of care device Cobas b 123, Roche Diagnostics, Basel, Switzerland.
  • Blood flow was continuously measured using liquid flow meters 38 (Levitronix, Zurich, Switzerland) at the indicated locations in Fig. 15. Gas flow was set and recorded manually at the gas blenders for Oxy Lung and Oxy ECMO and digitally using the flow control valves for Oxy VCO2/O2 .
  • lung blood flow was not directly regulated but was the indirect result of changing the venous pool at unchanged rotations per minute (steps 7– 10 in table 3).
  • lung gas flow was kept constant at 1.5 liters/min (FiO2 50%) and remained unchanged during each experimental step.
  • Blood CO 2 content (cCO2) was calculated for each sampling site with the method of Dash RK, Bassingthwaighte JB. Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O 2 , CO 2 , pH, 2,3-DPG and temperature levels. Ann Biomed Eng. 2010;38(4):1683-701).
  • VCO2 was calculated either from venous-arterial CO2 content difference multiplied by blood flow (VCO2 Blood ) or from gaseous measurements by multiplying the exhausted CO2 fraction times the gas flow (VCO2 Gas ).
  • O 2 content (cO 2 ) was calculated for each sampling site using formula 1 (pO 2 : O 2 partial pressure [mmHg], sO 2 : Saturation, Hb: Hemoglobin [g/L]):
  • VO2 was calculated by multiplying the arterial-venous O 2 blood content difference with blood flow.
  • Pulmonary right-to-left shunt fraction was calculated as shunt blood flow divided by total lung flow and compared to the classic Berggren shunt equation.
  • mean total flow was 2175 +/- 284 ml/min with a minimum of 1688 and a maximum of 2520 ml/min. This was achieved by a mean Q ECMO of 1825 +/- 192 ml/min and a mean QLung of 350 +/- 157 ml/min, as defined per study protocol.
  • Mean VCO2 Gas at OxyECMO was 87 +/- 13 ml/min and mean VCO2 Blood was 121 +/- 59 ml/min. VO2 values were 44 +/- 9 ml/min.
  • mean VCO2 Gas was 43 +/- 13 ml/min while mean VCO2 Blood was 60 +/- 15 ml/min.
  • Mean VO2 was 7 +/- 3.5 ml/min.
  • Mean arterial pH was 7.39 +/- 0.09 and mean venous pH was 7.29 +/- 0.09 at Baseline.
  • Baseline showed a mixed venous saturation of 83.8 +/- 8.0 %, corresponding to an O 2 content of 10.3 +/- 1.3 ml/100ml of blood and a mean mixed venous pCO2 of 49.7 +/- 4.4 mmHg corresponding to a CO 2 content of 54.5 +/- 12.6 ml/100ml of blood.
  • mean saturation was 98.2 +/- 3.4 % corresponding to an O 2 content of 12.3 +/- 1.0 ml/100ml of blood while mean pCO2 was 34.3 +/- 3.5 mmHg corresponding to a CO 2 content of 47.4 +/- 12.0 ml/100ml of blood.
  • OxyVCO2/VO2 N2 gas flow was kept between 4 and 6 liters/min while CO 2 gas flow was between 300 and 500 ml/min.
  • VLung Ventilation at the lung (VLung) was set between 1.4 and 1.5 L/min and remained unchanged.
  • V ECMO was either kept steady between 1.4 and 1.5 L/min for the maneuvers with a varying V/Q ECMO (steps 4– 6) and followed blood flow in the remaining maneuvers.
  • the correction factor c used in the normalization of V/Q was 10.8 +/- 2.1.
  • pulmonary shunt has a linear relationship to the difference in CO 2 content as it does with O 2 . This is of importance, as shunt has an influence on the model of calculating pulmonary blood flow according to the invention.
  • shunt or venous admixture is seen as the cause of hypoxemia, while excessive dead space ventilation with exhaustion of respiratory reserves explains hypercapnia.
  • pulmonary minute ventilation is kept constant, as would be the case during controlled mechanical ventilation, shunt is also a cause of increased arterial pCO2.
  • the results described above show that there is a strong relationship between blood flow through the oxygenator and VCO2 and VO2 in the gas phase.
  • the correlation with VCO2 and blood flow is improved through the normalization described above.
  • the normalization function using a correction factor c can estimate VCO2 from any V/Q for a V/Q of 1.
  • the calculation of c can be done by collecting a venous blood gas sample. If conditions remain steady, c does not have to be calculated for each weaning step.
  • ventilation at the lung was at a fixed rate of 1.5 L/min. Correlation between blood flow and VCO2 works best, if V/Q stays one.
  • VCO2 Gas might be corrected using alternative estimations of V/Q.
  • Multiple approaches exist such as MIGET, electrical impedance tomography and positron emission tomography.
  • a simple clinical approach would be the use of respiratory exchange ratio, which in theory might reflect V/Q. This would allow a bedside approach to estimating pulmonary blood flow during veno-arterial ECMO therapy.
  • a normalization using the respiratory exchange ratio introduces an error and decreases accuracy of the calculations. However, it also decreases the intercept and thus the bias introduced into the calculations. It therefore might be clinically more useful than using the not normalized VCO2 values.

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Abstract

The invention relates to a method for estimating a pulmonary blood flow (QLUNG) of a subject connected to an extracorporeal oxygenation device (10), wherein a first gas flow (VGLUNG) of a gas (G) exhaled by the subject is determined, a second gas flow (VGECMO) released from the extracorporeal oxygenation device (10) is determined, an external blood flow (QECMO) through the extracorporeal oxygenation device (10) is determined, and a pulmonary blood flow (QLUNG) of the subject is estimated from said first gas flow (VGLUNG), said second gas flow (VGECMO) and said external blood flow (QECMO), a device (20) for estimating a pulmonary blood flow (QLUNG) of a subject comprising a first unit (21) for determining the first gas flow (VGLUNG), a second unit (22) for determining the second gas flow (VGECMO), a third unit (23) for determining the external blood flow (QECMO) and a computing unit (24) for estimating the pulmonary blood flow (QLUNG) and a computer program for estimating a pulmonary blood flow (QLUNG).

Description

Method, device and computer program for estimating a pulmonary blood flow of a subject
The invention relates to a method, a device and a computer program for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly an extracorporeal membrane oxygenation device (ECMO).
Extracorporeal oxygenation (ECO), in particular extracorporeal membrane oxygenation (ECMO), is increasingly used as rescue therapy for severe cardiopulmonary failure.
In this technique, two large blood vessels of the subject are typically cannulated and connected to an external blood oxygenation device, such as a membrane oxygenator, to assist native lung function. Therein, blood drained from the venous system is oxygenated outside of the body, and then reintroduced either to the venous system (veno-venous extracorporeal oxygenation) or to the arterial system (veno-arterial extracorporeal oxygenation). Veno-venous extracorporeal oxygenation is typically used for patients with respiratory failure, while veno-arterial extracorporeal oxygenation can also be applied for patients suffering from cardiac and/or respiratory failure.
Exemplary ECMO devices of the prior art are described in WO 2013/128375 A1 and EP 2 455116 A1.
Liberation from extracorporeal oxygenation after improvement of heart and/or lung function is also termed weaning. During this procedure, blood flow (perfusion) and/or blood ventilation in the external oxygenator are typically reduced until the patient can be completely removed from the device.
Mortality during or after ECO treatment remains extremely high, often above 50%. Early liberation from ECO (weaning) carries a favorable prognosis. Weaning a patient from the extracorporeal support according to the prior art remains challenging and is based on expert opinion and experience rather than an objective, standardized approach.
To monitor the weaning procedure, the accurate and reliable assessment of blood flow through the lungs is highly desirable.
Pulmonary blood flow can be measured directly in a clinical setting i.e. by echocardiography or a pulmonary catheter. However, echocardiography is assessor dependent and not standardized, and measurement by a pulmonary catheter is difficult during ECO treatment. In animals, pulmonary blood flow can also be measured by an ultrasound flow probe on the pulmonary artery main trunk. However, especially in veno-arterial (VA) ECO treatment, the native heart and lung work in parallel with the extracorporeal circuit and the assessment of native cardiac output (i. e. blood flow through the lungs) is difficult. In particular, the ongoing unloading of the right ventricle even at low ECO blood flow makes assessment of cardiac function during ECO weaning challenging.
Therefore, it is the objective of the present invention to provide a method for estimating pulmonary blood flow of a subject connected to an extracorporeal oxygenation device which is improved in view of the described drawbacks of the prior art.
This objective is attained by the subject matter of the independent claims 1 (method), 8 (device) and 17 (computer program).
A first aspect of the invention relates to a method for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, in particular an extracorporeal membrane oxygenation device (ECMO), wherein
- a first gas flow of a gas exhaled by the subject is determined, wherein the gas is soluble in blood,
- a second gas flow of said gas released from the extracorporeal oxygenation device is determined,
- an external blood flow through the extracorporeal oxygenation device is determined, - a pulmonary blood flow of the subject is estimated from the first gas flow, the second gas flow and the external blood flow.
The gas may be any gas, which is at least in part soluble in blood and may be exhaled by the subject. Therein, the term“soluble” may relate to a solution mechanism of the gas involving or not involving a chemical reaction of the gas, such as i.e. the reaction CO2 + H2O « HCO3- + H+ of CO2.
In certain embodiments, the gas exhaled by the subject is CO2, O2 or an anesthetic gas, particularly CO2.
In certain embodiments, the gas exhaled by the subject is CO2 or O2.
The term“anesthetic gas”, as used herein, refers to a gas used in anesthesia of a patient, such as i.e. sevoflurane or desflurane.
Using CO2 as the exhaled gas is advantageous, because CO2 concentration or partial pressure is especially easy to detect.
In certain embodiments, the gas exhaled by the subject is CO2. Therefore, this embodiment relates to a method for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, in particular an extracorporeal membrane oxygenation device (ECMO), wherein
- a first CO2 flow exhaled by the subject is determined,
- a second CO2 flow released from the extracorporeal oxygenation device is determined, - an external blood flow through the extracorporeal oxygenation device is determined, and - a pulmonary blood flow of the subject is estimated from the first CO2 flow, the second CO2 flow and the external blood flow.
The method according to the invention provides a sufficiently accurate and reliable estimation of the pulmonary blood flow in a non-invasive manner from data which are readily available and easy to obtain.
To this end, the discovery that gas exchange during ECO reflects the combined effect of ventilation and perfusion of the native lung and those of the ECO circuit is used for estimation of the pulmonary blood flow.
The term“pulmonary blood flow” as used herein means a blood flow rate (in units of volume per time) of blood flowing through a blood vessel of the lung or leading to the lung, in particular through the pulmonary artery.
The term“external blood flow” refers to a blood flow rate (in units of volume per time) of blood flowing through the extracorporeal oxygenation device. The expression“external” is used to clarify that said blood flow is external from the subject body.
By means of the method according to the invention, the pulmonary blood flow is estimated, in other words not directly measured, but indirectly determined with a certain accuracy from other measured or known values. In particular, the pulmonary blood flow is estimated automatically.
Herein, the term subject means a living or non-living human or animal, in particular a patient. The subject is connected to an extracorporeal oxygenation device. This means that at least two cannula are placed in the subject’s blood vessels, and the cannula are in flow connection with an external oxygenation device, such that blood can be drained from the venous system (i.e. from the Vena femoralis or the Vena jugularis interna), oxygenated in the external oxygenation device and reintroduced into a vein (in case of veno-venous extracorporeal oxygenation) or into an arteria of the subject (in case of veno-arterial extracorporeal oxygenation, i.e. into the Arteria femoralis).
It should be noted that the method according to the present invention and its scope of protection are not meant to include the step of connecting the subject to the extracorporeal oxygenation device, in other words cannulating the subject. In contrast, the method described herein is to be performed on a subject which is already connected to an extracorporeal oxygenation device and is thus non-invasive.
The extracorporeal oxygenation device may be any suitable oxygenation device known in the art, such as for example a membrane oxygenation device. Such devices remove carbon dioxide from and introduce oxygen into blood flowing through the device.
As used herein, the term“gas flow” designates a flow rate (in units of volume per time) of the gas.
The gas is exhaled by the subject, in other words released from the subject during breathing. In certain embodiments, the first gas flow is determined by measuring the end-tidal gas partial pressure (petG) of the subject, particularly during exhalation, calculating the fraction of end-tidal gas (FeG) by dividing the end-tidal gas partial pressure by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject. The barometric pressure and the lung volume may be measured during the method or previously obtained.
In particular, in case the gas is O2, in addition to the expiratory gas partial pressure, the gas partial pressure of the inspired gas (also termed FiO2 when the gas is O2) must be known to determine the first gas flow. This is particularly relevant for patients who are artificially ventilated with O2 concentrations higher than that of the surrounding air.
As an alternative to determining the expiratory end-tidal partial pressure of the gas, the total amount of the gas in the expired air may also be directly measured. For example, this is possible with certain mainstream capnographs in case the exhaled gas is CO2.
In certain embodiments, the first gas flow is determined by measuring the end-tidal gas partial pressure (petG) of the subject, particularly during exhalation, determining the mean pulmonary expired gas (pEG) by averaging the measured end-tidal gas partial pressure or end-tidal gas curve over the respiratory cycle, in particular with correction for the inspiratory to expiratory (I:E) ratio, more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume, calculating the fraction of end-tidal gas (FeG) by dividing the mean pulmonary expired gas (pEG) by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation (VLUNG) of the subject. In particular, pEG and the first gas flow (VGLUNG) is calculated as follows:
Figure imgf000006_0001
Mean pulmonary expired gas may also be determined by integration of the expiratory partial pressure curve of the gas.
To measure the end-tidal gas partial pressure (petG), any suitable means of gas detection known in the art may be used, for example in case of CO2 a side stream or main stream capnograph placed near the mouth of the subject. Therein, in particular, the subject is mechanically ventilated by means of a tracheal tube.
The second gas flow reflects gas released at the extracorporeal oxygenation device per unit of time, which is equivalent to gas removed from the blood flowing through the extracorporeal oxygenation device.
In certain embodiments, the second gas flow is determined by measuring expiratory gas partial pressure at an exhaust of the extracorporeal oxygenation device, calculating the fraction of end-tidal gas by dividing the expiratory gas partial pressure by the barometric pressure, and multiplying the fraction of end-tidal gas with the ventilation rate VECMO (also designated as sweep gas flow) of the extracorporeal oxygenation device, in particular as follows:
Figure imgf000007_0001
Of course, the amount of the released gas may also be measured directly.
The external blood flow through the extracorporeal oxygenation device may be determined for example by measurement of the flow rate using a flow meter. Alternatively, for example, the external blood flow may be a parameter which is set at a pump of the extracorporeal oxygenation device.
In particular, the ventilation rate (sweep gas flow) of the ECO device is measured.
The pulmonary blood flow of the subject may be estimated from the first gas flow, the second gas flow and the external blood flow by means of a computing unit. In particular, this unit may be connected to sensors for measuring the expiratory gas partial pressure of the subject, the ventilation rate (sweep gas flow) of the ECO, the expiratory partial pressure of the ECO and/or the blood flow through the ECO device, such that the computing unit receives data from these sensors and computes the estimated pulmonary blood flow. This computing unit may also calculate the first and/or second gas flow from the measured gas partial pressures, in particular as described above, or at least one further computing unit (i.e. as part of a sensor unit) may be provided to implement this function.
In certain embodiments, the pulmonary blood flow is estimated according to the formula QLUNG=QECMO*(-VGLUNG/VGECMO), wherein QECMO is the external blood flow through the extracorporeal oxygenation device, VGLUNG is the first gas flow and VGECMO is the second gas flow.
In particular for veno-arterial ECO or ECMO, the following equations are satisfied, wherein Q is flow (Qtotal is the sum of the blood flow through the lung, QLUNG and the blood flow through the ECO device, QECMO) and Dv-aG is the inflow-outflow difference in blood gas content in a given segment Dn_aoG is the difference between venous and aortal gas content, Dn_LAG is the difference between venous and left atrial gas content and Dn_pmG is the difference between venous and post membrane gas content):
4 Qtotal = QLUNG + QECMO
5 VGtotal = VGLUNG + VG ECMO
6 VG = Q * Dv-aG
By implementing equations (4) and (6) into equation (5), the following equation can be derived:
7 Qtotal * Dn_aoG = QLUNG * Dn_LAG + QECMO * Dn_pmG Solving equation (7) for QLUNG yields:
Figure imgf000008_0001
,
Equation (8) can be modified with the following assumptions, wherein the sign
Figure imgf000008_0002
indicates “approximately equal to”:
9 Dn_aoG ~ VGtotal
10 Dn_LAG ~ VGLUNG
11 Dn_pmG ~ VG ECMO
These equations can be implemented into equation (8), yielding:
Figure imgf000008_0003
Equation (5) simplifies (12) to:
Figure imgf000008_0004
The sign of the first gas flow VGLUNG depends on the direction of the gas flow. For instance, for CO2, which is eliminated at the lung, the sign of VGLUNG is opposite to the VGLUNG for O2, which is taken up by the lung. In certain embodiments, the external blood flow through the extracorporeal oxygenation device and/or a ventilation rate (also called sweep gas flow) of the blood flowing through the extracorporeal oxygenation device is changed, particularly reduced, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow and/or ventilation rate is estimated.
Such a change may occur during weaning of the subject from the ECO / ECMO device. Advantageously, the method according to the invention allows the accurate and reliable estimation of the pulmonary blood flow during a weaning trial, when external blood flow and/or ventilation are reduced.
In certain embodiments, the external blood flow through the extracorporeal oxygenation device is changed, particularly reduced, wherein the ventilation rate of the blood flowing through the extracorporeal oxygenation device is kept constant, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow is estimated.
In certain embodiments, the ventilation rate of the blood flowing through the extracorporeal oxygenation device is changed, particularly reduced, wherein the external blood flow through the extracorporeal oxygenation device is kept constant, wherein a change of the pulmonary blood flow of the subject in response to the changed ventilation rate is estimated.
In certain embodiments, the external blood flow through the extracorporeal oxygenation device and the ventilation rate of the blood flowing through the extracorporeal oxygenation device are changed, particularly reduced, wherein a change of the pulmonary blood flow of the subject in response to the changed external blood flow and the changed ventilation rate is estimated.
In certain embodiments, the external blood flow through the extracorporeal oxygenation device and the ventilation rate of the blood flowing through the extracorporeal oxygenation device are changed, particularly reduced, wherein the ratio between the external blood flow and the ventilation rate stays constant, wherein particularly the ratio between the external blood flow and the ventilation rate equals 1. In other words, the external blood flow and ventilation rate are changed concurrently.
In particular, if the ratio between the external blood flow and the ventilation rate equals 1 during the concurrent change of the external blood flow and the ventilation rate, the following equation can be used to estimate the change in pulmonary blood flow ( DQLUNG):
Figure imgf000009_0001
However, in case the gas is CO2, if the ratio between the external blood flow and the ventilation rate is not constant, DVGECMO is influenced by VECMO and QECMO. QECMO determines the amount of the gas transported towards the membrane lung, while VECMO determines the amount of the gas eliminated over the membrane lung with a major impact on DVGECMO. DVGECMO does therefore not necessarily represent DQECMO, when V/QECMO differs from 1. In particular, during reduction of the external blood flow rate while keeping the ventilation rate constant, VG may decouple from QECMO. Accordingly, the ratio DVGECMO/DVGLUNG is affected by VECMO despite unchanged blood flows.
In order to correct for a ratio between the ventilation rate and the external blood flow (V/Q) unequal to 1, DVGECMO can be normalized into a new variable, DVGECMONORM, only dependent on QECMO and independent of VECMO with formula (15).
15 DVG ECMONORM = DVGECMO * f
VGECMONORM may also be designated “normalized second gas flow throughout this specification.
In certain embodiments, the gas exhaled by the subject is CO2 and the change of the pulmonary blood flow is estimated according to the formula DQLUNG= DQECMO*(- DVG / DVG ), wherein DQ is the change of the external blood flow, DVG is the change of the first gas flow, and DVGECMONORM is determined according to the formula DVGECMONORM= DVGECMO*f, wherein DVGECMO is the change of the second gas flow, and f is a normalization factor reflecting the quotient
Figure imgf000010_0001
Figure imgf000010_0003
, wherein
Figure imgf000010_0002
= 1N is the second gas flow when the ratio between the ventilation rate and the external blood flow equals 1, and wherein VGECMO is the second gas flow at any ratio between the ventilation rate and the external blood flow.
Advantageously, due to normalization, the estimated pulmonary blood flow is more accurate also when the ratio between external blood flow and ventilation changes, in particular during weaning of the subject.
In certain embodiments, the normalization factor is calculated according to the formula > =
Figure imgf000010_0004
wherein c is a constant. In certain embodiments, the constant is calculated according to the formula c = sG * R * T * + K C )1, wherein Z is the solubility of the gas in blood, R is the gas constant, T is the temperature in Kelvin and KC is the solubility equilibrium constant of the gas in blood at a given pH, particularly of the reaction CO2 + H2O « HCO3- + H+ at a given pH. In certain embodiments, the normalization factor and/or the constant is determined from a curve fitting function using pulmonary blood flow data measured at different ventilation-to- perfusion ratios (V/Q).
In certain embodiments, the normalization factor and/or the constant is directly determined from parameters obtained by a blood gas analysis.
As VGECMO is dependent on the sweep gas flow, normalization of the VG at any given V/Q ratio to a ventilation/perfusion (V/Q) ratio of 1 (VGECMONORM) will render a variable only dependent on blood flow (QECMO) and independent from ventilation (VECMO). This facilitates blood flow prediction in the lung.
The theoretical deduction of this normalization is based on the description of the V/Q ratio as described for CO2 by Keener JS, J.: Ventilation and Perfusion, Mathematical Physiology: Systems Physiology, Second Edition. Edited by Antman SM, J. Sirovich L. New York, Springer, 2009, pp 694-701: (16)
Figure imgf000011_0001
sG is the solubility of the gas in blood, R is the gas constant, T is temperature. PvG is venous partial pressure and PPMG is the post membrane partial pressure of the gas. Here, it is assumed that PPMG is equal to PeGECMO, which is measured at the ECMO gas outlet. Kc indicates the solubility equilibration constant of the gas in blood, particularly of the CO2 + H2O « HCO3- + H+ reaction at a given pH. It describes the additional liberation of gaseous carbon dioxide from bicarbonate during the passage through the membrane lung. pK is the acid dissociation constant.
Figure imgf000011_0002
The following values are assumed for BTPS conditions:
Figure imgf000011_0003
T = 310.5 Kelvin (K)
Kc = 12, pH = 7.35
Figure imgf000011_0004
Under the assumption of a constant pH, these individual constants can be combined into one overall constant c.
c = sG * R * T * (1 + Kc) For the derivation, a constant venous partial pressure of the gas is assumed in the calculation of the gas fraction of expired gas (FeG).
PvG = 45 mmHg
Figure imgf000012_0001
Equation (16) can be solved for PPMG.
Figure imgf000012_0002
The next step is to calculate VGECMO. It should be noted that the factor 1000 is needed to convert the results in ml/min.
Figure imgf000012_0003
In order the represent blood flow, the given VG is now normalized to a V/Q ratio of 1.
The correction factor f is defined as the ratio of VG at V/Q = 1 to the VG at any V/Q.
Figure imgf000012_0004
As VV/Q=1 is equal to Q:
Figure imgf000012_0005
This describes a hyperbolic dependency of f from V/Q scaled with V/Q and c. Note that for a V/Q of 1, the scaling and correction factor is 1.
Now, VGNORM can be calculated using equations (18) and (20).
21 VGNORM = VG * F V, Q
Figure imgf000013_0004
It is clear from this resolved equation (21), that VGNORM is dependent on Q and PvG, as well as the constant c which itself is dependent on temperature and pH.
In particular, when the gas is O2, a normalization as described for CO2 is not necessary, since under conditions of complete or almost complete hemoglobin oxygenation, which can be obtained i.e. at a ventilation-to-perfusion ratio of about 0.8, the concentration of freely dissolved O2 in blood is very low.
Most anesthetic gases also exhibit a very low solubility in blood, such that no normalization is necessary when these gases are used to determine the pulmonary blood flow according to the present invention.
In certain embodiments, the pulmonary blood flow QLUNG and/or the change in pulmonary blood flow DQLUNG is estimated from a normalized first gas flow VGLUNGNORM, the second gas flow VGECMO and the external blood flow QECMO, wherein the normalized first gas flow VGLUNGNORM is determined according to the formula VGLUNGNORM= VGLUNG*f’, wherein f’ is a normalization factor.
Not only the second gas flow VGECMO, but also the first gas flow VGLUNG may be influenced by a ventilation-to-perfusion ratio unequal to 1. In certain embodiments, the normalization factor reflects the quotient
Figure imgf000013_0001
, wherein
Figure imgf000013_0002
= is the first gas flow (VGLUNG) when the ratio between the ventilation rate (VLUNG) of the lung and the blood flow through the lung (QLUNG) equals 1.
In certain embodiments, the normalization factor f’ is calculated according to the formula
Figure imgf000013_0006
wherein c is a constant.
Figure imgf000013_0005
In certain embodiments, the V/Q ratio (at the lung) is estimated according to the formula wherein ca,02 is an O2 concentration of arterial blood of the subject, cv,02 is
Figure imgf000013_0003
an O2 concentration of venous blood of the subject, Fi,02 is an inspiratory O2 fraction and Fe,02 is an expiratory O2 fraction. In certain embodiments, the pulmonary blood flow is estimated according to the formula QLUNG=QECMO*(-VGLUNGNORM/VGECMO), wherein QECMO is the external blood flow, VGLUNGNORM is the normalized first gas flow and VGECMO is the second gas flow.
In certain embodiments, the change in pulmonary blood flow is estimated according to the formula DQLUNG= DQECMO*(- DVGLUNGNORM/ DVGECMONORM), wherein QECMO is the external blood flow, VGLUNGNORM is the normalized first gas flow and VGECMONORM is the normalized second gas flow.
In certain embodiments, the O2 concentration of the venous blood is determined according to the formula
Figure imgf000014_0001
, wherein s is the O2 saturation of the venous blood in per cent, and wherein Hb is the hemoglobin value of the venous blood. In particular, the O2 saturation of the venous blood is determined by blood gas analysis or by a sensor, more particularly a sensor comprised in a pulmonary catheter.
In certain embodiments, the O2 concentration of the arterial blood is determined according to the formula , wherein s is the O2 saturation of the arterial blood in per
Figure imgf000014_0002
cent, and wherein Hb is the hemoglobin value of the arterial blood. In particular, the O2 saturation of the arterial blood is assumed to be 100 per cent.
In certain embodiments, the extracorporeal oxygenation device is connected to the subject in parallel to the lung of the subject, wherein particularly the extracorporeal oxygenation device is connected to the subject by means of a first port to a vein of the subject and a second port to an artery of the subject, such that blood is able to flow from the vein through the first port into the extracorporeal oxygenation device, and blood oxygenated by the extracorporeal oxygenation device is able to flow through the second port into the artery.
Pulmonary blood flow is especially difficult to measure during veno-arterial extracorporeal oxygenation, particularly ECMO. Thus, the method according to the invention is especially advantageous in this context.
A second aspect of the invention relates to a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly by means of the method according to the first aspect of the invention, comprising at least the following components:
- a first unit adapted to determine a first gas flow of a gas exhaled by a subject, wherein the gas is soluble in blood,
- a second unit adapted to determine a second gas flow of the gas released from an extracorporeal oxygenation device to which the subject is connected, - a third unit adapted to determine an external blood flow through said extracorporeal oxygenation device, and
- a computing unit adapted to estimate a pulmonary blood flow of said subject from said first gas flow, said second gas flow and said external blood flow.
In certain embodiments, the gas is CO2, O2 or an anesthetic gas, particularly CO2. The term “anesthetic gas”, as used herein, refers to a gas used in anesthesia of a patient, such as i.e. sevoflurane or desflurane.
In certain embodiments, the gas is CO2 or O2.
In certain embodiments, the gas is CO2.
Using CO2 as the exhaled gas is advantageous, because CO2 concentration or partial pressure is especially easy to detect.
In certain embodiments, the gas is CO2. Therefore, this embodiment relates to a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device, particularly by means of the method according to the first aspect of the invention, comprising at least the following components:
- a first unit adapted to determine a first CO2 flow exhaled by a subject,
- a second unit adapted to determine a second CO2 flow released from an extracorporeal oxygenation device, to which the subject is connected,
- a third unit adapted to determine an external blood flow through the extracorporeal oxygenation device, and
- a computing unit adapted to estimate a pulmonary blood flow of the subject from the first CO2 flow, the second CO2 flow and the external blood flow.
This device provides a sufficiently accurate and reliable estimation of the pulmonary blood flow in a non-invasive manner from data which are readily available and easy to obtain. To this end, the discovery that gas exchange during ECO reflects the combined effect of ventilation and perfusion of the native lung and those of the ECO circuit is used for estimation of the pulmonary blood flow.
All embodiments, definitions and advantages stated above in the context of the method according to the first aspect of the invention also apply to the device according to the second aspect of the invention.
The first unit of the device may be a first sensor or comprise a first sensor for measuring a partial pressure, amount or concentration of the gas exhaled by the subject, particularly a capnograph. In addition, the first unit may comprise means for computation of values measured by the first sensor. Alternatively, the values measured by the first sensor may be transmitted to the computing unit and computation may take place in the computing unit. In particular, the first unit or the first sensor is adapted to be placed near a mouth of the subject, such that the partial pressure, amount or concentration of the gas exhaled by the subject can be measured by means of the first unit or the first sensor.
The second unit of the device may be a second sensor or comprise a second sensor for measuring a partial pressure, amount or concentration of the gas released or exhausted by the extracorporeal oxygenation device, particularly a capnograph. In addition, the second unit may comprise means for computation of values measured by the second sensor. Alternatively, the values measured by the second sensor may be transmitted to the computing unit and computation may take place in the computing unit.
In particular, the second unit or the second sensor is adapted to be placed near an exhaust of the extracorporeal oxygenation device, such that the partial pressure, amount or concentration of the gas released by the extracorporeal oxygenation device can be measured by means of the second unit or the second sensor.
The third unit may be a third sensor or comprise a third sensor for measuring a flow rate of the blood flowing through the extracorporeal oxygenation device, particularly a flow meter or flow probe, such as an ultrasonic flow probe. Alternatively, the third unit may be a data processing unit adapted to obtain a flow rate value from a pump transporting the blood through the extracorporeal oxygenation device, wherein the flow rate value reflects the current flow rate provided by the pump. The flow rate values measured or obtained by the third unit may then be transmitted to the computing unit for performing further computing steps.
In certain embodiments, the first unit or the first sensor is adapted to measure the end-tidal partial pressure of the gas (petG) of the subject, particularly during exhalation, and the first unit and/or the computing unit is adapted to determine the first gas flow by calculating the fraction of end-tidal gas (FeG) by dividing the end-tidal partial pressure of the gas by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject. The barometric pressure and the lung volume may be measured during the method or previously obtained.
In certain embodiments, the first unit or the first sensor is adapted to measure the end-tidal partial pressure of the gas (petG) of the subject, particularly during exhalation, and the first unit and/or the computing unit is adapted to determine the first gas flow by determining the mean pulmonary expired gas (pEG) by averaging the measured end-tidal partial pressure of the gas or end-tidal gas curve over the respiratory cycle, in particular with correction for the inspiratory to expiratory (I:E) ratio, more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume, calculating the fraction of end-tidal gas (FeG) by dividing the mean pulmonary expired gas (pEG) by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject. Mean pulmonary expired gas may also be determined by integration of the expiratory pG curve.
The second gas flow reflects the gas released at the extracorporeal oxygenation device per unit of time, which is equivalent to the gas removed from the blood flowing through the extracorporeal oxygenation device.
In certain embodiments, the second unit or the second sensor is adapted to measure an expiratory partial pressure of the gas at an exhaust of the extracorporeal oxygenation device, and the second unit or the computing unit is adapted to determine the second gas flow by calculating the fraction of end-tidal gas by dividing the expiratory partial pressure of the gas by the barometric pressure, and multiplying the fraction of end-tidal gas with the ventilation rate VECMO (also designated as sweep gas flow) of the extracorporeal oxygenation device. In certain embodiments, the device for estimating a pulmonary blood flow of a subject comprises a fourth sensor for measuring a ventilation rate (sweep gas flow) of the ECO device.
In certain embodiments, the computing unit is adapted to estimate the pulmonary blood flow according to the formula QLUNG=QECMO*(-VGLUNG/VGECMO), wherein QECMO is the external blood flow through the extracorporeal oxygenation device, VGLUNG is the first gas flow and VGECMO is the second gas flow. The derivation of this formula is described above for the method according to the invention.
In certain embodiments, the computing unit is adapted to estimate a change of the pulmonary blood flow of the subject in response to a change, particularly reduction, of the external blood flow and/or a ventilation rate of the blood flowing through the extracorporeal oxygenation device.
In certain embodiments, the computing unit is adapted to estimate the change of the pulmonary blood flow according to the formula DQLUNG= DQECMO*(- DVGLUNG/ DVGECMO), wherein DQECMO is the change of the external blood flow, DVGLUNG is the change of the first gas flow and DVGECMO is the change of the second gas flow. In particular, this formula may be applied if the ratio between ventilation (sweep gas flow) and blood flow through the extracorporeal oxygenation device is constant, more particularly equal to 1.
In certain embodiments, the computing unit is adapted to estimate the change of the pulmonary blood flow according to the formula DQLUNG= DQECMO*(- DVGLUNG/ DVGECMONORM), wherein said gas exhaled by the subject is CO2, and wherein DQECMO is the change of the external blood flow, DVGLUNG is the change of the first gas flow, and DVGECMONORM is determined according to the formula D VGECMONORM= DVGECMO*f, wherein DVGECMO is the change of the second gas flow, and f is a normalization factor reflecting the quotient is the second gas flow when the ratio
Figure imgf000018_0002
between the ventilation rate and the external blood flow equals 1, and wherein VGECMO is the second gas flow at any ratio between the ventilation rate and the external blood flow. In particular, this formula may be applied if the ratio between ventilation (sweep gas flow) and blood flow through the extracorporeal oxygenation device is not constant, more particularly not equal to 1.
In certain embodiments, the computing unit is adapted to calculate the normalization factor (f) according to the formula wherein c is a constant.
Figure imgf000018_0003
In certain embodiments, the computing unit is adapted to calculate the constant I according to the formula c = sG * R * T * 1 + Kc , wherein sG is the solubility of the gas in blood, R is the gas constant, T is the temperature in Kelvin and KC is the solubility equilibrium constant of the gas in blood, particularly of the reaction CO2 + H2O « HCO3- + H+, at a given pH.
In certain embodiments, the computing unit is adapted to estimate the pulmonary blood flow QLUNG and/or the change in pulmonary blood flow DQLUNG from a normalized first gas flow VGLUNGNORM, the second gas flow VGECMO and the external blood flow QECMO, wherein the normalized first gas flow VGLUNGNORM is determined according to the formula VGLUNGNORM= VGLUNG*f’, wherein f’ is a normalization factor.
Not only the second gas flow VGECMO, but also the first gas flow VGLUNG may be influenced by a ventilation-to-perfusion ratio unequal to 1. In certain embodiments, the normalization factor reflects the quotient
Figure imgf000018_0005
wherein
Figure imgf000018_0001
= 1N is the first gas flow (VGLUNG) when the ratio between the ventilation rate (VLUNG) of the lung and the blood flow through the lung (QLUNG) equals 1.
In certain embodiments, the normalization factor f’ is calculated according to the formula >¢ = wherein c is a constant.
Figure imgf000018_0004
In certain embodiments, the computing unit is adapted to estimate the V/Q ratio (at the lung) according to the formula wherein ca,02 is an O2 concentration of arterial
Figure imgf000018_0006
blood of the subject, cv,02 is an O2 concentration of venous blood of the subject, Fi,02 is an inspiratory O2 fraction and Fe,02 is an expiratory O2 fraction. In certain embodiments, the computing unit is adapted to estimate the pulmonary blood flow according to the formula QLUNG=QECMO*(-VGLUNGNORM/VGECMO), wherein QECMO is the external blood flow, VGLUNGNORM is the normalized first gas flow and VGECMO is the second gas flow. In certain embodiments, computing unit is adapted to estimate the change in pulmonary blood flow is estimated according to the formula DQLUNG= DQECMO*(- DVGLUNGNORM/ DVGECMONORM), wherein QECMO is the external blood flow, VGLUNGNORM is the normalized first gas flow and VGECMONORM is the normalized second gas flow.
In certain embodiments, the computing unit is adapted to determine the O2 concentration of the venous blood according to the formula wherein s is the O2
Figure imgf000019_0001
saturation of the venous blood in per cent, and wherein Hb is the hemoglobin value of the venous blood. In particular, the O2 saturation of the venous blood can be determined by blood gas analysis or by a sensor, more particularly a sensor comprised in a pulmonary catheter.
In certain embodiments, the computing unit is adapted to determine the O2 concentration of the arterial blood according to the formula , wherein s is the O2
Figure imgf000019_0002
saturation of the arterial blood in per cent, and wherein Hb is the hemoglobin value of the arterial blood. In particular, the O2 saturation of the arterial blood can be assumed to be 100 per cent.
In certain embodiments, the extracorporeal oxygenation device is an extracorporeal membrane oxygenation device (ECMO).
In certain embodiments, the first unit and/or the second unit comprises a capnograph or is a capnograph, particularly a side stream capnograph or a main stream capnograph.
In certain embodiments, the third unit comprises a flow meter or is a flow meter.
A third aspect of the invention relates to a system comprising a device for estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device according to the second aspect of the invention and an extracorporeal oxygenation device, particularly an extracorporeal membrane oxygenation device (ECMO device), wherein the second unit is adapted to determine a second gas flow released from the extracorporeal oxygenation device of the system, and the third unit is adapted to determine an external blood flow through the extracorporeal oxygenation device of the system.
A fourth aspect of the invention relates to a computer program comprising computer program code for performing at least the following step of the method according to the first aspect of the invention when the computer program is executed on a computer: estimating a pulmonary blood flow of the subject from the first gas flow, the second gas flow and the external blood flow, in particular automatically.
A fifth aspect of the invention relates to a computer program comprising computer program code for performing at least the following step when the computer program is executed on a computer: estimating a pulmonary blood flow of a subject connected to an extracorporeal oxygenation device from a first gas flow of a gas exhaled by the subject, wherein the gas is soluble in blood, a second gas flow of the gas released from the extracorporeal oxygenation device and an external blood flow through the extracorporeal oxygenation device, in particular automatically.
In certain embodiments, the computer program according to the fourth or fifth aspect is further adapted to perform any further step of embodiments of the first aspect of the invention, in particular automatically.
In certain embodiments, the computer program according to the fourth or fifth aspect is further adapted to perform at least one of the following steps, in particular automatically:
- determining the first gas flow of a gas exhaled by a subject, wherein the gas is soluble in blood;
- determining the second gas flow released from the extracorporeal oxygenation device, to which the subject is connected;
- determining an external blood flow through the extracorporeal oxygenation device; - determining the mean pulmonary expired gas (pEG), particularly by averaging the measured end-tidal partial pressure of the gas or end-tidal gas curve over the respiratory cycle, more particularly with correction for the inspiratory to expiratory (I:E) ratio, even more particularly by multiplication with the factor (I+E/E), wherein I designates the inspiratory volume and E designates the expiratory volume;
- calculating the fraction of end-tidal gas (FeG) by dividing the end-tidal partial pressure of the gas by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject;
- calculating the fraction of end-tidal gas (FeG) by dividing the mean pulmonary expired gas (pEG) by the barometric pressure and calculating the first gas flow by multiplying the fraction of end-tidal gas by the total lung ventilation of the subject;
- calculating the fraction of end-tidal gas by dividing the expiratory partial pressure of the gas by the barometric pressure, and multiplying the fraction of end-tidal gas with the ventilation rate VECMO (also designated as sweep gas flow) of the extracorporeal oxygenation device; - calculating a normalization factor reflecting the quotient wherein the gas exhaled by the subject is CO2, and wherein VGECM
Figure imgf000021_0001
the second gas flow when the ratio between the ventilation rate and the external blood flow of the ECO device equals 1, and wherein VGECMO is the second gas flow at any ratio between the ventilation rate and the external blood flow of the ECO device, - calculating a normalization factor reflecting the quotient wherein
Figure imgf000021_0002
is the first gas flow (VGLUNG) when the ratio between the
Figure imgf000021_0003
ventilation rate (VLUNG) of the lung and the blood flow through the lung (QLUNG) equals 1,
- determining the normalized first gas flow from the normalization factor and the first gas flow,
- estimating the V/Q ratio (at the lung) according to the formula
Figure imgf000021_0004
wherein ca,02 is an O2 concentration of arterial blood of the subject, cv,02 is an O2 concentration of venous blood of the subject, Fi,02 is an inspiratory O2 fraction and Fe,02 is an expiratory O2 fraction.
- determining the O2 concentration of the venous blood according to the formula
Figure imgf000021_0005
Figure imgf000021_0006
wherein s is an oxygen saturation of the venous blood;
- determine the O2 concentration of the arterial blood according to the formula
Figure imgf000021_0007
, wherein s is an oxygen saturation of the arterial blood.
Figure imgf000021_0008
Hereafter, further embodiments and advantages of the invention are described in respect of the attached Figures, which are meant to illustrate the invention, but not to limit its scope.
Fig.1 shows a schematic flow diagram illustrating an extracorporeal oxygenation device connected to a subject and a device for estimating a pulmonary blood flow according to the present invention;
Fig.2 illustrates an experimental ECMO weaning protocol with stepwise reduction of
VECMO and/or QECMO;
Fig.3 shows a plot of post membrane CO2 partial pressure at the extracorporeal oxygenation device as a function of ventilation/blood flow ratio from a simulation; Fig.4 shows a 3D-surface plot of post membrane CO2 partial pressure at the extracorporeal oxygenation device as a function of ventilation and blood flow from a simulation;
Fig.5 shows a 3D-surface plot of CO2 flow at the ECO device as a function of ventilation and blood flow from a simulation;
Fig.6 shows the relationship between the ventilation/blood flow ratio at the ECO device and the normalization factor f;
Fig.7 shows a 3D-surface plot of the normalized CO2 flow at the ECO device as a function of ventilation and blood flow from a simulation;
Fig.8 shows the relationship between the ventilation/blood flow ratio at the ECO device and an experimentally determined correction factor c.
Fig.9 shows a scatter plot of measured pulmonary blood flow (QLUNG) against the first CO2 flow (VCO2LUNG) in animals subjected to ECMO;
Fig.10 shows a scatter plot of external blood flow (QECMO) against normalized second
CO2 flow (VCO2ECMONORM) in animals subjected to ECMO;
Fig.11 shows a scatter plot comparing measured change in pulmonary blood flow
(deltaQ[real]) and calculated change in pulmonary blood flow (deltaQ[calc]) in animals subjected to ECMO;
Fig.12 shows a scatter plot of measured pulmonary blood flow (QLUNG) against the first CO2 flow (VCO2LUNG) (A) and the normalized first CO2 flow (VCO2LUNGNORM) (B) in animals subjected to ECMO;
Fig 13 shows a scatter plot of external blood flow (QECMO) against second CO2 flow
(VCO2ECMO) in animals subjected to ECMO;
Fig.14 shows the correlation between measured and calculated pulmonary blood flow
(QLUNG) determined from VO2 (A), determined from VCO2Lung (not normalized) (B), determined from VCO2Lung normalized to V/Q by O2 measurement via a pulmonary catheter (C) and determined from VCO2Lung normalized by O2 measurement via blood gas analysis (D). Normalization by estimating V/Q according to the formula
Figure imgf000022_0001
Fig.15 schematically depicts an simulator device for in-vitro lung / ECMO simulation comprising two parallel circuits (ECMO circuit, lung circuit) with the ability to shunt the oxygenator of the lung circuit. Blood samples could be drawn after the oxygenator of the ECMO circuit (post membrane), after the oxygenator of the lung circuit (post lung), from the left atrium, the aorta and the right atrium; Fig.16 shows a schematic plot of flow rate vs. time for the experimental setups of the simulator depicted in Fig. 15 under constant V/Q ratio (A) and varying V/Q ratio (B);
Fig.17 shows a schematic plot of flow rate vs. time for the experimental setups of the simulator depicted in Fig. 15 under limited venous return (A) and cardiac limitation (B) conditions;
Fig.18 shows the true shunt vs. calculated shunt from O2 and CO2 content [%] using the simulator device shown in Fig. 15. A: For O2, the regression yielded y = 0.82 * x– 2.4, for CO2 the regression was y = 0.88 * x + 2.2. B: Linear regression showed y = 0.76*x + 8.03;
Fig.19 shows VCO2 and VO2 [ml/min] measured at the lung circuit and ECMO circuit of the simulator shown in Fig. 15 plotted against blood flow. (A): VCO2Gas vs. blood flow at the oxygenator of the lung circuit and the oxygenator of the ECMO circuit [ml/min]. (B): VCO2Gas, normalized for a V/Q of 1 vs. blood flow. (C): VCO2Blood vs. blood flow. (D): VO2 calculated from blood content vs. blood flow.
Fig.20 shows VCO2/VO2 and VCO2 blood vs. VCO2 gas. [ml/min] obtained by means of the simulator shown in Fig. 15 A: System VCO2 and VO2, which represents the oxygen elimination and CO2 introduction into the system measured at the oxygenator of the metabolic chamber vs. VCO2 and VO2 at the oxygenator of the lung circuit and the oxygenator of the ECMO circuit. Linear regression shows y = 0.53 * x + 79.6, p<0.001 for VCO2 and y = 1.09 * x– 6.5 , p<0.001 for VO2. B: Relationship between VCO2Blood and VCO2Gas. The regression yielded y = 0.23 * x + 41.955. A regression forced through the origin showed an estimate of y = 0.61 * x, p<0.001;
Fig.21 shows multiple linear regression for differences in CO2/O2 content, blood flow and VCO2/VO2 obtained by means of the simulator shown in Fig. 15. Blood flow is in [ml/min], VCO2 and VO2 are in [ml/min], difference in cCO2/cO2 is in [ml/100ml of blood]. Grids show the calculated model while dots represent actual data points. A: VCO2Blood. B: VO2. C: VCO2Gas. D: Normalized VCO2Gas; Fig.22 shows the relationship between V/Q and respiratory exchange ratio obtained by means of the simulator shown in Fig. 15. A: Scatter plot between V/Q and R with y = 1.01 * x + 1.0183. B: Bland-Altman Plot for V/Q and R. Note that R was corrected using a factor of 0.8; Fig.23 shows calculations of simulated pulmonary blood flow during steady state obtained by means of the simulator shown in Fig. 15. A: Calculated for normalized VCO2Gas ECMO and normalized VCO2Gas Lung. B: Calculated for normalized VCO2Gas ECMO and normalized VCO2Gas Lung using the respiratory exchange ratio. C: Calculated for normalized VCO2Gas ECMO and VCO2Gas Lung D: Calculated for VCO2Blood E: Calculated for VO2Blood
Fig.24 shows bland-Altman plots of the data shown in Fig.23.
Fig. 1 is a schematic flow diagram illustrating an extracorporeal oxygenation device 10 connected to a subject and a device for estimating a pulmonary blood flow 20 according to the present invention. The extracorporeal oxygenation device 10 is an extracorporeal membrane oxygenation device (ECMO) connected to the subject in parallel to the native lung L according to a veno-arterial setup, wherein the gas exhaled by the subject is CO2.
Body parts of the subject as well as components of the extracorporeal oxygenation device 10 and the device for estimating a pulmonary blood flow 20 are schematically depicted as boxes. The blood vessels connecting the body parts of the subject and the tubings connecting parts of the extracorporeal oxygenation device 10 are shown as lines. Blood flow B and CO2 flow VCO2LUNG, VCO2ECMO are indicated as arrows.
Blood flow in the subject occurs from the right heart RH via the native lung L, the left heart LA the arterial system A to the organs O and back to the right heart RH via the venous system V. The extracorporeal oxygenation device 10 is connected to the subject via a first port 11 introduced into the venous system V and a second port 12 introduced into the arterial system A. Blood flow through the extracorporeal oxygenation device 10 is driven by a pump 13 and occurs from the first port 11 connected to the venous system V via a membrane 14, where the blood is oxygenated, and via a post membrane compartment PM to the second port 12 connected to the arterial system A.
The pulmonary blood flow rate is indicated by QLUNG and the blood flow rate through the extracorporeal oxygenation device 10 is indicated by QECMO. Due to the parallel arrangement of the native lung L and the extracorporeal oxygenation device 10, the total blood flow rate Qtotal (not shown here) is equal to the sum QLUNG + QECMO.
CO2 partial pressures are indicated at different locations in the subject and the extracorporeal oxygenation device 10: cvCO2 indicates venous CO2 partial pressure, caoCO2 indicates arterial CO2 partial pressure, particularly at the aorta, cLACO2 indicates CO2 partial pressure at the left heart LA, and cpmCO2 indicates CO2 partial pressure at the post membrane compartment PM of the extracorporeal oxygenation device 10. Both at the native lung L and the membrane 14 of the extracorporeal oxygenation device 10 gas exchange takes place resulting in release of CO2 and blood oxygenation. The CO2 flow from the lung L is indicated by VCO2LUNG and the CO2 flow from the extracorporeal oxygenation device 10 is indicated by VCO2ECMO.
Furthermore, components of the device for estimating a pulmonary blood flow 20 are depicted in Fig.1.
The device 20 comprises a first unit 21 for determining the first CO2 flow released from the native lung L during gas exchange. The first unit 21 may comprise a capnograph placed near the subject’s mouth to measure the CO2 partial pressure in the exhaled air, and optionally a processing unit adapted to convert the measured CO2 partial pressure to the first CO2 flow. Of course, a separate device, i.e. the computing unit 24, may also be used to implement this conversion. In particular, the calculation of the first CO2 flow may take into account the current barometric pressure, the inspiration to expiration ratio and/or the lung ventilation rate (see equations (1) and (2) above).
Furthermore, the device 20 comprises a second unit 22 adapted to determine the second CO2 flow released from the extracorporeal oxygenation device 10 during gas exchange at the membrane 14. In particular, the second unit 22 may comprise a capnograph positioned near an exhaust of the extracorporeal oxygenation device 10 to measure the CO2 partial pressure in the gas mixture released from the extracorporeal oxygenation device 10. Subsequently, the CO2 partial pressure may be mathematically converted into the second CO2 flow by means of a processing unit of the second unit 22 or by a separate device, such as the computing unit 24. Therein, in particular, the current barometric pressure as well as the ventilation of the extracorporeal oxygenation device 10 may be utilized, i.e. by equation (3) shown above.
A third unit 23 of the device 20 is configured to measure or otherwise obtain the blood flow rate through the extracorporeal oxygenation device 10, in other words the external blood flow QECMO. In case the external blood flow is directly measured, the third unit 23 may be formed by or comprise a flow meter, such as i.e. an ultrasound flow meter attached to a tubing of the extracorporeal oxygenation device 10. According to an alternative embodiment, the third unit 23 may be the pump 13 or part of the pump 13, wherein the external blood flow is obtained from a pump setting, or the third unit 23 may be a processing unit adapted to receive a pump setting value from the pump 13 to determine the external blood flow.
The device 20 further comprises a computing unit 24 adapted to calculate the pulmonary blood flow QLUNG of the subject from the first CO2 flow VCO2LUNG, the second CO2 flow VCO2ECMO and the external blood flow QECMO, in particular as described above (see equations (4) to (21) above). To obtain the input parameters VCO2LUNG, VCO2ECMO and QLUNG, the computing unit 24 is connected to the first unit 21, the second unit 22 and the third unit 23 by means of data connections 25 depicted by dashed lines in Fig. 1. These data connections 25 may be realized by cable connections, wireless connections or any other suitable means of connection known in the art.
The device 20 shown in Fig.1 may be utilized to estimate the pulmonary blood flow QLUNG in an easy and non-invasive manner, especially during weaning of the subject from the extracorporeal oxygenation device 10.
Example 1– Estimation of pulmonary blood flow during veno-arterial ECMO in a porcine model
Gas exchange during ECMO should reflect the combined effect of ventilation and perfusion of the native lung and those of the ECMO circuit. It is hypothesized that during ECMO weaning the ratio between changes in VCO2ECMO and VCO2Lung is the same as the ratio between changes in the respective flows (QECMO and QLUNG). In this proof-of-concept study, this hypothesis was tested by measuring the elimination of CO2 over the native lung and the ECMO and the respective blood flows and comparing the calculated flow changes with those directly measured from the pulmonary artery and ECMO circuit.
Methods
Animal Care, anesthesia management
The study complied with the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, 1996) and Swiss National Guidelines and was approved by the Commission of Animal Experimentation of Canton Bern, Switzerland (BE119/17).
Four healthy pigs (domestic, 40-50kg) underwent VA-ECMO with right atrial-aortic cannulation (Maquet Cardiohelp, Quadrox MECC oxygenator, Rastatt, Germany). The pigs fasted for 12h with free access to water. After induction and oral intubation with intravenous midazolam and atropine, anesthesia was maintained with propofol and fentanyl and the depth was controlled by repeatedly testing the response to nose pinch additionally to bispectral index target < 60 (BIS™ Quatro, Covidien, Mansfield, MA). Additional injections of fentanyl (50 µg) or midazolam (5 mg) were given as needed. Muscle relaxation was induced with rocuronium (0.5 mg/kg). During surgery, fluid was supplemented with Ringer's lactate at an initial rate of 5 ml kg-1 min-1 and increased to 10ml kg-1 min-1 during surgery. Any visible blood loss was replaced by hydroxyethyl starch (HES; 6% Voluven; Fresenius Kabi, Bad Homburg, Germany), aiming to achieve a mixed or central venous saturation > 50%. Measurements and data recording
Pulmonary blood flow, i. e. cardiac output (QLUNG) and ECMO blood flow (QECMO) were measured using ultrasound flow probes on the pulmonary artery main trunk and arterial ECMO tubing (Transonic PAU series, Ithaca, USA). Pulmonary end-tidal pCO2 (etCO2LUNG) and pCO2 at the membrane lung (peCO2ECMO) were measured with a sidestream capnograph (GE Medical, Module E-COVX with automated correction to BTPS conditions). Sweep gas flow (VECMO) was recorded manually. Arterial blood gases were taken before and after the study period. Pulmonary ventilation (VLUNG) was kept constant. In the first animal, ventilator settings were kept identical to those before ECMO (tidal volume (VT) 0.465 L, 12 breaths/min), whereas in the subsequent animals, VLUNG was reduced to 2 liters/minute (VT 0.25, 8 breaths /min) as ECMO was started and kept constant thereafter. In all animals 5 cmH2O PEEP and volume control mode was used (Servo-i, Maquet, Solna, Sweden). The fraction of inspired oxygen was set at 0.30. Measurements were performed in healthy animals, 30 minutes after surgery was completed and before systemic inflammation was induced. Eventually, the pigs were euthanized by injection of 40 mmol of potassium chloride and ECMO stopped in deep anesthesia. Data were recorded using Labview™ (National Instruments Corp., Austin, TX,) for offline analysis with Soleasy (Alea Solutions, Zürich, Switzerland).
Experimental protocol
The experiment consisted of three phases with varying ventilation/perfusion (V/Q) ratios in order to determine how the V/Q relationship at the ECMO influences extracorporeal CO2 elimination (VCO2ECMO). First, QECMO and VECMO were reduced in parallel (stable V/Q = 1, phase:“reduction of V&Q”, Fig. 2A). Then VECMO was lowered with a constant QECMO (V/Q towards shunt, phase:“reduction of V”, Fig.2B). Finally, an acute, pragmatic ECMO weaning trial was tested, where QECMO was reduced but VECMO was kept constant (V/Q towards dead space, phase:“reduction of Q”, Fig.2C).
QECMO and VECMO were set at 4 L/min each at baseline and afterward reduced– depending on the respective phase - to 75%, 50%, and 25% of baseline with an interval of one minute for each condition (Fig.2).
Calculation of VCO2 for ECMO
Expiratory concentration of CO2 at the ECMO exhaust was calculated from the expiratory partial pressure of CO2 at the ECMO exhaust, and used to calculate VCO2, assuming a barometric pressure of 760mmHg.
Figure imgf000027_0001
Calculation of VCO2 for the lung
Mean pulmonary expired carbon dioxide (pECO2) was calculated by averaging the end-tidal carbon dioxide (petCO2) curve over the respiratory cycle with correction for the inspiratory to expiratory (I:E) ratio:
Figure imgf000028_0001
This was verified by integration of the expiratory pCO2 curve, which delivers the same result. Then VCO2LUNG was calculated as follows:
Figure imgf000028_0002
Blood flow calculations
Fig. 1 depicts the situation during VA-ECMO schematically. The following relationships are defined, whereby Q is flow and Dv-aCO2 is the inflow-outflow difference in blood CO2 content in a given segment (Dv-aoC02 is the difference between venous and aortal CO2 content, D()^,^^2 is the difference between venous and left atrial CO2 content, Dv_pmCO2 is the difference between venous and post membrane CO2 content):
(E4) Qtotal = QLUNG + QECMO
(E5) VC02total = VC02LUNG + VC02 ECMO
(E6) VC02 = Q * Dv-aCO2
Equation (E4) and (E6) are then implemented into equation (E5):
(E7) Qtotal * Dv_aoCO2 = QLUNG * Dv_LACO2 + QECMO * Dv_pmCO2 Equation (E7) is now solved for QLUNG:
Qtotal * Dv_aoCO2 = QLUNG * Dv_LACO2 + QECMO * Dv_pmCO2 ( QLUNG + QECMO * Dv_aoCO2 = QLUNG * Dv_LACO2 + QECMO * Dv_pmCO2 QLUNG *(Dv_aoCO2—Dv_LACO2) = QECMO * ( Dv_pmCO2—Dv_aoCO2)
Figure imgf000028_0003
As the aim of the method is to calculate QLUNG with expired gas phase measurements only rather than calculating blood gas content from multiple blood gas samples, equation (E8) is modified with the following assumptions, wherein the sign“~” indicates“approximately equal to”:
(E9) Dv_aoC02 ~ VC02total (E10) Dv_LACO2 ~ VCO2LUNG
(E11) Dv_pmC02 ~ VCO2ECMO
These equations (E9-E11) are now implemented into equation (E8).
Figure imgf000029_0001
Equation (E5) simplifies (E12) to:
Figure imgf000029_0002
There is a fixed relationship of QLUNG and QECMO with the respective eliminated CO2. This expresses the hypothesis that the ratio between the differences in VCO2ECMO and VCO2Lung is the same as the ratio between the differences in the respective flows (QECMO and QLUNG).
Figure imgf000029_0003
Normalization of V/Q ratios unequal to 1 at the ECMO
During phase:“reduction of VQ” with a constant V/QECMO of 1, relationship (E14) is expected to work. However, DVCO2ECMO is influenced by VECMO and QECMO. QECMO determines the amount of CO2 transported towards the membrane lung, while VECMO determines the amount of CO2 eliminated over the membrane lung with a major impact on DVCO2ECMO. DVCO2ECMO does therefore not necessarily represent DQECMO, when V/QECMO differs from 1. During the phase “reduction of Q”, VCO2 may decouple from QECMO. Accordingly, the ratio DVCO2ECMO/DVCO2LUNG is affected by VECMO despite unchanged blood flows.
In order to correct for uneven V/Q, DVCO2ECMO was normalized into a new variable, DVCO2ECMONORM, only dependent on QECMO and independent of VECMO with formula (E15). The correction factor f is expressed in formula (E16).
(E15) DVC02E CMONORM = DVC02E CMO * f
Figure imgf000029_0004
The theoretical deduction of this normalization is based on the description of the V/Q ratio as:
Figure imgf000029_0005
sCO2 is the solubility of CO2 in blood, R is the gas constant, T is temperature. PvCO2 is venous partial pressure and PPMCO2 is the post membrane CO2 partial pressure. It is assumed that PPMCO2 is equal to PeCO2ECMO, which is measured at the ECMO gas outlet. Kc indicates the equilibration constant of the CO2 + H2O « HCO3- + H+ reaction at a given pH. It describes the additional liberation of gaseous carbon dioxide from bicarbonate during the passage through the membrane lung. pK is the acid dissociation constant.
Figure imgf000030_0001
The following values are assumed for BTPS conditions:
Figure imgf000030_0002
T = 310.5 Kelvin (K)
Kc = 12, pH = 7.35
Figure imgf000030_0003
Under the assumption of a constant pH, these individual constants can be combined into one overall constant c.
c = s * R * T * (1 + Kc)
For the derivation, a constant venous carbon dioxide partial pressure is assumed and gas fraction of expired CO2 (FeCO2) is calculated.
PvC02 = 45 mmHg
Figure imgf000030_0004
Eq. E17 is solved for PPMCO2.
Figure imgf000030_0005
A plot of this function shows the known hyperbolic dependency of alveolar, i. e. postmembrane pCO2 from ventilation (Fig.3 and 4; V and Q values are assumed from 0 to 4 with an interval of 0.25 l/min).
The next step is to calculate VCO2ECMO and plot the function (Fig. 5). Note that the factor 1000 is needed to convert the results in ml/min.
Figure imgf000030_0006
The diverging effects of the ventilation on the ECMO on PCO2 and VCO2 become apparent. In order the represent blood flow, the given VCO2 is now normalized to a V/Q ratio of 1. The correction factor f is defined as the ratio of VCO2 at V/Q = 1 to the VCO2 at any V/Q. This correction factor f is plotted against V/Q (Fig.6).
Figure imgf000031_0001
As VV/Q=1 is equal to Q, the following can be written:
Figure imgf000031_0002
This describes a hyperbolic dependency of f from V/Q scaled with V/Q and c (Fig. 6). Note that for a V/Q of 1, the scaling and correction factor is 1.
Now, VCO2NORM can be calculated using eq. (E19, E21). This new function VCO2NORM is independent of V or V/Q (Fig.7).
, (E22)Q VCO2)NORM = VC02 * > f V
Figure imgf000031_0003
It is clear from this resolved eq. (E22), that VCO2NORM is dependent on Q and PvCO2, as well as the constant c which itself is dependent on temperature and pH.
It seems intuitive that this equation (E22) can simply be achieved by implementing V/Q = 1 and substituting Q for V in eq. (E19). This calculation eliminates the dependency of ventilation and VCO2NORM will represent blood flow at any V/Q (see Fig.7).
This derivation assumes perfect conditions and depends on venous pvCO2 and pH, which are unknown. Therefore, it is advantageous to approximate the function from measured data, as described in the following section.
The necessary correction factors were calculated using the measured data and eq. E20. Then, the correction factors were plotted against V/Q and the coefficient c was received (Fig. 8).
Figure imgf000032_0001
c = 1.157; 95% CI Interval: [1.097,1.216]; r2 = 0.9954 The measurements of sweep gas flow performed during the study underlying this example (set and read by hand) are much more inaccurate than the blood flow readings. Additionally, instantaneous PvCO2 and pH measurements to calculate c are not available. Inexact ventilation measurements will introduce an error in the position of the normalization curve, where a small shift around a V/Q of 1 will have a large impact on the slope of the function. Small errors in measurement of VCO2, V or Q will therefore largely influence c (Fig. 6). However, the calculated function with empirically derived c shows almost perfect goodness of fit and the normalization of VCO2ECMO with this correction function shows very strong correlations between VCO2ECMONORM and QECMO within the range of the measurements (Fig. 10).
Statistical Analysis
For statistical, mathematical and graphical analysis, used Sigmaplot 13.0 (Systat Software, Germany) and Matlab R2017b (MathWorks, Natick, Massachusetts, USA) were used. Data are presented either as raw data or as range. Correlation coefficients are calculated using Pearson’s square (r2). Agreement between methods (calculated and measured QLUNG) was assessed with Bland-Altman analysis.
Results
Baseline
At baseline VECMO and QECMO of 4 L/min, VCO2ECMO was between 205 and 243 ml/min, while VCO2LUNG was between 13 and 193 ml/min, corresponding to a measured QLUNG of 10 to 964 mL/min (Table 1) and representing a normal VCO2 production for swine.
Table 1: Baseline conditions
Figure imgf000032_0002
Figure imgf000033_0001
Table 1. Individual data for all animals at baseline. Note that in animal 1 ventilation is high because baseline settings at respirator were 5.6l/min (TV 465ml, 12 Freq). This was the first animal and the ventilator settings were not adjusted from previous settings. Measurements at the lung
During reduction of QECMO in phase:“reduction of V&Q” and phase:“reduction of Q”, QLUNG increased from its low baseline values to 928 - 1550 ml/min, and 328 - 1914 ml/min, respectively. During unchanged QECMO (phase:“reduction of V”) it remained close to baseline (2 - 980 ml/min). VCO2LUNG followed the changes in QLUNG to 74.2– 232 ml/min (rise of 28– 57 ml/min from baseline) for“reduction of V&Q” and 39– 233 ml/min for“reduction of Q” (rise of 18– 45 ml/min from baseline), and remained steady at full QECMO (phase:“reduction of V”, 21– 188 ml/min, change of 7– 8 ml/min from baseline), with a high correlation between QLUNG and VCO2LUNG (Fig.9).
Measurements at the ECMO
The normalization function was calculated by fitting the data points into formula (16) and retrieving the constant c = 1.157 (r2 = 0.995).
Per protocol, QECMO remained unchanged from baseline during phase:“reduction of V" (98.2 – 100.4 % of baseline or 3989 - 4186 l/min) and was reduced to a quarter of baseline in phase“reduction of V&Q" (641 -1178 ml/min, 15.7– 29.0 % of baseline). In phase“reduction of Q", reduction had to be stopped at 50% in one animal due to hemodynamic instability. For the remaining animals QECMO was reduced to approximately a quarter (25.4– 49.5% of baseline or 1048 -1994 ml/min). The VCO2ECMO values for phase:“reduction of V&Q" dropped to roughly a quarter from baseline (64 - 74 ml/min, 25.2– 33.6% of baseline) in parallel with reduced QECMO.
In phase“reduction of V", reducing VECMO without any change in QECMO, VCO2ECMONORM was 194– 249 ml/min or 93.3– 100.1 % of baseline. Without normalization, VCO2ECMO decoupled from QECMO with a decrease from 205– 246 ml/min to 73– 96 ml/min in this phase. During phase:“reduction of Q", VCO2ECMONORM was 84– 156 ml/min or 38.3– 57.9 % of baseline. VCO2ECMONORM correlated highly with QECMO (Fig.10). Calculation of QLUNG
The change in QLUNG (DQ[calculated]) is accurate in 3 out of 4 animals with very good correlation to the real change in QLUNG (DQ[real]). (Animal 1: 0.983; Animal 2: 1.000; Animal 3: 0.991; Animal 4: 0.974; cumulated r2 for phase:“reduction of V&Q, V and Q” for each animal, Table 2, Fig. 11). In phase:“reduction of V”, no change in measured QLUNG was observed as well as calculated QLUNG, whereas in phase:“reduction of V&Q” and phase: “reduction of Q”, measured and calculated QLUNG rises during reduction of QECMO (Table 1). The calculated change in QLUNG predicts the direction of flow change and, within acceptable limits, the absolute amount of flow. True blood flow is underestimated since bias is positive and increases with increasing flow.
Discussion
The model presented herein for the estimation of QLUNG using the change in VCO2 and change in QECMO predicts the directional change and absolute amount of pulmonary blood flow, i. e. cardiac output with acceptable accuracy. The measurements needed are QECMO, VECMO, VLUNG, peCO2ECMO, etCO2LUNG with standard side-stream capnographs, all of which are readily available in an ICU setting or an operating theater and require no specific training. As expected from the ventilation-perfusion concept and the gas content equations derived from the setup shown in Fig. 1, it was found that a decrease in QECMO and the consecutive increase in QLUNG could be calculated through the change in VCO2LUNG and VCO2ECMONORM. A closer look at formula (E8) as the background of the hypothesis shows an adaptation of the classic Berggren-shunt equation.
This seems intuitive, as the VA-ECMO is in concept an anatomical right-to-left shunt, where the ability to ventilate and oxygenate the shunted blood will clearly affect its functional influence (Fig. 1). Changing the V/Q ratio on the ECMO will vary the function of this anatomical shunt from true shunt (VECMO = 0 at any QECMO) to dead space (QECMO = 0 at any VECMO). VCO2ECMO only represents the shunt correctly, as long as V/Q on the ECMO are kept at a ratio of 1 (in phase“reduction of V&Q”). For V/Q ratios differing from one, sweep gas flow (VECMO) will drastically change the amount of the eliminated CO2 independently of blood flow - a known phenomenon in states of shock or multiorgan failure. It was possible to simulate this in the derivation of the described normalization procedure (See Fig.3 and 4). The normalization of VCO2ECMO reestablishes a V/Q ratio of 1, and therefore restores the correlation between VCO2ECMONORM and QECMO and enables the prediction of QLUNG. The data were used to calculate the constant c with a curve fitting function, in order to stay independent from blood gas measurements. The almost perfect goodness of fit of this normalization procedure is seen as an indirect proof of the concept presented herein (see Fig. 8). Normalization might be particularly helpful to wean a low blood flow system with the primary intention to eliminate CO2, where the effect of increased ventilation is most relevant (see Fig.4).
Table 2
Figure imgf000035_0001
Table 2. VQ, V and Q refers to the reduction in each phase. DQ[real] is the measured delta in pulmonary blood flow, DQ[calculated] is the calculated delta in pulmonary blood flow, DQ[ECMO] is the change in ECMO flow [ml/min]. DVCO2[LUNG] and DVCO2[ECMONORM] are the changes in VCO2 [ml/min].
A reduction in VECMO will lead to a decrease in eliminated CO2 and thus to a rise in venous CO2 content. This might in turn increase VCO2LUNG, to achieve a new steady state. However, as the ECMO and the lung both drain venous blood from the right atrium, VCO2ECMO should increase simultaneously with the new steady state in order to fulfill formula (E5). The short measurement periods did preclude a steady state for CO2 elimination. As QLUNG was calculated through a deliberate step change in VCO2, a steady state is not necessary, as there is no need for an absolute reference point.
The ratio of ventilation to perfusion in the lung will vary with hypoxic vasoconstriction, shunt, alveolar collapse and dead space. VCO2LUNG– estimated from end-tidal pCO2 in healthy lungs - showed an acceptable relationship with QLUNG, but stable minute ventilation on the lung was mandatory. As QLUNG is the quantity to be calculated, a normalization procedure is not possible. As VCO2LUNG can only represent blood flow that participates in gas exchange, shunt due to supine positioning of the animals could explain the bias of underestimation of pulmonary blood flow with the method presented herein. In conclusion, it is demonstrated in this example that blood flow estimation from exhaled CO2 in a VA-ECMO setting is feasible with simple, non-invasive measurements and acceptable accuracy. This concept can be derived from basic physiological equations and accuracy can be increased with normalizing the ECMO sweep gas flow and blood flow to a V/Q ratio of 1. This may be implemented to realize a simple, reproducible weaning procedure for the liberation from VA-ECMO devices.
Example 2 – Cardiac output on veno arterial (VA) Extracorporeal membrane oxygenation (ECMO): Estimation by gas exchange
In a randomized experimental porcine study with VA-ECMO, it was determined whether there is a proportional relationship between the change of VCO2 elimination over ECMO and lung as well as the change in respective blood flow.
Methods
The animals (type: domestic pigs, weight approximately: 40-50 kg) were sedated with ketamine (15mg/kg), midazolam (0.5mg/kg) and methadone (0.2 mg/kg) administered intramuscular (IM) behind the ear. Fifteen minutes after the injection the sedation was evaluated and if deemed insufficient, further ketamine (up to 5 mg/kg) and midazolam (up to a maximum of 1 mg/kg) were administered. Once the sedation was judged adequate, the pigs were lifted on a table and supplemented with oxygen administered through a facial mask.
A central venous cannula was placed through the right jugular vein and after preparation of the surgical field, the induction of general anesthesia was provided through propofol to effect (1-4 mg/kg). Cefuroxime (1.5g) was given at induction of general anesthesia and 6 hours later. After intubation of the trachea, anesthesia was deepened and maintained with total intravenous anesthesia (TIVA) based on propofol (2- 8 mg×kg-1×h-1) and fentanyl (5-30 mg×kg-1×h-1). The doses of TIVA were titrated aiming at the absence of nociceptive autonomic responses and varied accordingly to the intensity of nociceptive stimuli. Additional boluses of fentanyl (100-200 mg) and/or increases of the rate infusions were provided in case an increase of 20% from the baseline of HR and blood pressure. Positive pressure ventilation was started after tracheal intubation in a volume-controlled mode (Servo-I, Maquet Critical Care, Solna, Sweden) using PEEP of 5cmH2O, an FiO2 of 0.30, and a tidal volume of 8- 12mL/kg body weight, targeting a PaCO2 of 40-45 mmHg. During general anesthesia, continuous monitoring of heart rate, respiratory rate, oxygen arterial saturation, capnography, invasive blood pressure, non- invasive blood pressure (Doppler technique) until an arterial line was placed, oesophageal temperature, inspired and expired fraction of gases (air, etCO2), central venous pressure and EEG (through BIS monitoring) were provided. Additional analgesia during the surgical phase were provided with ropivacaine 0.5%, maximum of 2 mg/kg, and morphine 0.1 mg/kg injected in a spinal catheter introduced through median access at the lumbosacral space. A mean arterial blood pressure (MAP) of 70 mmHg was targeted and hypotension was addressed with the use of inotropes/vasopressors titrated to effect. The depth of anesthesia and adequacy of nociception was continuously monitored by targeting a bispectral index <60 (BIS Quatro, Covidien, Mansfield, MA, USA) and through tracking of nociceptive withdrawal reflexes (Pain tracker, Dolosys, GmBh, Germany). After 6-8 hours after the spinal injection, ropivacaine was repeated in case the analgesia was deemed insufficient.
During ECMO, tidal ventilation was continued with the respiratory rate fixed at 6-8/min and tidal volume of 10 ml/kg. The flow rate of oxygenator sweep gas (60% O2, higher if needed) was initially adjusted to keep arterial pCO2 in the normal range (ABL90Flex, Radiometer Medical Aps, Brønshøj, Denmark).
The following catheters were surgically placed: a left carotid artery catheter (5Fr introducer sheath) for arterial pressure measurement and blood sampling, a right-sided jugular triple lumen catheter with the tip in the right atrium for pressure measurement and a left-sided jugular triple lumen for drugs administration. A left atrial catheter was surgically placed for left atrial blood gas sampling. A pulmonary artery catheter was placed through an introductory sheath in the right jugular vein for measurement of pulmonary artery pressure and mixed venous blood gas sampling. The thoracic cavity was accessed via a sternotomy and the pericardium opened. After administration of 5000 U.I. sodium heparin the right atrium, and ascending aorta were cannulated (29 Fr 3-stage venous cannula MC2X and 18 Fr elongated- one-piece arterial cannula, Medtronic, Minnesota, USA) and connected to an ECMO circuit (Cardiohelp MECC Set, Quadrox oxygenator, Maquet, Rastatt, Germany). Intermittent heparin boluses kept activated clotting time >180s. Epicardial electrodes (MYO/Wire™ Temporary Atrial Cardiac Pacing Wires, A&E Medical Corporation, Farmingdale, New Jersey, USA) were put in place with an Osypka Pace 203 external pacemaker. An appropriately sized transit time ultrasonic flow probe (Transonic PAU series, Ithaca, USA) was placed around the pulmonary artery main trunk as well as the right pulmonary artery. The left pulmonary artery was equipped with an intermittently operable tourniquet. Catheters and cables were guided outside the thoracic cavity. Passive pleural drains were placed with the free ends connected to an underwater seal. The pericardium, the sternum and the wound layers were closed in an airtight fashion. The urinary output was monitored through a transmural urinary catheter (Foley) introduced into the bladder after celiotomy. A bronchial blocker was introduced in the left lung (9.0FR, Uniblocker, Fuji Systems Corporation, Nishigo, Japan) and used to intermittently exclude the left lung from ventilation. Disposable fiberoptics (Ambu aScope 3, Xiamen, China) were used to control bronchial blocker placement. During surgery, Ringer’s lactate was infused at a rate of 5 mL/kg/h, and thereafter reduced progressively of 25% each hour down to 3mL/kg/h, provided cardiovascular stability. Hydroxyethyl starch (HES; 6% Voluven; Fresenius Kabi, Bad Homburg, Germany) was supplemented in case of hemodynamic instability during or after surgery.
Intravascular and airway pressures were measured using transducers (xtrans®, Codan Medical, Germany) and a multi-modular monitor (S/5 Critical Care Monitor®; Datex-Ohmeda, GE Healthcare, Helsinki, Finland), including ECG and end-tidal CO2. Output from pressure transducers and ultrasonic blood flow probes were recorded at 240 Hz in a data acquisition system (Labview™; National Instruments Corp., Austin, TX, USA), and processed off-line using a customized analysis software (Soleasy, Alea Solutions, Zürich, Switzerland). Additionally a volumetric CO2 measurement device was installed at the lung with dedicated data recording (Capnostat 5, Hamilton, Bonaduz, Switzerland). Dead space on a breath by breath analysis was recorded throughout the experiment. At the ECMO, a sidestream capnography was installed attached to the gas exhaust port.
Pressures were zeroed against the atmosphere and two-point calibrated using a water manometer. Flow probes were zeroed and calibrated electronically before the study measurements. Baseline drift for pressures and flows were checked at the end of the experiment.
After surgery, a stabilization period of 30 minutes was granted, after which measurements began. HES was given to ensure an ECMO blood flow to ensure a mixed venous oxygenation of 50 to 60% and close to 4 L/min blood flow. Throughout the experiment, ventilator settings (VLUNG) were set at 6 breaths/minute x 10ml/kgBW and kept constant.
The protocol consisted of weaning trials from VA-ECMO under different pulmonary conditions. Reductions in ECMO blood flow was stepwise. During the process of weaning, the function of RV and LV was supported with volume load, and once the preload was deemed adequate with perfusion of inotropes (dobutamine: 0.5-5 mcg/kg/min). In case of a major drop in blood pressure, the attempt was aborted and noradrenaline (0.1-1 mcg/kg/min) combined to dobutamine in order to restore hemodynamic stability.
After baseline measurements, animals were randomized into two experimental groups in which either dead space or shunt was induced. In group 1, first shunt was produced by temporarily inducing one lung ventilation by disconnecting the left lung from the respirator with a bronchial blocker. After measurements in this state, two-lung ventilation was initiated and the left pulmonary artery was temporarily clamped and measurements were redone. The animals in group 2 first had their pulmonary artery clamped, thus creating dead space before one-lung-ventilation was introduced. After measurements during each of these two experimental steps, two-lung-ventilation was reinitiated and the clamping was released.
Baseline measurements
ECMO blood flow (QECMO) was set to 4 liters per minute (l/min). If this could not be achieved, the maximum flow was defined as the highest QECMO possible without suctioning of the cannulae over the respiratory cycle, rounded down in steps of 500ml/min (e.g. maximum flow 3.2 liters, QECMO was set to 3 l/min). Sweep gas flow (VECMO) then was set to match half QECMO, which resulted in a V/Q ratio of 0.5. After 5 minutes under these conditions, a peripheral arterial, a central arterial (left atrial), and a pulmonary venous bloodgas sample were drawn, additionally to blood gases pre- (venous) and post-membrane (arterial) lung. Baseline 1.1 (Step 1)
The first step consisted of a consecutive, stepwise reduction in sweep gas flow of 500ml/min to zero, thus producing a diminishing V/Q ratio. Then sweep gas flow was increased in steps of 500ml/min up to 4l/min but not higher than QECMO, which resulted in a rising V/Q ratio. QECMO and ventilator settings were not changed. After each change in VECMO, the settings remained this way for 2 minutes.
Baseline 1.2 (Step 2)
The second step then consisted of reducing QECMO in steps of 500ml/min as long as the RV and LV function could be supported enough with inotropes and vasopressors to produce a systemic mean arterial pressure of at least 40 mmHg. The new flow settings were maintained until pulmonary blood flow remained unchanged. This time was limited to a maximum of 5 minutes, after which it was continued with the next reduction of blood flow by 500ml/min. If the cardiorespiratory system of the animal did not support the weaning, QECMO was set to initial values and the experimental step was redone once. VECMO remained unchanged.
Baseline 1.3 (Step 3)
Step 3 consisted of the same ECMO flow changes as described in Step 2, but with a simultaneous reduction of VECMO to produce a V/Q ratio of 1.
Blood gas analyses
Blood gas analyses were drawn at the beginning of each step. Additionally there were blood gas analyses after each reduction of 1 l/min QECMO and/or VECMO. This lead to precise information about the immediate changes in gas content and acid-base status and provided a comparison between gaseous measurements and blood measurements. The relationships between carbon dioxide elimination over the lung or membrane and the transported carbon dioxide could be investigated. Blood oxygen and blood carbon dioxide content was calculated according to the method of Dash RK, Bassingthwaighte JB. Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng.2010;38(4):1683-701).
Randomization and induction of a reversible pathological state
After baseline measurements, the animals were randomized into two groups (sealed opaque envelopes). Measurements described under step 1– 3 were repeated for both experimental steps in the same manner as baseline measurements. Between the two one-lung-ventilation and pulmonary clamping (or vice versa) there was again a stabilization period of 15-20 minutes with repetitive recruitment maneuvers using increase in PEEP and peak airway pressure.
Induction of irreversible pathological state (lung damage), permanent shunt
After releasing the clamp and returning to two-lung-ventilation, lung damage resulting in acute respiratory distress syndrome (ARDS) was induced by applying a lavage with 0.9% Saline (50 - 100 ml/kg) to the lung. Measurement steps were repeated in this now pathological state. Shunt fractions were calculated using oxygen content and dead space was asserted by volumetric capnography.
To obtain VCO2ECMONORM as described above in equation E15 (Example 1), the function f(V,Q) was determined as follows
Figure imgf000040_0001
using data points presented by Sun L, Kaesler A, Fernando P, Thompson AJ, Toomasian JM, Bartlett RH. CO2 clearance by membrane lungs. Perfusion.2017:267659117736379. The necessary correction factor was plotted to get VCO2 values independent of V against V/Q and retrieved the function (E24). Thus, V/QECMO was corrected towards a value of 1, only depending on QECMO.
Data were extracted from Labview with the Soleasy Viewer 1.5. Data analysis periods always consisted of the last 60 seconds of each measurement step.
Data was analyzed using SPSS software (Version 21; SPSS Inc., Chicago Illinois, USA) and Microsoft Excel 2016 (Microsoft Corporation, REDMOND, US). Normality was assessed using Shapiro-Wilk’s test. Pairwise comparisons was done according to normality with either Student's t-test or Wilcoxon’s rank sign test. Multiple time series were compared with repeated measurement ANOVA or Friedman’s test, as appropriate. Measurements were expressed either individually as a range or as a mean with SD. The calculated and the measured changes in blood flow were compared using Pearson's square and Bland-Altman methods. Results
As shown in Fig. 12A there is a linear relationship between pulmonary blood flow (QLUNG, Lung Blood Flow) calculated according to the method of the present invention and measured CO2 elimination via the lung (VCO2LUNG, Lung VCO2). This dependency is stronger when VCO2LUNG is normalized to reflect the influence of the ventilation/perfusion ratio V/Q as shown in Fig.12B. For the normalization, V/Q was approximated by
Figure imgf000041_0001
where ca,O2 is the arterial O2 concentration, cv,O2 is the venous O2 concentration, Fi,O2 is the inspiratory O2 fraction and Fe,O2 is the expiratory O2 fraction.
As shown in Fig. 13, there is also a clear linear relationship between blood flow at the extracorporeal circuit (ECMO Blood Flow, QECMO) and CO2 elimination at the ECMO (ECMO VCO2, VCO2ECMO), where the V/Q ratio is kept constant.
Fig. 14 A-D show correlation plots of measured pulmonary blood flow QLUNG (abscissa) and pulmonary blood flow QLUNG (ordinate) as calculated according to the method of the present invention. For the data shown in Fig. 14 A, QLUNG was calculated from measured O2 exchange at the lung and the ECMO (VO2LUNG, VO2ECMO) and blood flow through the ECMO (QECMO). In other words, equation 13 was used to calculate QLUNG, wherein G is molecular oxygen (O2). In contrast, for the data shown in Fig. 14 B, QLUNG was calculated from measured CO2 exchange at the lung and the ECMO (VCO2LUNG, VCO2ECMO) and blood flow through the ECMO (QECMO). Thus, QLUNG was determined from equation 13, where G equals carbon dioxide (CO2). Fig. 14C shows the correlation between measured QLUNG and calculated QLUNG from equation 13 with G=CO2 and normalized by the V/Q ratio as described above (using Eq. E25) determined from the venous O2 concentration measured using a pulmonary catheter, and Fig. 14D depicts the correlation between measured QLUNG and calculated QLUNG from equation 13 with G=CO2 and normalized by the V/Q ratio as described above (using Eq. E25) determined from the venous O2 concentration measured by blood gas analysis. In both cases (Fig. 14C and 14D), the oxygen concentration was estimated according to
Figure imgf000041_0002
Where s designates oxygen saturation in per cent, and Hb designates the hemoglobin value or hemoglobin level in grams per deciliter. The venous oxygen saturation was determined by direct measurement via a pulmonary catheter (Fig.14 C) or by blood gas analysis (Fig.14D). The arterial oxygen saturation was assumed to be 100 per cent. FiO2 was pre-set in the experiment and FeO2 was directly measured. Example 3– Cardiac output estimations based on gas exchange during extracorporeal membrane oxygenation– an in vitro model
Materials and Methods
The simulation consisted of two parallel circuits - one representing the ECMO blood flow with extracorporeal gas exchange, the other lung and heart, merged into the systemic circulation (Fig. 15). One circuit 31 represents the human heart and lung. It consisted of a micro- diagonal pump 40 (DeltaStream DP-II, Medos, Stolberg, Germany), generating non-pulsatile flow, as the heart and an oxygenator 37 (OxyLung QUADROX-i Pediatric Oxygenators; MAQUET, Hirrlingen, Germany) as the natural lung, including a blood flow bypass 43 around the OxyLUNG for the simulation of anatomical or functional right-to-left shunt. The second circuit 30, consisting of the same type of pump 40 and oxygenators 37, represents the ECMO (OxyECMO). Both oxygenators 37 were operated at a fraction of inspired oxygen of 50% throughout the experiment. These two circuits 30, 31 (Lung and ECMO) were merged into one mixed flow, representing the Aorta and then guided into a simulated metabolic chamber 32. Here, over two oxygenators 37 (OxyVCO2/O2, Terumo Capiox RX25R, Ann Arbor, MI, USA) carbon dioxide was introduced into the system and oxygen washed out with a nitrogen/carbon dioxide gas blend to ensure venous pCO2 values between 50 and 80 mmHg and mixed venous saturations of 70– 90 %. Gas flow was regulated with high precision flow control valves (Vögtlin RED-Y, Basel-Land, Switzerland). Blood was collected in a venous, air-free reservoir bag above the functional right atrium to ensure steady perfusate supply at different blood flow rates. Blood flow between the circuits 30,31 and the shunt 43 was regulated with simple flow restrictors 39.
Priming volume of the system was approximately 2.2 liters. It was filled with a mixture of discarded human red blood cells and lactated Ringer’s solution in a ratio of 3:1 to reach a hemoglobin value of 8 - 10 g/L. 50 - 100 mmol of Sodium Bicarbonate was added to reach physiological pH values between 7.3 -7.4. Glucose 20% was added to keep glucose level above 5 mmol/l. Boluses of 5000 I. E. Heparin were added every 2 to 3 hours to prevent clotting. The system was heated to 36.8°C using a temperature control system (HCV, Type 20–602, JostraFumedica, Muri/CH).
Exhaust CO2 at the ECMO was measured using a standard side-stream capnometer (Vamos, Dräger, Lübeck, Germany) with a constant 200 mL/min sidestream flow and a measurement accuracy of +/- 3.3 mmHg + 8% relative error. After every experimental maneuver, blood gas samples were drawn at the specified ports 41 in Fig. 15 and analyzed with a point of care device (Cobas b 123, Roche Diagnostics, Basel, Switzerland). Blood flow was continuously measured using liquid flow meters 38 (Levitronix, Zurich, Switzerland) at the indicated locations in Fig. 15. Gas flow was set and recorded manually at the gas blenders for OxyLung and OxyECMO and digitally using the flow control valves for OxyVCO2/O2. It was aimed at a total flow of 2500 mL in the systemic circulation, measured after the metabolic chamber 32. At baseline, this flow was partitioned in 2’000ml/min running through the ECMO circuit 30 and 500 ml/min running through the lung circuit 31. Aortal pCO2 at baseline was aimed at 40mmHg corresponding to a simulated CO2 production of approximately 120– 150 ml/min.
From this baseline, multiple weaning trials were performed by 500-mL-wise reductions of ECMO blood flow with either a constant V/Q ratio of 1 (gas flow matches blood flow) or varying V/Q ratios (constant gas flow of 1,5 liters/min during reduction of blood flow) on the ECMO and consecutive increases in lung blood flow of 500 ml, matching the ECMO blood flow reduction (steps 1– 6 in Table 3).
Table 3
Figure imgf000043_0001
Figure imgf000044_0004
In a second step, lung blood flow was not directly regulated but was the indirect result of changing the venous pool at unchanged rotations per minute (steps 7– 10 in table 3).
In a clinical setting the pulmonary blood flow is unknown and establishing steady V/Q or its prediction is not possible. Therefore, lung gas flow was kept constant at 1.5 liters/min (FiO2 50%) and remained unchanged during each experimental step.
Calculations
Blood CO2 content (cCO2) was calculated for each sampling site with the method of Dash RK, Bassingthwaighte JB. Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng. 2010;38(4):1683-701). VCO2 was calculated either from venous-arterial CO2 content difference multiplied by blood flow (VCO2Blood) or from gaseous measurements by multiplying the exhausted CO2 fraction times the gas flow (VCO2Gas). O2 content (cO2) was calculated for each sampling site using formula 1 (pO2: O2 partial pressure [mmHg], sO2: Saturation, Hb: Hemoglobin [g/L]):
Figure imgf000044_0001
VO2 was calculated by multiplying the arterial-venous O2 blood content difference with blood flow.
Blood flow calculations were performed as described above in examples 1 and 2. QLUNG was determined using equation (13) using CO2 and O2 gas flows as follows:
Figure imgf000044_0002
Normalization of VCO2 towards a V/Q ratio of 1 was performed as described above (see equations (E15) to (E23) in example 1.
Pulmonary right-to-left shunt fraction was calculated as shunt blood flow divided by total lung flow and compared to the classic Berggren shunt equation.
Figure imgf000044_0003
Additionally, we calculated shunt using cCO2 with the Berggren Shunt formula. For statistical, mathematical and graphical analysis, Matlab R2017b (MathWorks, Natick, Massachusetts, USA) was used. Data are presented as mean with standard deviation or as range. Correlation coefficients were calculated using Pearson’s square (r2). Multiple linear regression was used to assess the relationship between VCO2, blood flow and differences in CO2 content. Agreement between methods was assessed with linear regression and Bland- Altman analysis. p < 0.05 was considered significant.
Results
At baseline (e.g. the beginning of each experimental step) mean total flow was 2175 +/- 284 ml/min with a minimum of 1688 and a maximum of 2520 ml/min. This was achieved by a mean QECMO of 1825 +/- 192 ml/min and a mean QLung of 350 +/- 157 ml/min, as defined per study protocol. Mean VCO2Gas at OxyECMO was 87 +/- 13 ml/min and mean VCO2Blood was 121 +/- 59 ml/min. VO2 values were 44 +/- 9 ml/min. For OxyLung, mean VCO2Gas was 43 +/- 13 ml/min while mean VCO2Blood was 60 +/- 15 ml/min. Mean VO2 was 7 +/- 3.5 ml/min. Mean arterial pH was 7.39 +/- 0.09 and mean venous pH was 7.29 +/- 0.09 at Baseline.
Baseline showed a mixed venous saturation of 83.8 +/- 8.0 %, corresponding to an O2 content of 10.3 +/- 1.3 ml/100ml of blood and a mean mixed venous pCO2 of 49.7 +/- 4.4 mmHg corresponding to a CO2 content of 54.5 +/- 12.6 ml/100ml of blood. On the arterial side of the system, mean saturation was 98.2 +/- 3.4 % corresponding to an O2 content of 12.3 +/- 1.0 ml/100ml of blood while mean pCO2 was 34.3 +/- 3.5 mmHg corresponding to a CO2 content of 47.4 +/- 12.0 ml/100ml of blood. At OxyVCO2/VO2 N2 gas flow was kept between 4 and 6 liters/min while CO2 gas flow was between 300 and 500 ml/min.
Ventilation at the lung (VLung) was set between 1.4 and 1.5 L/min and remained unchanged. VECMO was either kept steady between 1.4 and 1.5 L/min for the maneuvers with a varying V/QECMO (steps 4– 6) and followed blood flow in the remaining maneuvers. The correction factor c used in the normalization of V/Q was 10.8 +/- 2.1.
True shunt varied from 16.8 to 62.8%. Fig.18 shows the scatter plots for calculated and true shunt values using CO2 and O2 content. Correlations for calculations with O2 content were r2 = 0.604, p < 0.001 and for calculations with CO2 content r2 = 0.396, p < 0.001. There was a significant correlation between shunt calculated from O2 and CO2 (r2 = 0.333, p = 0.002). The relationships between VO2 and VCO2 and the respective blood flows were assessed over the oxygenator during the steady state phases of the simulation (Fig 19). For OxyLung, VCO2Gas (r2 = 0.659, p< 0.001), VCO2Blood (r2 = 0.273, p<0.001) and VO2 (r2 = 0.666, p<0.001) showed significant correlations with blood flows. A normalization of VCO2Gas improved correlations (r2 = 0.861, p<0.001, Fig. 19B). For OxyECMO, correlations were also significant for VCO2Gas (r2 = 0.796, p< 0.001), VCO2Blood (r2 = 0.368, p<0.001) and VO2 (r2 = 0.785, p<0.001). A normalization of VCO2Gas at OxyECMO improved correlations (r2 = 0.963, p<0.001).
As physiologically derived in equation (E7), there is a strong correlation between VCO2Blood and VO2 at OxyECMO and OxyLung with the VCO2Blood and VO2 of the total system at OxyVCO2/O2 (r2 = 0.541, p<0.001 for VCO2 and r2 = 0.925, p < 0.001 for VO2, Fig. 20A). Note that Fig. 20A is calculated only for true blood flow at OxyLung ignoring shunt blood flow. VCO2Blood correlated well with VCO2Gas (r2 = 0.587, p < 0.001. Fig.20B).
VCO2 is a product of blood flow and the differences in gas content. Therefore, the relationship between the differences in CO2 and O2 content was explored over the oxygenators 37, respective blood flow and VCO2Blood and VO2 as a product of these differences multiplied by blood flow using a multiple linear regression (Fig.21A and 21B). As VCO2Blood and VO2 are a direct product of the independent variables (blood flow and difference in gas content) the multiple linear regression showed an r2 of 1. The same model was then applied for VCO2Gas (r2 = 0.751, p < 0.001, Table 4A, Fig. 21C) and normalized VCO2Gas (r2 = 0.974, p < 0.001, Table 4B, Fig.21D).
Table 4A
Figure imgf000046_0001
Multiple linear regression for VCO2Gas. Model: y = Intercept + x1 * x2. Table 4B
Figure imgf000046_0002
Multiple linear regression for normalized VCO2Gas. Model: y = Intercept + x1 * x2.
The relationship between V/Q and the respiratory exchange ratio R was then analyzed. The scatter plot shows a significant correlation between the two variables (r2 = 0.601, p < 0.001, Figure 22A) while the Bland-Altman Plot shows wide limits of agreement with a positive bias of 0.89 (Figure 22B). The slope of the respiratory exchange ratio was corrected using the factor c = 0.8, as this represents the true expiratory exchange ratio in humans.
Calculations of simulated pulmonary blood flow during steady state were done using equations (E28) and (E29) and were based on five different values: 1) VCO2Gas, normalized for ECMO and lung, 2) VCO2Gas, normalized through the expiratory exchange ratio 3) VCO2Gas, only normalized for ECMO, 4) VCO2Blood and 5) VO2.
These calculations were performed firstly for blood flow over the oxygenator without right-to- left shunt (Fig.23A to E) and then for total blood flow passing the lung, thus including shunt. 1) For normalized VCO2Gas, true blood flow correlates significantly with calculated blood flow (y = 1.12 *x– 144.51, r2 = 0.959, p < 0.001, Fig. 23A). Shunt decreases the accuracy (y = 0.88 * x - 72.1, r2 = 0.847, p < 0.001).
2) If VCO2 Gas is normalized using the respiratory exchange ratio, correlation decreases but stays significant (y = 0.46 * x + 148.6, r2 = 0.723, p < 0.001, Fig. 23B). Shunt again further decreases this correlation (y = 0.359 * x + 180.25, r2 = 0.627, p < 0.001).
3) If VCO2Gas at OxyLung is not normalized, correlations remain high with an increased intercept in the linear regression (y = 0.54 * x + 716.0, r2 = 0.806, p < 0.001, Fig. 23C). As expected, shunt decreases the correlation (y = 0.45 *x + 728.67, r2 = 0.788, p < 0.001).
4) For VCO2Blood, there is no significant correlation (shunt excluded, r2 = 0.0473, p = 0.19, Fig.23D; shunt included: r2 = -0.014, p = 0.4797).
5) Using VO2 values, calculations of blood flow during the steady state show significant correlations (shunt excluded: y = 0.95 * x + 70.1, r2 = 0.972, p < 0.001, Fig. 23E; shunt included: y = 0.76 * x + 120.5, r2 = 0.88 , p < 0.001). Figure 24A to E shows the respective Bland-Altman plots.
Discussion
Two competing blood circuits (ECMO and lung) were successfully simulated with a deoxygenation and carboxylation unit reaching physiological parameters. In this in vitro study, multiple findings of importance could be shown:
Firstly, pulmonary shunt has a linear relationship to the difference in CO2 content as it does with O2. This is of importance, as shunt has an influence on the model of calculating pulmonary blood flow according to the invention. In the classic physiological literature, shunt or venous admixture is seen as the cause of hypoxemia, while excessive dead space ventilation with exhaustion of respiratory reserves explains hypercapnia. As shown herein, when pulmonary minute ventilation is kept constant, as would be the case during controlled mechanical ventilation, shunt is also a cause of increased arterial pCO2.
Secondly, the results described above show that there is a strong relationship between blood flow through the oxygenator and VCO2 and VO2 in the gas phase. As ventilation majorly influences the amount of CO2 transported to the oxygenator, the correlation with VCO2 and blood flow is improved through the normalization described above. In summary, the normalization function using a correction factor c can estimate VCO2 from any V/Q for a V/Q of 1. The calculation of c can be done by collecting a venous blood gas sample. If conditions remain steady, c does not have to be calculated for each weaning step. In the experiment according to this example, ventilation at the lung was at a fixed rate of 1.5 L/min. Correlation between blood flow and VCO2 works best, if V/Q stays one. If not, the influence of ventilation is removed by applying the normalization. This phenomenon is shown in Fig.19A, where the regression lines cross at the point where V/QLung is one. Such a normalization is unnecessary for VO2, as oxygen is mostly transported by binding hemoglobin, which is mathematically represented in equation (E27). As long as post oxygenator saturation reaches 100%, VO2 becomes mostly independent of V/Q ratio and represents blood flow. Only if hemoglobin were to become incompletely saturated, ventilation would have an impact on VO2. An increase in FiO2 will correct this phenomenon. In a clinical setting, it seems therefore reasonable not to go below a limit of 50-60% of FiO2 if V/Q ratios go below 0.8. The high correlation between blood flow and VCO2 / VO2 values is interpreted as proof that blood flow calculations are possible from changes in these parameters. Furthermore, it could be shown that equation (E7), which lays the basis of the approach described herein, holds true in an in vitro simulation (see Fig.20A).
Thirdly, it could be shown that the differences in CO2 or O2 content share a relationship with VCO2 and VO2. This serves as physiological background to replace these differences in gas content with the measured values of VCO2 and VO2 and leads to equation (E28). The slope of the grids shown in Figure 21A, 21B and 21C represent the proportionality between the differences in gas content and VCO2. As VCO2 is a product of these differences times gas flow, the r2 is 1 for VCO2Blood and VO2. For VCO2Gas, the linear model shows high goodness of fit. It is of note, that the model for VCO2Gas shows the delta in CO2 content as well as blood flow as significant determinants whereas after the normalization only blood flow remains as a significant factor of the model. If blood flow remains steady, different VCO2 values will arise from different ventilation settings. This will result in various CO2 content differences for the same blood flow. Using the normalization, this effect can be discarded. The normalization shown in Figure 21D removes the effect of the difference in CO2 content. Normalized VCO2 now is only dependent on blood flow. This improves the accuracy of the blood flow estimations, as values now implemented into equation (E28) that are directly and only proportional to blood flow.
Fourthly, simulated pulmonary blood flow was calculated with high precision and correlations using VCO2Gas or VO2 values. The underlying physiological principles were investigated thoroughly and it can be shown in this in-vitro simulation that CO2 production and O2 consumption must be in equilibrium in two competing systems with two circuits and oxygenators. This allows to calculate blood flow. It is of note that the accuracy of flow calculations are impaired by high shunt and V/Q mismatch. Shunted blood will not participate in gas exchange and is therefore not detected by the method described herein. It can be clearly shown that shunt consistently decreases accuracy of the calculations. V/Q mismatch will additionally introduce error into the calculation. Furthermore, high V/Q will lead to an overestimation of pulmonary blood flow as shown in Figure 24C. In a clinical setting, VCO2Gas might be corrected using alternative estimations of V/Q. Multiple approaches exist such as MIGET, electrical impedance tomography and positron emission tomography. However, a simple clinical approach would be the use of respiratory exchange ratio, which in theory might reflect V/Q. This would allow a bedside approach to estimating pulmonary blood flow during veno-arterial ECMO therapy. It is of note, that a normalization using the respiratory exchange ratio introduces an error and decreases accuracy of the calculations. However, it also decreases the intercept and thus the bias introduced into the calculations. It therefore might be clinically more useful than using the not normalized VCO2 values. Blood flow calculations are not reliable using VCO2Blood values, because there is no normalization applied and calculating the CO2 blood content can be challenging. CO2 in the blood is transported through three mechanisms: it is dissolved freely, bound to hemoglobin and as bicarbonate and calculating each partition correctly is in itself prone to error. On the other hand, gas measurements are easily done and calculating VCO2 from exhaust capnography is simple, readily available and reliable. This is a motivation to ultimately realize the model of pulmonary blood flow calculations using measurements of exhaust gas. Nevertheless, the multiple linear regression shows a strong relationship between VCO2Gas and VCO2Blood, which proves the underlying physiological principle.
In the here presented study using a highly controllable environment, such a steady state is reached much faster than in animal studies (see examples 1 and 2). Therefore, the method could be validated using these steady state conditions rather than differences in gas change during weaning.
Transferring the findings to a clinical setting imply that estimations of pulmonary blood flow during ECMO weaning are possible using FiO2, exhaust pCO2/pO2, venous pH, ECMO blood flow, ECMO ventilation, lung alveolar ventilation and lung dead space. The two latter parameters are readily available using volumetric capnography, and all of these parameters can easily be measured in an intensive care unit where ECMO therapy is performed. In general, volumetric capnography and caliometric modules are available for the lung and ECMO and might increase overall precision of the calculations. The method described herein is limited by high shunt and V/Q mismatch, which can only be partially correct for as a normalization of VCO2Lung is not possible in a clinical setting.
List of reference signs
Figure imgf000050_0001
Figure imgf000051_0001

Claims

Claims
1. A method for estimating a pulmonary blood flow (QLUNG) of a subject connected to an extracorporeal oxygenation device (10), wherein
- a first gas flow (VGLUNG) of a gas (G) exhaled by the subject is determined, wherein said gas (G) is soluble in blood,
- a second gas flow (VGECMO) of said gas released from the extracorporeal oxygenation device (10) is determined,
- an external blood flow (QECMO) through the extracorporeal oxygenation device (10) is determined,
- a pulmonary blood flow (QLUNG) of the subject is estimated from said first gas flow (VGLUNG), said second gas flow (VGECMO) and said external blood flow (QECMO).
2. The method according to claim 1, wherein said gas (G) is CO2, O2 or an anesthetic gas, particularly CO2.
3. The method according to claim 1 or 2, wherein said pulmonary blood flow (QLUNG) is estimated according to the formula QLUNG=QECMO*(-VGLUNG/VGECMO), wherein QECMO is said external blood flow, VGLUNG is said first gas flow and VGECMO is said second gas flow.
4. The method according to any one of the preceding claims, wherein said external blood flow (QECMO) and/or a ventilation rate (VECMO) of the blood flowing through the extracorporeal oxygenation device (10) is changed, particularly reduced, wherein a change of said pulmonary blood flow ( DQLUNG) of the subject in response to said changed external blood flow (QECMO) and/or ventilation rate (VECMO) is estimated.
5. The method according to claim 4, wherein said gas (G) is CO2, and wherein said change of said pulmonary blood flow ( DQLUNG) is estimated according to the formula
DQLUNG= DQECMO*(- DVGLUNG/ DVGECMONORM), wherein DQECMO is the change of said external blood flow, DVGLUNG is the change of said first gas flow, and DVGECMONORM is determined according to the formula DVGECMONORM= DVGECMO*f, wherein DVGECMO is the change of the second gas flow, and f is a normalization factor reflecting the quotient
Figure imgf000052_0001
wherein is said second gas flow (VGECMO) when the ratio between said
Figure imgf000052_0003
ventilation rate (VECMO) and said external blood flow (QECMO) equals 1, wherein particularly said normalization factor (f) is calculated according to the formula
Figure imgf000052_0002
wherein c is a constant, wherein more particularly said constant (c) is
Figure imgf000052_0004
calculated according to the formula c = sG * R * T * 1 + Kc , wherein sG is the solubility of said gas (G) in blood, R is the gas constant, T is the temperature in Kelvin and KC is the solubility equilibrium constant of the gas (G) in blood at a given pH.
6. The method according to any one of the preceding claims, wherein said extracorporeal oxygenation device (10) is connected to the subject in parallel to the lung (L) of the subject, wherein particularly said extracorporeal oxygenation device (10) is connected to the subject by means of a first port (11) to a vein (V) of the subject and a second port (12) to an artery (A) of the subject, such that blood (B) is able to flow from said vein (V) through said first port (11) into said extracorporeal oxygenation device (10), and blood (B) oxygenated by the extracorporeal oxygenation device (10) is able to flow through said second port (12) into said artery (A).
7. The method according to any one of the preceding claims, wherein said pulmonary blood flow (QLUNG) and/or said change in pulmonary blood flow ( ^QLUNG) is estimated from a normalized first gas flow (VGLUNGNORM), said second gas flow (VGECMO) and said external blood flow (QECMO), wherein said normalized first gas flow (VGLUNGNORM) is determined according to the formula VGLUNGNORM= VGLUNG*f’, wherein f’ is a normalization factor, wherein particularly said normalization factor (f’) is calculated according to the formula
Figure imgf000053_0001
wherein c is a constant, wherein more particularly the V/Q ratio is estimated
Figure imgf000053_0002
according to the formula wherein ca,02 is an O2 concentration of arterial
Figure imgf000053_0003
blood of the subject, cv,02 is an O2 concentration of venous blood of the subject, Fi,02 is an inspiratory O2 fraction and Fe,02 is an expiratory O2 fraction.
8. A device (20) for estimating a pulmonary blood flow (QLUNG) of a subject connected to an extracorporeal oxygenation device (10), particularly by means of the method according to any one of the claims 1 to 7, comprising at least the following components:
- a first unit (21) adapted to determine a first gas flow (VGLUNG) of a gas (G) exhaled by a subject, wherein said gas (G) is soluble in blood,
- a second unit (22) adapted to determine a second gas flow (VGECMO) of said gas (G) released from an extracorporeal oxygenation device (10) to which the subject is connected, - a third unit (23) adapted to determine an external blood flow (QECMO) through said extracorporeal oxygenation device (10), and
- a computing unit (24) adapted to estimate a pulmonary blood flow (QLUNG) of said subject from said first gas flow (VGLUNG), said second gas flow (VGECMO) and said external blood flow (QECMO).
9. The device (20) according to claim 8, characterized in that said computing unit (24) is adapted to estimate said pulmonary blood flow (QLUNG) according to the formula QLUNG=QECMO*(-VGLUNG/VGECMO), wherein QECMO is said external blood flow, VGLUNG is said first gas flow and VGECMO is said second gas flow.
10. The device (20) according to claim 8 or 9, characterized in that said computing unit (24) is adapted to estimate a change of said pulmonary blood flow ( DQLUNG) of the subject in response to a change, particularly reduction, of said external blood flow (QECMO) and/or a ventilation rate (VECMO) of the blood flowing through the extracorporeal oxygenation device (10).
11. The device (20) according to claim 10, characterized in that said computing unit (24) is adapted to estimate said change of said pulmonary blood flow ( DQLUNG) according to the formula DQLUNG= DQECMO*(- DVGLUNG/ DVGECMONORM), wherein said gas is CO2, and wherein DQECMO is the change of said external blood flow, DVGLUNG is the change of said first gas flow, and DVGECMONORM is determined according to the formula DVGECMONORM= DVGECMO*f, wherein DVGECMO is the change of the second gas flow, and f is a normalization factor reflecting the quotient wherein is said second gas flow
Figure imgf000054_0001
Figure imgf000054_0002
(VGECMO) when the ratio between said ventilation rate (VECMO) and said external blood flow (QECMO) equals 1.
12. The device (20) according to claim 11, characterized in that said computing unit (24) is adapted to calculate said normalization factor (f) according to the formula
Figure imgf000054_0003
wherein c is a constant.
Figure imgf000054_0004
13. The device (20) according to claim 12, characterized in that said computing unit (24) is adapted to calculate said constant (c) according to the formula c = sG * R * T * 1 + Kc , wherein sG is the solubility of the gas (G) in blood, R is the gas constant, T is the temperature in Kelvin and KC is the solubility equilibrium constant of the gas (G) in blood at a given pH.
14. The device (20) according to any one of the claims 8 to 13, characterized in that said computing unit (24) is adapted to estimate said pulmonary blood flow (QLUNG) and/or said change in pulmonary blood flow ( DQLUNG) from a normalized first gas flow (VGLUNGNORM), said second gas flow (VGECMO) and said external blood flow (QECMO), wherein said computing unit (24) is adapted to determine said normalized first gas flow (VGLUNGNORM) according to the formula VGLUNGNORM= VGLUNG*f’, wherein f’ is a normalization factor, wherein particularly said computing unit (24) is adapted to calculate said normalization factor (f’) according to the formula wherein c is a constant, wherein more particularly said
Figure imgf000054_0005
computing unit (24) is adapted to estimate the V/Q ratio according to the formula V/Q = , wherein ca,02 is an O2 concentration of arterial blood of the subject, cv,02 is an O2
Figure imgf000055_0001
concentration of venous blood of the subject, Fi,02 is an inspiratory O2 fraction and Fe,02 is an expiratory O2 fraction.
15. The device (20) according to any one of the claims 8 to 14, characterized in that said extracorporeal oxygenation device (10) is an extracorporeal membrane oxygenation device (ECMO).
16. The device (20) according to any one of the claims 8 to 15, characterized in that said first unit (21) and/or said second unit (22) comprises a capnograph, particularly a side stream capnograph or a main stream capnograph.
17. A computer program comprising computer program code for performing at least the following step of the method according to any one of the claims 1 to 7 when the computer program is executed on a computer: estimating a pulmonary blood flow (QLUNG) of the subject from said first gas flow (VGLUNG), said second gas flow (VGECMO) and said external blood flow (QECMO).
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