Oxygen Consumption and Energy Expenditure Monitoring

Abstract

A patient ventilation system and a computing device-implemented method determine oxygen consumption in a mechanically ventilated subject includes receiving a signal representing a total flow at an inspiratory outlet of a ventilator, calculating a transport delay time between inspiratory and expiratory gas sample points in a patient ventilation circuitry, transmitting a signal to an inlet selector valve to selectively open a fluid path between the inspiratory gas sample point and an oxygen sensor or between the expiratory gas sample point and the oxygen sensor, receiving data representing oxygen content and carbon dioxide content over a period of time, calculating oxygen consumption data over the period of time from the data representing the total flow, oxygen content and carbon dioxide content and from the transport delay time, and displaying the oxygen consumption data over the period of time.

Claims

1. A computing device-implemented method to determine oxygen consumption in a mechanically ventilated subject, the method comprising: receiving a signal representing a total flow at an inspiratory outlet of a ventilator; calculating a transport delay time between inspiratory and expiratory gas sample points in a patient ventilation circuitry; transmitting a signal to an inlet selector valve to selectively open a fluid path between the inspiratory gas sample point and an oxygen sensor or between the expiratory gas sample point and the oxygen sensor; receiving data representing oxygen content and carbon dioxide content over a period of time; calculating oxygen consumption data over the period of time from the data representing the total flow, oxygen content and carbon dioxide content and from the transport delay time; and displaying the oxygen consumption data over the period of time.

2. The method of claim 1, further comprising repeating the transmitting and receiving steps over an observation period longer than the period of time.

3. The method of claim 1, wherein calculating oxygen consumption comprises calculating a number of whole breaths of a patient from the delay time.

4. The method of claim 1, further comprising correcting the signal representing the total flow for viscosity dependence.

5. The method of claim 1, further comprising calculating flow-weighted averages of the inspiratory oxygen content and carbon dioxide content.

6. The method of claim 1, further comprising calculating a respiratory quotient of a patient.

7. The method of claim 1, further comprising calculating carbon dioxide production of a patient.

8. The method of claim 1, further comprising calculating energy expenditure of a patient.

9. The method of claim 1, further comprising calculating a transport delay time between a Y-connector that is attachable to a patient and the expiratory gas sample point.

10. The method of claim 1, wherein the subject is a neonate.

11. A patient ventilation system comprising: a ventilation fluid circuit with a fluid path connected to sources of air and oxygen, a patient, and a fluid outlet; a flowmeter located in the fluid path between the sources of air and oxygen and the patient; an inhalation fluid sampling line connected at an inhalation gas sample point of the fluid path located between the sources of air and oxygen and the patient; an exhalation fluid sampling line connected to an exhalation gas sample point of the fluid path located between the patient and the fluid outlet or a mixing chamber fluidly connected to the fluid outlet; an oxygen sensor and a carbon dioxide sensor configured to measure an oxygen and a carbon dioxide concentration of a gas passing along a sensing path through the sensor, wherein the sensing path is connected to the inhalation fluid sampling line and to the exhalation fluid sampling line; a selector valve arranged to selectively connect either the inhalation fluid sampling line or the exhalation fluid sampling line to the sensing path; and a computing device comprising a memory configured to store instructions and a processor to execute the instructions to perform operations comprising: receiving a signal representing a total flow at an inspiratory outlet of a ventilator; calculating a transport delay time between inhalation and exhalation gas sample points; transmitting a signal to the selector valve to selectively connect either the inhalation fluid sampling line or the exhalation fluid sampling line to the sensing path; receiving data representing oxygen content and carbon dioxide content over a period of time; calculating oxygen consumption data over the period of time from the data representing the total flow, oxygen content and carbon dioxide content and from the transport delay time; and displaying the oxygen consumption data.

12. The system of claim 11, wherein the inhalation fluid sampling line, the exhalation fluid sampling line, or both the inhalation fluid sampling line and the exhalation fluid sampling line, are water permeable gas tubes that equilibrate their contents to ambient humidity.

13. The system of claim 11, wherein a portion of the ventilation fluid circuit is inside a ventilator.

14. The system of claim 11, wherein the computing device performs a further operation comprising calculating a respiratory quotient of the patient.

15. The system of claim 12, wherein the computing device performs a further operation comprising calculating carbon dioxide production.

16. The system of claim 12, wherein the computing device performs a further operation comprising calculating an energy expenditure of the patient.

17. The system of claim 11, wherein the oxygen sensor comprises a laser diode sensor and the carbon dioxide sensor is a nondispersive infra-red sensor.

18. A computing device-implemented method of claim 1, further comprising: correcting the signal representing the flow for viscosity dependence; calculating a transport delay time between a Y-connector that is attachable to a patient and the expiratory gas sample point; and calculating flow-weighted averages of the oxygen content and carbon dioxide content.

19. A patient ventilation system comprising: a ventilation fluid circuit with a fluid path connected to sources of air and oxygen, a patient, and a fluid outlet; an inhalation fluid sampling line connected at an inhalation gas sample point of the fluid path located between the sources of air and oxygen and the patient; an exhalation fluid sampling line connected to an exhalation gas sample point of the fluid path located between the patient and the fluid outlet or a mixing chamber fluidly connected to the fluid outlet; an oxygen sensor and a carbon dioxide sensor configured to measure an oxygen and a carbon dioxide concentration of a gas passing along a sensing path through the sensor, wherein the sensing path is connected to the inhalation fluid sampling line and to the exhalation fluid sampling line; a selector valve arranged to selectively connect either the inhalation fluid sampling line or the exhalation fluid sampling line to the sensing path; and a computing device comprising a memory configured to store instructions and a processor to execute the instructions to perform operations comprising: receiving a signal representing a total flow at an inspiratory outlet of a ventilator; correcting the signal representing the flow for viscosity dependence; calculating a transport delay time between inspiratory and expiratory gas sample points in a patient ventilation circuitry; calculating a transport delay time between a Y-connector that is attachable to a patient and the expiratory gas sample point; transmitting a signal to an inlet selector valve to selectively open a fluid path between the inspiratory gas sample point and an oxygen sensor or between the expiratory gas sample point and the oxygen sensor; receiving data representing oxygen content and carbon dioxide content over a period of time; calculating flow-weighted averages of the oxygen content and carbon dioxide content; calculating oxygen consumption data over the period of time from the data representing oxygen content and carbon dioxide content and from the transport delay time; and displaying the oxygen consumption data over the period of time.

Description

DESCRIPTION OF DRAWINGS

[0091] FIG. 1 is a schematic of a system with a specialized device for accurate measurement of oxygen consumption.

[0092] FIG. 2 is a flowchart that shows a measurement sequence to be used for control, data acquisition and calculation.

[0093] FIG. 3 is a flowchart that shows the calculations for a respiratory cycle comprising measurements from the inspiratory and expiratory gas sample inlets.

[0094] FIG. 4 is a flowchart that shows the initial tasks to determine the transport delay.

[0095] FIG. 5 an explanatory schematic of the portion of the inspiratory and expiratory tubing near the Y-piece for defining circuit volumes.

[0096] FIGS. 6A and 6B are exemplary inspiratory and expiratory signal diagrams using the system for determining flows and time periods as depicted with respect to FIG. 5.

[0097] FIG. 7 is a graphical representation of the timing sequence for calculations for each inspiratory and expiratory gas sample measurement cycle.

[0098] FIG. 8 is a schematic of a lung simulator that permits the quantification of oxygen consumption and carbon dioxide production during phasic ventilation of the apparatus described herein.

[0099] Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

[0100] The methods and apparatus described herein can determine oxygen consumption (VO.sub.2) in mechanically ventilated subject, including neonates, by sampling inspired and expired gas and measuring inspiratory flow. Unlike other techniques, these techniques are suitable for use in mechanically ventilated pediatric patients including neonates and premature infants where ventilation is low and respiratory rates are high. Oxygen content of inspiratory gas is determined by flow-weighted averaging for maximum accuracy and precision. Expiratory gas contents of oxygen and carbon dioxide are determined by averaging during expiration. Inspiratory and expiratory gas contents are compared using a time delay, which accounts for circuit compliance and bias flow.

[0101] The technique additionally accounts for the transport delay time of gases travelling between a Y-piece attached to a patient and an expiratory sampling site, to limit the expiratory sampling period. Accounting for this time delay ensures no shift in measured mixed expired gas concentrations caused by alternating gas sampling sites and combines mixed expired concentrations with the measured total flow in the inspiratory limb corrected for gas sample flow. The flow-weighting and dynamic time delays allow accurate determination of oxygen consumption in the single-digit ml/min range at the fluctuating inspired oxygen concentrations typical for ventilators used for newborns and other patients.

Ventilator Systems

[0102] The new systems overcome several compounding errors in oxygen consumption measurements. First, ventilators are known to deliver fluctuating oxygen concentrations (F.sub.IO.sub.2), which can have significant effects on metabolic measurements. By compensating measures of inspiratory flow of dry gas for F.sub.IO.sub.2-dependent changes in viscosity and flow-weighting F.sub.IO.sub.2 measurements (rather than simple time-weighted estimates, as other current instruments do), it is possible to determine both inspired volume flow and average F.sub.IO.sub.2 accurately and make the measurement relatively insensitive to fluctuations in F.sub.IO.sub.2 from the ventilator. Expired concentrations are measured at the exhaust port of the ventilator to obtain reliable average estimates. By combining inspired flow and F.sub.IO.sub.2 with time shifted F.sub.EO.sub.2 and F.sub.ECO.sub.2, it is possible to determine expired flow, VO.sub.2, VCO.sub.2, RQ, and REE. The system also accounts for the presence of bias flow (used to enable flow triggering of patient breaths in modern ventilators), uses a lower sampling rate (60 mL/min) than any device on the market, and can account for higher sampling rates as well. The system also measures respiratory quotient and resting energy expenditure, which helps in understanding how many calories the patient consumes over time. One can titrate how much nutrition the patient should receive based on this information, which could decrease time on ventilator in the ICU.

[0103] FIG. 1 shows a VO.sub.2 system 100 for taking oxygen consumption measurements in newborns, such as patient 102. The patient 102 is connected to a conventional ventilator 104 using a Y-piece attachment 106, as is typically done in treatment centers and with typically available equipment. The VO.sub.2 system 100 enables the patient 102 to use a novel VO.sub.2 device 108 that includes an O.sub.2/CO.sub.2 sensor 110 that has an O.sub.2 sensor (e.g., a laser diode sensor) with CO.sub.2 module (e.g., a nondispersive infrared sensor or NDIR) and a differential pressure sensor 112.

[0104] The ventilator 104 is connected to air and O.sub.2 sources 116. The air and O.sub.2 are mixed in the ventilator in a mixer 118. The mixed air and oxygen flow out of the ventilator 104 and are measured by an inspiratory flowmeter 120, which can be a differential pressure type pneumotach, e.g., a device with a screen inserted in the fluid flow that creates a known pressure drop directly proportional to the fluid velocity. The flowmeter 120 is connected to the VO.sub.2 device 108 using double-lumen rubber tubing 126 and is used for taking measurements at the flowmeter 120 to the device 108. The mixed air and O.sub.2 in the inspiration line is sampled and the sample is carried to O.sub.2/CO.sub.2 sensor 110 via inspiration sampling line 122. The mixed O.sub.2/air then flows through an optional humidifier 124 that adds a controlled amount of water to the mix. The inspiration sampling line 122 takes a sample before the humidifier 124, so that the O.sub.2/air mixture sample is upstream of the humidifier 124. The sample taken at the upstream sampling point is therefore dry inspiratory gas, which is analyzed by the O.sub.2/CO.sub.2 sensor 110. In some embodiments, the inspiration sampling line 122 can be downstream of the humidifier 124.

[0105] The humidified air/O.sub.2 mix flows into the patient 102 via one branch of the Y-piece attachment 106 and then back out through the second branch of the Y-piece attachment 106. The pressure of the expiration gas can be measured at the Y-piece attachment 106 via pressure line 132, or another place in the inspiratory limb of the circuit. The expired gas passes through an optional bacterial filter 130, and back through the ventilator 104 and out through the ventilator exit port 114. A small mixing chamber 134 may be attached to the ventilator exit port 114 and mixes the expired gas as it exits the ventilator 104. A sample of the expiration gases is diverted from the mixing chamber 134 or exit port via expiration sampling line 136 and measured by the O.sub.2/CO.sub.2 sensor 110 of the VO.sub.2 device 108.

[0106] The VO.sub.2 device 108 includes an inlet selector valve 138 (e.g., a solenoid valve or pinch valve) controlled by a controller 140 to automatically alternate between inspiratory (INSP) and expiratory (EXP) gas measurements.

[0107] The tubes connecting the VO.sub.2 device 108 and inspiration fluid circuit (i.e., the inspiration sampling line 122 for measurement of the inspired oxygen concentration F.sub.IO.sub.2) and between the VO.sub.2 device 108 and the output of the mixing chamber (i.e., expiration sampling line 136 for measurement of mixed expired oxygen concentration F.sub.EO.sub.2), respectively are preferably water-permeable tubes, such as Nafion gas sample tubes. Nafion gas sample tubes are water permeable gas tubes that equilibrate their contents to ambient humidity. This equilibration is particularly important on the expiration line, because the measurement is downstream of the humidifier 124 and the patient 102 and may be fully saturated. Saturated gas can cause rain-out where the tubing sampling gas from the expiration line becomes wet from condensation, which distorts subsequent readings. The water permeability and a chemical reaction inside the Nafion gas sample tubes eliminate this problem.

[0108] The VO.sub.2 device 108 connects to normal ventilator circuitry in a manner similar to that of available devices on the market. The VO.sub.2 system 108 is different from such devices in that the O.sub.2/CO.sub.2 sensor 110, inspiration gas sample line 122, and expiration gas sample line 136 are connected at the ventilator ports, remote from the proximal Y-piece 106. This feature avoids the addition of dead space, and also the risks associated with a weighted sensor attached to a small tracheal tube, which risks displacement. The technique is based on sampling of inspired and mixed expired gas and measurement of inspiratory flow. Unlike other techniques, this technique is suitable for use in mechanically ventilated pediatric patients where minute ventilation is low, metabolic rate is low (e.g., 5 or 10 ml/min) and respiratory rates are high (e.g., 60 or 80 bpm).

[0109] The VO.sub.2 system 100 determines both inspired volume flow (V.sub.I) and average F.sub.IO.sub.2 accurately, effectively coping with fluctuations in F.sub.IO.sub.2 from the ventilator 104. The VO.sub.2 system 100 measures inspiratory flow of dry gas corrected for changing viscosity when F.sub.IO.sub.2 changes, and flow-weighted F.sub.IO.sub.2 corrected for flow-gas delay. Expired concentrations (F.sub.EO.sub.2 and F.sub.ECO.sub.2) are measured at the outlet of the mixing chamber 134. By combining F.sub.IO.sub.2 and FICO.sub.2 (which is generally close to zero) with time shifted F.sub.EO.sub.2 and F.sub.ECO.sub.2 it is possible to determine V.sub.E, VO.sub.2, VCO.sub.2, as well as derived parameters including respiratory quotient (RQ) and resting energy expenditure (REE) of the patient.

[0110] Once the patient 102 is attached to the ventilator 104 via the Y-piece attachment, the inlet selector valve 138 is set to the INSP position by the controller 140, and the inlet is flushed. O.sub.2 concentration is measured over one or more complete respiratory cycles as determined by the flowmeter 120. This is measured with the flow-gas delay taken into account (as discussed below). The instantaneous flow is measured at the same time.

[0111] Thereafter, the inlet selector valve 138 switches to the EXP position and the EXP inlet is flushed. O.sub.2 and CO.sub.2 concentrations are measured, preferably over one or more complete respiratory cycles as determined e.g. by the flowmeter 120.

[0112] The oxygen uptake, or VO.sub.2, is calculated as the amount of oxygen extracted from the inspired gas per minute. As discussed in detail below, this is the difference between the oxygen volume inspired and expired divided by time, taking into account the inspiration/expiration delay when comparing inspired and expired values. The system then repeats the steps for as long as monitoring is required.

[0113] Using the VO.sub.2 system 100, the patient 102 does not need to breathe through a specialized device, but rather is attached to a standard ventilator. Prior systems use a mixed expired technique where no sensors are attached proximal to the patient, however, system 100 measures inspired flows rather than concentrating on just expiration with an expiration meter that measures wet gas. Instead, the system measures the flow of inspired gas, which is always dry. Since gas concentration from a ventilator is not steady and fluctuates a great deal the inspired average concentration is determined, rather than simply the instantaneous concentration. As gas flow and concentrations both change over time, a simple arithmetic mean is insufficient for accuracy; the system uses a flow-weighted average to take the flow into account. In prior systems, oscillations of2% O.sub.2 are too high to make accurate measurements without flow-weighted averaging. Now fluctuations are compensated for by flow-weighted averaging.

Ventilator Software

[0114] Software for controlling the VO.sub.2 system 100 can be stored on and executed by the controller 140, and can include setup, calibration, and measurement options.

[0115] The flow chart in FIG. 2 shows the measurement sequence 300 used for control, data acquisition, and calculation. To take a measurement, the software sequence 300 causes the controller 140 to send a signal to the inlet selector valve 138 to switch to the INSP inlet (step 310) and then starts data acquisition (step 312). The system then performs initial tasks as detailed in FIG. 4 (step 314) and restarts data acquisition (step 316). Curves representing the data are displayed (step 318), and the system switches to INSP inlet (step 320) and acquires data for a desired number (e.g., 5-10) of breaths at step 322 and switches to the EXP inlet (step 324) and acquires data for a desired number of breaths at step 326. The concentrations, flows, and other parameters are calculated (as described in detail with respect to FIG. 3) and displayed at step 328. When sufficient data has been acquired, the system saves the data and results and ends the measurement. If more data is desired, e.g., for long-term monitoring, the system returns to step 320 and switches back to the INSP inlet and repeats the steps.

[0116] As discussed in relation to FIGS. 5 and 6, the optimum number of breaths (X breaths) in steps 322 and 326 of FIG. 2 may be different, and during non-steady conditions the optimum number of breaths should be determined continuously based on the actual flow rate V.sub.I,tot and known circuit volumes by integration of flow from breath to breath using the appropriate steps from step 328, and not only as part of the initial tasks (step 314 and FIG. 4).

[0117] The flow chart in FIG. 3 shows the calculation and display steps 400 in detail for each cycle comprising measurements from the inspiratory and expiratory gas sample inlets, respectively, which are the details of step 328 in the flow chart of FIG. 2.

[0118] Oxygen consumption is calculated using the equations below. Components are average values, appropriately adjusted for the inspiration-expiration (I-E) delay time. The I-E delay is the transport delay in the patient circuitry between inspiratory and expiratory gas sample points (truncated corresponding to a whole number of breaths).

[0119] The following 3 basic equations assume that the N.sub.2 exchange is zero (steady-state, equation 1):

V.sub.E=V.sub.IVO.sub.2+VCO.sub.2(1)

VO.sub.2=V.sub.IF.sub.IO.sub.2V.sub.EF.sub.EO.sub.2(2)

VCO.sub.2=V.sub.EF.sub.BCO.sub.2V.sub.IF.sub.ICO.sub.2(3)

[0120] In these and the following equations all flows (V) are given at the same conditions (e.g., STPD, which stands for standard temperature and pressure, dry; oxygen consumption; and carbon dioxide production are standardized to standard temperature (0 C.), barometric pressure at sea level (101.3 kPa) and dry gas) and all concentrations F are fractional concentrations of dry gas as measured using the Nafion tubing.

[0121] Substituting V.sub.E from equation 1 into equations 2 and 3 gives:

V.sub.IF.sub.IO.sub.2=VO.sub.2+(V.sub.IVO.sub.2+VCO.sub.2)F.sub.EO.sub.2(4)

V.sub.IF.sub.ICO.sub.2+VCO.sub.2=(V.sub.IVO.sub.2+VCO.sub.2)F.sub.ECO.sub.2(5)

[0122] Rearranging each equation gives:

(1F.sub.EO.sub.2)VO.sub.2+(F.sub.EO.sub.2)VCO.sub.2=(F.sub.IO.sub.2F.sub.EO.sub.2)V.sub.I(6)

(F.sub.ECO.sub.2)VO.sub.2+(1F.sub.ECO.sub.2)VCO.sub.2=(F.sub.ECO.sub.2F.sub.ICO.sub.2)V.sub.I(7)

[0123] As V.sub.I and all fractional concentrations are measured and therefore known, these are two equations in two unknowns, VO.sub.2 and VCO.sub.2, which can be solved:

[00001]$\begin{array}{cc}{V}^{}.Math.O_2=V_I^{}\frac{F_I.Math.O_2\left(1-F_E.Math.{\mathrm{CO}}_2\right)-F_E.Math.O_2\left(1-F_I.Math.{\mathrm{CO}}_2\right)}{1-F_E.Math.O_2-F_E.Math.{\mathrm{CO}}_2}& \left(8\right)\\ V^{}.Math.{\mathrm{CO}}_2=V_I^{}\frac{F_E.Math.{\mathrm{CO}}_2\left(1-F_I.Math.O_2\right)-F_I.Math.{\mathrm{CO}}_2\left(1-F_E.Math.O_2\right)}{1-F_E.Math.O_2-F_E.Math.{\mathrm{CO}}_2}& \left(9\right)\end{array}$

[0124] The denominator is the fractional concentration of nitrogen. It appears as the amounts of nitrogen in inspired and expired gas at steady-state are assumed to be equal. Therefore, these equations can also be derived using the Haldane transformation, V.sub.IF.sub.IN.sub.2=V.sub.EF.sub.EN.sub.2, instead of equation 1.

[0125] Using the Haldane transformation (V.sub.IF.sub.IN.sub.2=V.sub.EF.sub.EN.sub.2) and the equations 9a and 9b together with equations (2) and (3) can also be used to directly derive equations 8 and 9:

F.sub.IN.sub.2=1F.sub.ICO.sub.2F.sub.IO.sub.2(9a)

F.sub.EN.sub.2=1F.sub.ECO.sub.2F.sub.EO.sub.2(9b)

[0126] Substituting VO.sub.2 and VCO.sub.2 according to equations 8 and 9 into equation 1 gives:

[00002]$\begin{array}{cc}{V}_E^{}=V_I^{}\frac{1-F_I.Math.O_2-F_I.Math.{\mathrm{CO}}_2}{1-F_E.Math.O_2-F_E.Math.{\mathrm{CO}}_2}& \left(10\right)\end{array}$

[0127] These equations (and the method) become less accurate when used when breathing close to 100% O.sub.2 as the denominator would be close to zero. The method becomes more prone to gas measurement errors as the oxygen concentration increases.

[0128] The respiratory quotient is determined:

[00003]$\begin{array}{cc}R.Math..Math.Q=\frac{V^{}.Math.{\mathrm{CO}}_2}{V^{}.Math.O_2}& \left(11\right)\end{array}$

[0129] Inspiratory minute ventilation V.sub.I is determined by integration of inspiratory flow over one or more complete breaths:

[00004]$\begin{array}{cc}{V}_I^{}=\frac{\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp}}^{}\left(n\right)}{N}& \left(12\right)\end{array}$

[0130] where V.sub.insp(0) and V.sub.insp(N1) are the first and last inspiratory flow samples, respectively, in a breath (or a sequence of breaths).

[0131] A reliable average F.sub.IO.sub.2 estimate (allowing for F.sub.IO.sub.2 fluctuations at the inspiratory outlet of the ventilator) is obtained by flow-weighted averaging:

[00005]$\begin{array}{cc}{F}_I.Math.O_2=\frac{\underset{n=0}{\overset{N-1}{.Math.}}.Math.F_{\mathrm{insp}}.Math.O_2\left(n\right)V_{\mathrm{insp}}^{}\left(n\right)}{\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp}}^{}\left(n\right)}& \left(13\right)\end{array}$

[0132] FICO.sub.2 is determined in the same way as F.sub.IO.sub.2 by replacing F.sub.inspO.sub.2 with F.sub.inspCO.sub.2 in equation 13 (or calculated as an arithmetic mean or set to zero).

[0133] F.sub.EO.sub.2 is calculated as a time-weighted average value (preferably during expiration(s) only, i.e. when V.sub.insp is zero or equal to the bias flow in case of bias flow, V.sub.bias):

[00006]$\begin{array}{cc}{F}_E.Math.O_2=\frac{\underset{m=0}{\overset{M-1}{.Math.}}.Math.F_{\exp }.Math.O_2\left(m\right)}{M}& \left(14\right)\end{array}$

[0134] Likewise for F.sub.ECO.sub.2:

[00007]$\begin{array}{cc}{F}_E.Math.{\mathrm{CO}}_2=\frac{\underset{m=0}{\overset{M-1}{.Math.}}.Math.F_{\exp }.Math.{\mathrm{CO}}_2\left(m\right)}{M}& \left(15\right)\end{array}$

[0135] Inspiratory minute ventilation V.sub.I is corrected from atmospheric temperature and pressure (ATP) to STPD assuming that inspired gas flow (as measured) is at ambient temperature:

[00008]$\begin{array}{cc}{V}_I^{}\left(\mathrm{STPD}\right)=V_I^{}\frac{273}{273+t_{\mathrm{amb}}}\frac{P_B-P_{H_2.Math.O,\mathrm{insp}}}{760}& \left(16\right)\end{array}$

[0136] P.sub.H2O,insp may be set to zero if inspiratory gas from ventilator is dry, as follows:

[00009]$\begin{array}{cc}{V}_I^{}\left(\mathrm{STPD}\right)=V_I^{}\frac{273}{273+t_{\mathrm{amb}}}\frac{P_B}{760}& \left(17\right)\end{array}$

[0137] Average fractional concentrations of dry gas and V.sub.I(STPD) can now be inserted into equations 8 and 9 to yield STPD values of VO.sub.2 and VCO.sub.2.

[0138] The BTPS (body temperature and pressure, saturated: volumes and flows are standardized to barometric pressure, body temperature, saturated with water vapor) value of V.sub.E is determined by correcting V.sub.I from STPD to BTPS in equation 10:

[00010]$\begin{array}{cc}{V}_E^{}\left(B.Math..Math.T.Math..Math.P.Math..Math.S\right)=V_I^{}\left(S.Math..Math.T.Math..Math.P.Math..Math.D\right)\frac{310}{273}\frac{760}{P_B-47}\frac{1-F_I.Math.O_2-F_I.Math.{\mathrm{CO}}_2}{1-F_E.Math.O_2-F_E.Math.{\mathrm{CO}}_2}& \left(18\right)\end{array}$

[0139] All fractional concentrations used in calculations must be time-shifted corresponding to the transit and rise time (response time) between instantaneous flow and delayed gas measurement:

F(n)=F.sub.meas(n+n.sub.delay)(19)

[0140] n.sub.delay is corrected for the influence of viscosity. This is particularly important in equation 12, which can be rewritten:

[00011]$\begin{array}{cc}{F}_I.Math.O_2\left(n\right)=\frac{\underset{n=0}{\overset{N-1}{.Math.}}.Math.F_{\mathrm{insp}}.Math.O_2\left(n+n_{\mathrm{delay}}\right)V_{\mathrm{insp}}^{}\left(n\right)}{\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp}}^{}\left(n\right)}& \left(20\right)\end{array}$

[0141] Assuming that inspiratory gas composition (oxygen concentration) is measured close to the flowmeter 120, measured flow rates can be corrected for changes in viscosity of the inspired gas mixture (assuming a Lilly-type pneumotachometer).

[0142] Inspired gas consists of O.sub.2 and N.sub.2. Since the inspired oxygen concentration delivered by the ventilator is almost constant for longer periods, it is adequate to correct each estimate of V.sub.I (and not V.sub.insp). The correction presumes that the flow calibration is done using atmospheric air. For each respiratory cycle a viscosity gain factor is calculated and used for correction of the measured flow.

[0143] The viscosity gain factor is calculated as:

[00012]$\begin{array}{cc}{G}_{\mathrm{flow}}=\frac{{}_{\mathrm{air}}}{{}_{\mathrm{insp}}}& \left(21\right)\end{array}$

[0144] Corrected inspired flow rate (inspired minute ventilation) is calculated as:

V.sub.I,corr=V.sub.IG.sub.flow(22)

[0145] V.sub.insp is corrected for P.sub.insp and t.sub.insp in order to obtain V.sub.I at STPD:

[00013]$\begin{array}{cc}{V}_I^{}\left(\mathrm{STPD}\right)=\frac{\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp}}^{}\left(n\right)\frac{273}{273+t_{\mathrm{insp}}}\frac{P_{\mathrm{insp}}-P_{H_2.Math.O,\mathrm{insp}}}{760}}{N}& \left(23\right)\end{array}$

[0146] P.sub.H2O,insp is set to zero and t.sub.insp is constant (dry inspiratory gas at constant temperature from ventilator) in the following:

[00014]$\begin{array}{cc}{V}_I^{}\left(\mathrm{STPD}\right)=\frac{\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp}}^{}\left(n\right)\frac{P_{\mathrm{insp}}}{760}}{N}\frac{273}{273+t_{\mathrm{insp}}}& \left(24\right)\end{array}$

[0147] Since the inspiratory gas sample point is downstream from the flow measurement site the gas sample flow must be subtracted from the measured V.sub.I:

V.sub.I,corr=V.sub.IV.sub.gas sample(25)

[0148] The gas sample flow is the sum of inspiratory and optional airway sample flow.

[0149] Correction of expiratory minute ventilation, V.sub.E, for bias flow is:

[00015]$\begin{array}{cc}{V}_{E,\mathrm{corr}}^{}=V_E^{}-V_{\mathrm{bias}}^{}\frac{T_E}{T_I{T}_E}& \left(26\right)\end{array}$

[0150] In equations 8-10, where both inspired (I) and expired (E) flows and fractional concentrations appear, an I-E delay time must be applied in order to provide the best possible correction when F.sub.IO.sub.2 or V.sub.I is changing. It is reasonable to apply an I-E delay correction on a whole breath basis only, i.e. to determine the number of tidal volumes in the circuitry between inspiratory and expiratory gas sample points:

.sub.i=1.sup.N.sup.breaths,I-EV.sub.T(i)V.sub.circuit(27)

[0151] N.sub.breaths,I-E only needs to be recalculated when a significant change in V.sub.I is detected.

[0152] The flow chart in FIG. 4 shows the sequence 500 of initial tasks to determine the inspiration-expiration (I-E) delay needed to compare the inspired and expired gas (step 314 of FIG. 2). The system 100 includes a timing algorithm that compensates for this delay, which otherwise can result in up to 10-20% error depending on gas sampling flow and total flow delivered by the ventilator. The system therefore must determine the time it takes for gas to travel along the fluid circuit, and alternate between two sample points while taking into account this time period.

[0153] This latter time shift must be taken into account when comparing inspired and expired gas concentrations in the calculation of VO.sub.2, etc. To do so, it is assumed that the concentrations F.sub.E and the flow in the expiratory limb (equal to V.sub.I,tot if assuming an RQ of 1) match each other (i.e., have been measuring for a very long time using the EXP inlet). Gas sampling is switched to the INSP inlet. All the gas downstream from the INSP inlet will now move at a lower speed (V.sub.I,totV.sub.gas sample).

[0154] Gas contained in the expiratory limb after the Y-piece will now move towards the EXP inlet at this lower speed. At the same time, gas entering the expiratory limb at the Y-piece will now change average concentrations corresponding to the lower flow (V.sub.I,totV.sub.gas sample), e.g., to a higher F.sub.ECO.sub.2 and lower F.sub.EO.sub.2 (higher F).

[0155] Gas is sampled from the INSP inlet during a period T.sub.INSP, after which the system is switched back to the EXP inlet and sample taken from this inlet during a period T.sub.EXP. All the gas downstream from the INSP inlet will now move at the higher speed V.sub.I,tot.

[0156] Referring to FIG. 5, which shows the relevant circuit volumes at or near the Y-piece attachment 106 to ensure constant concentrations F.sub.E measured during the entire period T.sub.EXP, the period T.sub.INSP must be long enough to ensure that the circuit between the Y-piece and the EXP inlet has been flushed with the flow V.sub.I,totV.sub.gas sample. This can be expressed by the following criterion:

[00016]$\begin{array}{cc}{T}_{\mathrm{INSP}}\frac{V_{Y.Math.\text{-}.Math.\mathrm{EX}.Math..Math.P}}{V_{I,\mathrm{tot}}^{}-V_{\mathrm{gas}.Math..Math.\mathrm{sample}}^{}}& \left(28\right)\end{array}$

[0157] At the same time, the period T.sub.EXP must be shorter than the time it takes to flush the circuit between the Y-piece and the EXP inlet with the flow V.sub.I,tot. This can be expressed by the following criterion:

[00017]$\begin{array}{cc}{T}_{E.Math..Math.\mathrm{XP}}\frac{V_{Y.Math.\text{-}.Math.\mathrm{EX}.Math..Math.P}}{V_{I,\mathrm{tot}}^{}}& \left(29\right)\end{array}$

[0158] Also, we are aiming at T.sub.INSP=T.sub.EXP to compare essentially the same sample of gas from the inspiratory and expiratory limbs, which, however, is not possible according to the inequalities for T.sub.INSP and T.sub.EXP from which it follows that T.sub.INSP>T.sub.EXP.

[0159] A solution which would work at both low ventilations (where the gas sample flow constitutes a significant part of the total flow in the circuit) and high ventilations (where total flow is high with resulting short cycle times according to the above) is one in which the sampling periods T.sub.INSP and T.sub.EXP both meet the requirements according to the inequalities above to ensure constant mixed expired concentrations during T.sub.EXP, but the period used for averaging during the INSP period can be shortened by using only the first part of T.sub.INSP corresponding to the length of T.sub.EXP (T.sub.INSP,a), and making sure that the spacing between the periods is equal to T.sub.INSP-EXP, where

[00018]$\begin{array}{cc}{T}_{\mathrm{INSP}.Math.\text{-}.Math.E.Math..Math.\mathrm{XP}}=\frac{V_{\mathrm{INSP}.Math.\text{-}.Math.E.Math..Math.\mathrm{XP}}}{V_{I,\mathrm{tot}}^{}-V_{\mathrm{gas}.Math..Math.\mathrm{sample}}^{}}& \left(30\right)\end{array}$

[0160] Accounting for the gas transport time T.sub.INSP-EXP allows the quantification of O.sub.2 and CO.sub.2 concentrations on essentially the same sample of gas from the inspiratory and expiratory limbs.

[0161] When ensuring that the T.sub.INSP and T.sub.EXP inequalities are met there should be no need to skip breaths or data in the end of each sampling and analysis period.

[0162] To flush the gas sample tubes after switching, data corresponding to the flow-gas delay time (gas sample tube flush time) should be excluded from the analysis. Inlet flushing may be of limited importance during steady conditions, but as a minimum the common internal tubing between solenoid and measurement cells must be flushed.

[0163] Additional flushing (skip of breaths) may be used to account for diffusion/mixing of gases and circuit volume uncertainties during the transitions.

[0164] The optimal solution can be summarized as:

INSP sampling period:

[00019]$\begin{array}{cc}{T}_{\mathrm{INSP}}=T_{\mathrm{INSP}.Math.\text{-}.Math.E.Math..Math.\mathrm{XP}}=\frac{V_{\mathrm{INSP}.Math.\text{-}.Math.E.Math..Math.\mathrm{XP}}}{V_{I,\mathrm{tot}}^{}-V_{\mathrm{gas}.Math..Math.\mathrm{sample}}^{}}& \left(31\right)\end{array}$

EXP sampling period:

[00020]$\begin{array}{cc}{T}_{\mathrm{EX}.Math..Math.P}=\frac{V_{Y.Math.\text{-}.Math.E.Math..Math.\mathrm{XP}}}{V_{I,\mathrm{tot}}^{}}& \left(32\right)\end{array}$

INSP analysis period:

T.sub.INSP,a=T.sub.EXP(33)

Spacing between analysis periods:

T.sub.INSP-EXP=T.sub.INSP(34)

TABLE-US-00001 N.sub.SKIP, insp, start Corresponds to the flow-gas delay time N.sub.SKIP, insp, end Zero N.sub.SKIP, exp, start Corresponds to the flow-gas delay time N.sub.SKIP, exp, end Zero (or a manually entered value to account for volume uncertainties)

[0165] The program performs initial calculations according to sequence 500. In detail, the first step is to determine T.sub.I and T.sub.E from the airway pressure signal Paw as average values of T.sub.I and T.sub.E from a number of respiratory cycles.

[0166] Then the system determines P.sub.peak from the airway pressure signal P.sub.aw as the average value of a number of P.sub.peak values, each determined during a respiratory cycle.

[0167] The system then determines P.sub.PEEP from the airway pressure signal P.sub.aw as an average value of P.sub.aw measured in each expiration over a number of respiratory cycles.

[0168] The system then determines F.sub.IO.sub.2 as an average value of F.sub.inspO.sub.2 measured over a number of respiratory cycles.

[0169] Then correcting the inspiratory flow signal V.sub.insp for viscosity (F.sub.IO.sub.2):

V.sub.insp,corr(n)=V.sub.insp(n)G.sub.flow(35)

[0170] Thereafter, the system determines V.sup..sub.bias from the inspiratory flow signal V.sub.insp as an average value of V.sub.insp, corrected for viscosity (F.sub.IO.sub.2), V.sub.insp,corr, measured in each expiration over a number of respiratory cycles.

[0171] The system then calculates RR as an average value:

[00021]$\begin{array}{cc}\mathrm{RR}=\frac{1}{T_I+T_E}=\frac{60.Math..Math.s.Math.\text{/}.Math.\min }{T_I+T_E}& \left(36\right)\end{array}$

[0172] The system then calculates the effective bias flow (at ATP):

[00022]$\begin{array}{cc}.Math.V_{\mathrm{bias},\text{?}}^{}=V_{\mathrm{bias}}^{}\frac{1}{\frac{T_I}{T_E}+1}.Math..Math.\text{?}.Math.\text{indicates text missing or illegible when filed}& \left(37\right)\end{array}$

[0173] Thereafter, the system calculates the compliance effect (at atmospheric temperature and pressure, ATP):

[00023]$\begin{array}{cc}.Math.V_{\mathrm{compl}}^{}=\left(V_{\mathrm{DS},I}+V_{\mathrm{DS},E}\right)\frac{\left(P_{\mathrm{peak}}-P_{\mathrm{PEEP}}\right)\frac{760}{\text{?}}}{P_B}\mathrm{RR}.Math..Math.\text{?}.Math.\text{indicates text missing or illegible when filed}& \left(38\right)\end{array}$

[0174] The system can also determine inspired minute ventilation V.sub.I (at ATP) as an average value by integration of inspiratory flow V.sub.insp, corrected for viscosity (F.sub.IO.sub.2), V.sub.insp,corr, over a number of consecutive respiratory cycles as follows:

[00024]$\begin{array}{cc}{V}_I^{}=\frac{1}{N}\underset{n=0}{\overset{N-1}{.Math.}}.Math.V_{\mathrm{insp},\mathrm{corr}}^{}\left(n\right)-V_{\mathrm{gas}.Math..Math.\mathrm{sample}}^{}-V_{\mathrm{bias},e}^{}-V_{\mathrm{compl}}^{}& \left(39\right)\end{array}$

[0175] where V.sub.insp,corr(0) and V.sub.insp,corr(N1) are the first and last inspiratory flow samples, respectively, in the consecutive respiratory cycles. This determination (at ATP) assumes no use of humidifier in the inspiratory limb but can be modified to account for humidification.

[0176] The system can calculate the water vapor pressure in the inspired gas:

P.sub.H2O,insp=P.sub.H2O,sat(t.sub.amb)RH(t.sub.amb),(40)

[0177] where P.sub.H2O,sat is a function of temperature.

[0178] In addition, the system estimates the expired minute ventilation V.sub.E (at BTPS) by use of (initial) VO.sub.2 and RQ value (settings):

[00025]$\begin{array}{cc}{V}_E^{}=V_I^{}\frac{310}{273+t_{\mathrm{amb}}}\frac{P_B-P_{H.Math..Math.2.Math.O,\mathrm{insp}}}{P_B-47}-V^{}.Math.O_2\left(1-\mathrm{RQ}\right)\frac{310}{273}\frac{P_B}{P_B-47}& \left(41\right)\end{array}$

[0179] The system can also calculate the total inspiratory ventilation (at ATP), i.e., the total flow which flushes the whole length of the inspiratory limb:

V.sub.I,tot=V.sub.I+V.sub.compl+V.sub.bias,e(42)

[0180] In the next step, the system calculates the total expiratory ventilation (mixture of ATP and BTPS amounts), i.e., the total flow which flushes the whole length of the expiratory limb, assuming no change in temperature of expired gas from Y-piece to mixing chamber:

V.sub.E,tot=V.sub.E+V.sub.compl+V.sub.bias,e(43)

[0181] The system can also calculate the I-E delay time:

[00026]$\begin{array}{cc}{T}_{I.Math.\text{-}.Math.E.Math..Math.\mathrm{delay}}=\left(\frac{V_{\mathrm{DS},I-Y}}{V_{I,\mathrm{tot}}^{}}+\frac{\left(V_{\mathrm{DS},E}+V_{\mathrm{DS},V}+V_{\mathrm{DS},M}\right)}{V_{E,\mathrm{tot}}^{}}\right)60.Math..Math.s.Math.\text{/}.Math.\min & \left(44\right)\end{array}$

[0182] In addition, the system can calculate the number of whole breaths corresponding to the I-E delay time:

[00027]$\begin{array}{cc}{N}_{I.Math.\text{-}.Math.E.Math..Math.\mathrm{delay}}=\left[\frac{T_{I.Math.\text{-}.Math.E.Math..Math.\mathrm{delay}}}{60.Math..Math.s.Math.\text{/}.Math.\min }\mathrm{RR}\right]& \left(45\right)\end{array}$

[0183] The system can also calculate the number of breaths to skip to allow flushing of the gas sample inlets after switching inlet between inspiration and expiration:

[00028]$\begin{array}{cc}{N}_{\mathrm{skip}}=\left[\frac{T_{\mathrm{FDG},I}+T_{\mathrm{flush}}}{60.Math..Math.s.Math.\text{/}.Math.\min }\mathrm{RR}\right]+1& \left(46\right)\end{array}$

[0184] The system can also calculate the number of samples corresponding to the lengths of the gas sample tubing:

[00029]$\begin{array}{cc}{N}_{\mathrm{FGD},I}=\left[\frac{T_{\mathrm{FGD},I}}{.Math..Math.t}\right]& \left(47\right)\\ N_{\mathrm{FGD},E}=\left[\frac{T_{\mathrm{FGD},E}}{.Math..Math.t}\right]& \left(48\right)\end{array}$

[0185] Gas calibrations as well as subsequent measurements are performed using the Nafion sample tubes for accurate gas analysis. As the tubes work for both drying and humidifying gas streams they also humidify dry calibration gases, which allows calibration at humidity levels equal to those seen during measurements. Since calibration set points are given for dry gas, subsequent measurements will also provide fractional concentrations of dry gas no matter if the gas is dry (inspiration) or wet (expiration).

[0186] The flowmeter 120 is calibrated on e.g. air at ATP using a syringe (e.g., 1 L). The offset is calibrated automatically prior to a measurement (and regularly during long-term measurements) by connecting both differential pressure sensor ports to the same pressure tube or ambient air using one or two solenoid valves. The flow-gas delay is factory calibrated and only needs re-calibration in case the sample flow or length of inspiratory gas sample tubing is changed.

[0187] FIGS. 6A and 6B are exemplary inspiratory and expiratory signal diagrams using the system for determining flows and time periods. FIG. 6A shows qualitatively, and assuming steady-state conditions, how flow rates and transport delay times vary depending on which sampling inlet is active (i.e. sampling gas). The change in the upper curve, V.sub.I,tot, is caused by the fact that the ventilator is assumed to compensate for the gas consumed by the inspiratory inlet during the INSP sampling period when using pressure controlled ventilation mode. FIG. 6B illustrates qualitatively, using CO.sub.2 as example and assuming steady-state conditions, how mixed expired gas concentration measured at the expiratory sampling point changes depending on the timing sequence. The upper panel shows a steady F.sub.ECO.sub.2 level obtained with an optimal timing sequence. The panel in the middle shows how the F.sub.ECO.sub.2 level decays if the expiratory sampling period is too long. The change in F.sub.ECO.sub.2 level is more clearly detected in the beginning of the expiratory sampling period at the transition when the expiratory sampling inlet (containing gas from the previous expiratory sampling period) has been flushed. Likewise, the lower panel shows what could happen if the previous inspiratory sampling period was too short. In this case, the initial F.sub.ECO.sub.2 level reflects the correct concentration from the end of the previous period, however, after flushing of the expiratory sampling inlet there will be an intermediate period with a decrease in F.sub.ECO.sub.2 level caused by the increased dilution of expiratory gas with inspiratory gas when sampling from the expiratory sampling inlet, combined with the fact that the correct concentration has not yet reached the expiratory sampling point because of a too short inspiratory sampling period.

[0188] FIG. 7 shows the timing sequence for calculations for each inspiratory and expiratory gas sample measurement cycle, respectively. Using O.sub.2 as example, and assuming steady-state and optimal timing, the figure shows how the measured gas concentration changes between inspiratory and expiratory sampling periods.

EXAMPLES

[0189] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

Example 1In Vitro Lung Simulator Experiments

[0190] FIG. 8 shows the setup for using a lung simulator 700 to quantify oxygen consumption and carbon dioxide production during phasic ventilation. Gold standard measures of each are provided by an inflow of precise volumes of oxygen and carbon dioxide using a mass flow controller.

[0191] The lung simulator 700 had artificial lungs in which VO.sub.2 and VCO.sub.2 are simulated with precision using a mass flow controller. This in vitro system had a silicone bellows reservoir including a minimum volume (i.e. FRC) and a tidal volume. To simulate metabolic gas exchange, a flow of a precision test gas with known fractional concentrations of CO.sub.2 and O.sub.2 (50% CO.sub.2, balance O.sub.2 with 0.03% absolute accuracy) was continuously infused at a constant rate (0-50 mL/min using a mass flow controller with an accuracy of0.6% at full-scale). It should be noted that the lung simulator produces negative VO.sub.2 (i.e., O.sub.2 production). The system permitted a standard ventilator to drive phasic respiration, to apply bias flow, to titrate F.sub.IO.sub.2, and to permit simultaneous humidification.

[0192] The performance of the novel device among a range of VO.sub.2, RR and F.sub.IO.sub.2 values are shown in Table 1. Note that in all cases the error was <1 mL/min of VO.sub.2 (most were <0.5 mL/min), even when interrogated at RR as high as 80 breaths/minute, V.sub.T as low as 10 mL, and F.sub.IO.sub.2 as high as 60%. These findings cover the clinically relevant range in infants and neonates, and provide significant optimism that this system will be able to accurately measure VO.sub.2. VCO.sub.2 is measured by this system with even greater accuracy (since F.sub.ICO.sub.2 is always negligible).

TABLE-US-00002 TABLE 1 Ventilator settings VO2 Error FIO2 VT RR Set Meas. Abs. % mL BPM mL/min* mL/min* mL/min* 21 15 30 10 9.98 0.02 21 10 30 5 4.90 0.10 40 15 30 10 9.38 0.62 40 10 30 5 4.72 0.28 60 15 30 10 9.50 0.50 60 10 30 5 5.10 0.10 40 10 20 5 4.62 0.38 40 10 45 5 4.99 0.01 40 10 60 5 4.73 0.27 40 10 80 5 5.33 0.33

Example 2In Vivo Rat Experiments

[0193] Referring to FIG. 8, to simulate the performance of the device in extremely low birth weight infants, we compared measures of VO.sub.2 and VCO.sub.2 in Sprague Dawley (N=5, weight 66261 g). Animals were intubated and the trachea sealed against the ETT using suture purse string. They were ventilated using a Servo-i ventilator in pressure control, bias flow of 0.5 L/min, PEEP of 5 cmH.sub.2O, peak pressure 20 cmH.sub.2O and mandatory rate of 30 bpm. F.sub.IO.sub.2 was maintained at 0.4. In each experiment, VO.sub.2 measurements were made under two conditions: 40% F.sub.IO.sub.2 provided by the ventilator as in clinical practice, and when provided using a certified gas mixture of 40% F.sub.IO.sub.2 with<0.03% absolute accuracy. The latter condition was used to obviate the complicating factor of fluctuations in F.sub.IO.sub.2 as described above. In both conditions, device measurements were compared to those calculated using a Douglas bag method.

[0194] Expired gases were collected within a 5 L non-diffusing gas collection bag connected to the exhaust port of the ventilator. The bag was flushed three times with expired gas and emptied. Then, measurements were performed with the device and gas collected simultaneously for comparison over6 minutes. The contents of the bag were subsequently analyzed, its volume measured with a calibrated syringe, and VO.sub.2 and VCO.sub.2 calculated using the Douglas technique. As shown in Table 2, differences between device estimates and reference measurements were below 0.4 mL/min in all cases, which would be clinically acceptable for even the smallest infants. During the completion of these experiments, we did not note any significant technical problems with the ventilator and its interaction with the ventilation of the animal.

TABLE-US-00003 TABLE 2 Mixing technique Douglas bag Difference Insp. VO.sub.2 VCO.sub.2 VO.sub.2 VCO.sub.2 VO.sub.2 VCO.sub.2 source mL/min mL/min mL/min mL/min mL/min mL/min Avg. 7.84 6.46 8.17 6.24 0.34 0.23 Vent. 8.00 6.71 8.35 6.51 0.35 0.20 Tank 7.67 6.22 8.00 5.97 0.33 0.25 N = 5 (625-770 g)

OTHER EMBODIMENTS

[0195] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. For example, the principle discussed herein also works in circuits where a bias flow is being applied. The bias flow leads to higher inspiratory flow rates but correspondingly lower I-E differences in O.sub.2 and CO.sub.2 concentrations and therefore equal metabolic rates. However, such a system is more prone to gas measurement errors in case a bias flow is applied for flow triggering by the ventilator.

[0196] Other aspects, advantages, and modifications are within the scope of the following claims.