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Respiratory Physiology & Neurobiology 247 (2018) 112–115

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Respiratory Physiology & Neurobiology


journal homepage: www.elsevier.com/locate/resphysiol

A new method for noninvasive measurement of pulmonary gas exchange MARK


using expired gas

John B. West , G. Kim Prisk
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0623, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Measurement of the gas exchange efficiency of the lung is often required in the practice of pulmonary medicine
Alveolar gas and in other settings. The traditional standard is the values of the PO2, PCO2, and pH of arterial blood. However
Alveolar-arterial oxygen difference arterial puncture requires technical expertise, is invasive, uncomfortable for the patient, and expensive. Here we
Alveolar PO2 describe how the composition of expired gas can be used in conjunction with pulse oximetry to obtain useful
Alveolar PCO2
measures of gas exchange efficiency. The new procedure is noninvasive, well tolerated by the patient, and takes
Oxygen dissociation curve
only a few minutes. It could be particularly useful when repeated measurements of pulmonary gas exchange are
required. One product of the procedure is the difference between the PO2 of end-tidal alveolar gas and the
calculated PO2 of arterial blood. This measurement is related to the classical alveolar-arterial PO2 difference
based on ideal alveolar gas. However that traditional index is heavily influenced by lung units with low ven-
tilation-perfusion ratios, whereas the new index has a broader physiological basis because it includes con-
tributions from the whole lung.

1. Introduction physiology. At that time, the analysis of the gas was carried out by
collecting individual samples, and using chemical methods such as the
It is frequently necessary to measure the efficiency of gas exchange Haldane gas analyzer (Haldane, 1920). However about 60 years ago,
of the lung, and this is often essential in many patients with pulmonary rapidly responding gas analyzers were introduced, and, for example, a
disease. In these instances, it is common to make a measurement at the mass spectrometer could provide a rapid, accurate analysis of all the
time of diagnosis, and then do subsequent measurements in order to respiratory gases (West et al., 1957). This equipment was generally
follow the progress of the disease. The traditional method of measuring large and cumbersome.
gas exchange is that using arterial blood gases. This typically gives the In the last few years miniaturized, rapidly responding, accurate gas
arterial PO2, PCO2, and pH. However this measurement has some analyzers have become available, and these have been exploited here to
disadvantages. The procedure is invasive, may be uncomfortable for the make a device that can be hand-carried to the patient to give immediate
patient, requires a technically skilled person, has occasional complica- results. When used in conjunction with a pulse oximeter, valuable in-
tions, and is expensive. Therefore it would be valuable to have a non- formation about the efficiency of pulmonary gas exchange can be de-
invasive method of measuring gas exchange efficiency that was well rived.
tolerated by the patient and could be easily repeated. This would not Pulse oximetry by itself also has a role in obtaining information
necessarily obviate the use of an arterial blood gas measurement, about pulmonary gas exchange. It has the great advantage of being
especially in the early stage of management, but could be useful in noninvasive. However it is a blunt instrument. Because of the shape of
following the progress of the disease. the oxygen dissociation curve, it is possible for the arterial PO2 to fall
Another population of people in which this method could be useful from about 100 to 60 mmHg, that is by 40%, while the SpO2 changes
is normal subjects, or patients with lung disease, who are living at high from 97 to 90%, that is by only 7%. Therefore although the arterial
altitude. All these people have hypoxemia, and therefore the limitations oxygen saturation can be useful in following the progress of a patient
discussed later requiring a reduced arterial PO2 would not apply. with lung disease, the signal from the oximeter changes relatively little.
In this report, the potential of using the composition of expired gas Nevertheless the device is extensively used in a hospital setting to de-
to determine gas exchange efficiency is explored. The analysis of ex- termine treatment, for example, in the mechanical ventilation of pa-
pired gas goes back over 100 years to the early days of respiratory tients.


Corresponding author at: UCSD, Department of Medicine, 0623A, 9500 Gilman Drive, La Jolla, CA, 92093-0623, United States.
E-mail address: jwest@ucsd.edu (J.B. West).

http://dx.doi.org/10.1016/j.resp.2017.09.014
Received 28 July 2017; Received in revised form 11 September 2017; Accepted 26 September 2017
Available online 29 September 2017
1569-9048/ © 2017 Elsevier B.V. All rights reserved.
J.B. West, G.K. Prisk Respiratory Physiology & Neurobiology 247 (2018) 112–115

Fig. 1. Typical screenshot of the output of the device. Note the continuous records of inspired and expired PO2 (red) and PCO2 (blue). Nine breaths are shown. Below these are plots of
the end-tidal PO2 and PCO2 for 18 breaths to show whether the patient is in a steady state. Other information in the output includes the end-tidal PO2 and PCO2 values, respiratory
exchange ratio (RQ), respiratory rate, calculated arterial PO2, difference between the end-tidal and calculated PO2 here called the Oxygen Deficit, heart rate, SpO2, barometric pressure,
and inspired PO2.

2. Hardware arterial PO2 is done using the Hill equation:

PO2^n = P50^n × [SO2/(1-SO2)]


The device consists of a small portable box containing the rapidly
responding oxygen and carbon dioxide sensors, a pump to draw in the where the symbol ^ means raised to the power of, P50 is the PO2 for
gas sample, the appropriate software, and a screen to display the data. 50% oxygen saturation, n is 2.7, and SO2 is the arterial oxygen sa-
For oxygen, fast-responding electrochemical cells such as those avail- turation given by the SpO2. In order to invert the Hill equation, that is
able from Teledyne are available. For carbon dioxide, thermal con- to calculate the PO2 from the SO2, the software takes the logarithm of
ductivity or infrared sensor cells are suitable. For the measurement, the the equation. This allows it to be solved algebraically. Severinghaus
patient wears a nose clip, and breathes through a disposable cardboard (1979) and others have shown that this equation given above fits the
tube about 8 cm long and 1.5 cm diameter. A capillary sampling tube is oxygen dissociation curve closely. For example, between the satura-
inserted into the side of this tube, and a small volume of the inspired tions of 94 and 30%, the error in the calculated PO2 is less than
and expired gas is continually transported to the analyzers by a small 5 mmHg.
pump. The result is a continuous display of the inspired and expired The software also takes account of the effects of changes in the
PO2 and PCO2 as shown in Fig. 1. In practice the patient breathes PCO2 on the pH of the blood, because changes in the pH alter the
through the tube for only 2 or 3 min until a steady state has been oxygen affinity of hemoglobin. This is done using the Kelman sub-
achieved. routines (Kelman, 1966, 1968) which allow the P50 to be calculated
from the arterial PCO2 assuming that the base excess is zero, that is that
3. Software the blood is on the normal buffer line. The equation is:

As can be seen from Fig. 1, the instantaneous values of the inspired P50 = 0.221 × PCO2 + 17.9.
and expired PO2 and PCO2 are continually displayed. In addition, the The end-tidal PCO2 is used for the arterial value. The effects of
software reads off the end-tidal values for both the PO2 and PCO2 and changes in the PCO2 on the P50 are relatively small. For example, an
the values of the preceding five breaths are averaged. These end-tidal increase in PCO2 from 40 to 50 mmHg results in a change in P50 of only
values are also displayed over a period of about a minute on another about 2 mmHg. In patients with severe COPD, the end-tidal PCO2 will
tracing to determine whether a steady state of gas exchange has been be appreciably lower than the arterial value because of the contribution
achieved. The software also calculates the respiratory exchange ratio of alveolar dead space.
from the end-tidal and inspired values for PO2 and PCO2. Steady state
can also be ascertained by monitoring the stability of the respiratory
exchange ratio, RQ in Fig. 1. As indicated in Fig. 1, the display also 4. Analysis
reads out the barometric pressure (from a miniature barometer), in-
spired PO2, and respiration rate. The SpO2 and heart rate are also As indicated above, the device gives the difference between the end-
displayed from the pulse oximeter. tidal PO2 and the calculated arterial PO2 (as derived from the pulse
A software package calculates the arterial PO2 from the arterial oximeter reading). Fig. 2 shows a graphic display of this value, and how
oxygen saturation given by the SpO2. Modern oximeters measure the it compares with the traditional alveolar-arterial oxygen difference
oxygen saturation with considerable accuracy. The derivation of using the calculated PO2 of ideal alveolar gas.

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J.B. West, G.K. Prisk Respiratory Physiology & Neurobiology 247 (2018) 112–115

Fig. 2. Classical oxygen-carbon dioxide diagram showing the ventilation-


perfusion ratio line connecting the mixed venous point v with the inspired
gas point I (here shown for sea level conditions and with a typical mixed
venous point). The ideal alveolar point, i is shown at the intersection of the
blood and gas R lines where R stands for respiratory exchange ratio. The
traditional alveolar-ideal alveolar difference is shown as number 1. The
alveolar-arterial oxygen difference given by the new device is shown as
number 2. Note that number 1 is mainly determined by lung units with
low ventilation-perfusion ratios. By contrast, 2 has contributions from
these lung units, and also lung units with abnormally high ventilation-
perfusion ratios.

This classical oxygen- carbon dioxide diagram shows the gas com- Another limitation is that the device does not take account of any
position of lung units for all ventilation-perfusion ratios from zero, the changes in the oxygen affinity of hemoglobin caused by alterations in
value for mixed venous blood, to infinity, the value of inspired gas base excess, body temperature, or 2,3 diphosphoglycerate (DPG). In
(Rahn and Fenn, 1955). For simplification, the diagram shows the in- practice the last two limitations will not apply to many patients.
spired PO2 and PCO2 to be those of air at sea level, and the mixed However some patients such as those with long-standing COPD are
venous point is that for the normal lung with a PO2 of 40 and PCO2 of likely to have changes in their base excess. The same is true of people
45 mmHg. The VA/Q line shows all possible values for the PO2 and who are acclimatized to high altitude
PCO2 and lung units throughout the lung. Ideally the patient should be in a steady state of gas exchange. Some
First look at the derivation of number 1. This uses the measured patients hyperventilate when asked to breathe through a mouthpiece,
arterial PO2 and PCO2 from an arterial blood gas sample (labeled “a”). although if they are asked to close their eyes and relax this often helps.
However the alveolar values are not known in this classical analysis. This is frequently a problem when an arterial blood gas sample is taken
Instead the so-called ideal alveolar PO2 is calculated. The ideal alveolar because of the apprehension associated with the procedure. In practice,
gas composition is that which the lung would have if there were no if an arterial blood sample shows an unexpectedly low PCO2 associated
ventilation-perfusion inequality and the respiratory exchange ratio was with an unexpectedly high pH, we commonly attribute this to hy-
the same as the actual lung (labeled “i”). This calculation is done by perventilation caused by the anxiety of the procedure.
taking the PCO2 of the arterial sample, and assuming that the PCO2 of
ideal alveolar gas is the same. This is a reasonable assumption because
6. Preliminary results
the line joining the alveolar ideal point and the arterial point is almost
horizontal as shown in the figure. The alveolar gas equation is then used
The main purpose of this report is to describe a new potential
to calculate the ideal alveolar PO2 using the inspired PO2 and the
method of measuring abnormal pulmonary gas exchange. However a
measured or assumed respiratory exchange ratio.
number of measurements have been made on outpatients with lung
Now turn to the derivation of number 2. Again we have the arterial
disease at UCSD after appropriate IRB approval. These have shown that
PO2 on the left, although this is calculated as described above from the
in 22 patients who had an arterial oxygen saturation of 93% or less
SpO2. On the right we have the alveolar PO2, which is given by the end-
(average 91, SD 1.83), the differences between the end-tidal and cal-
tidal value (labeled “A”). It can be seen that the difference between
culated arterial PO2 was generally in the range of 30–70 mmHg
alveolar and arterial PO2 measured by the new device is larger than the
(average 47, SD 19). By contrast, the corresponding differences in
traditional PO2 difference between arterial blood and ideal alveolar
people with normal lungs are very small, approaching zero. These re-
gas.
sults show that, as expected, the index shown as # 2 in Fig. 2 has a
It could be argued that this new value shown in number 2 is more
substantial value in patients whose lung disease is severe enough to
informative than the traditional value shown in number 1. The tradi-
result in appreciable desaturation (Fig. 3).
tional value depends heavily on the contribution of lung units with low
More extensive measurements, including arterial blood gas values,
ventilation-perfusion ratios. By contrast, the new value shown in
have been made in 5 inpatients all of whom had severe chronic ob-
number 2 includes both the contributions of lung units with low ven-
structive pulmonary disease. These studies were made in the Stevenson
tilation-perfusion ratios, and those with abnormally high ratios. It is
Memorial Hospital, Alliston, ON, Canada after IRB approval. The dif-
therefore a more comprehensive metric for the distribution of ventila-
ference between the end-tidal and calculated arterial PO2 ranged from
tion-perfusion ratios in the lung.
54 to 98 mmHg, and the difference between these values and the
classical ideal alveolar- arterial oxygen difference averaged 24 mmHg.
5. Limitations
These results confirm that, as expected, the difference between index 1
and 2 in Fig. 2 is substantial, and are consistent with the assertion that
The device described here has limitations. One is that it is only
the new technique is a more comprehensive index of abnormal gas
accurate when the arterial oxygen saturation is abnormally low, that is
exchange that the traditional one based on ideal alveolar gas.
in patients with hypoxemia, or subjects at high altitude. The reason is
that the oxygen dissociation curve has such a shallow slope above a
saturation of about 93% that the calculation of arterial PO2 from the Disclosures
SpO2 is inaccurate. Many patients with lung disease, and millions of
people who live at high altitude have an arterial oxygen saturation The University of California San Diego has licensed MediPines
below 93%. Therefore the population for which the new device will be Corp., Newport Beach CA to develop the device. John B West states a
valuable is large. financial interest.

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J.B. West, G.K. Prisk Respiratory Physiology & Neurobiology 247 (2018) 112–115

Fig. 3. Graphical representation of some preliminary clinical results for outpatients (A) and inpatients (B).

Acknowledgments Kelman, G.R., 1966. Calculation of certain indices of cardiopulmonary function using a
digital computer. Respir. Physiol. 1, 335–343.
Kelman, G.R., 1968. Computer program for the production of O2-CO2 diagrams. Respir.
We thank Peter D Wagner for help with deriving the arterial PO2 Physiol. 4, 260–269.
from the arterial oxygen saturation, and Dipen Makadia, Pranav Rahn, H., Fenn, W.O., 1955. A Graphical Analysis of the Respiratory Gas Exchange.
American Physiological Society, Washington DC.
Agarwal and Oswaldo Ramirez for some of the data. Severinghaus, J.W., 1979. Simple, accurate equations for human blood O2 dissociation
computations. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 599–602.
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Haldane, J.S., 1920. Methods of Air Analysis, 3rd edition. Griffin, London.

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