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FIELD OF THE INVENTION
This invention generally relates to the methods and apparatus employed to
measure regional blood flow and tissue mass; more particularly to
measurements of cardiac output and lung edema.
BACKGROUND OF THE INVENTION
Assessments of fluid volume of the lung, as well as determination of
cardiac output, are of importance for clinical medicine and physiological
research. Acute respiratory insufficiency is a major cause of mortality in
patients, being commonly a complication of various disturbances in lung
fluid balance leading to the development of pulmonary edema. The latter
can be caused by a number of factors and its appropriate treatment
requires adequate diagnosis and early therapy.
Both direct and indirect methods for assessing the fluid volume of the
lungs have been developed and thoroughly investigated for their potential
significance and accuracy in clinical and experimental research. Generally
only indirect, or non-distructive measures can be applied in clinical
investigations, although they are not so accurate as direct ones. Among
the indirect measurements are: lung mechanics and pulmonary gas exchange,
non-gaseous and gaseous indicator-dilution procedures, measurement of
transthoracic impedance and radiological methods. All of these, based on
different physical principles of measurement, have specific limitations,
for theoretical and methodologic reasons.
Lung mechanics are changed in edema due to progressive engorgement by edema
fluid, which decreases lung compliance and increases resistance to
airflow. But, these changes are not specific for edema, being caused also
by changes in alveolar surface tension or vascular hypertension. Also,
non-specific changes in lung mechanics due to bronchoconstriction can
alter the results significantly.
Gas exchange disturbances usually occur in lung edema. However, these
disturbances are also non-specific and provide information more of a
qualitative, than of a quantitative nature. Being influenced by numerous
variables of ventilation and perfusion, anatomical and physiological
shunting and various feedback regulatory mechanisms gas exchange
disturbances are of importance mainly for the detecting final alveolar
flooding stage of pulmonary edema.
Radiological methods are mostly of a semi-quantitative character, based on
special radiographic criteria and are not likely to provide objective or
fast monitoring information, although it is the most widely available
pulmonary edema diagnostic procedure. Utilizing others kinds of external
energy sources, for example, microwave sources and corresponding detectors
(U.S. Pat. No 4,488,559, Iskander M.) also does not provide enough
accuracy and quantitiveness for lung water measurements.
As lung tissue is a conductor of electric current and lung conductivity
varies strikingly with inflation and water content of lung tissue, changes
in transthoracic impedance can be used for the lung water measurements.
Limitations of this method are in the inability to distinguish
conductivity of the lung itself from the surrounding tissue (chest wall),
low sensitivity, demands of stable chest geometry and electrode
positioning and inability to determine absolute values.
Indicator dilution procedures are most commonly used for quantitative
measurements of lung water content. Indicators are injected
intravascularly and indicator concentrations are measured in the systemic
arterial blood or by external probes in the case of gamma-emitting
isotopes. Two indicators: one non-permeable (vascular reference) and the
other permeable (extravascular reference) are utilized. The vascular
reference indicator remains confined to the vascular volume, while the
permeable indicator readily diffuses into the extravascular compartment of
the lung.
For the extravascular reference tritiated water or heat seem to be most
appropriate, having the highest diffusion coefficients. Reference, for
example , U.S. Pat. No. 4,230,126, Elings V. From the time-course of both
indicators appearance and concentration in systemic arterial blood, it is
possible to calculate the blood flow through the lung (vascular reference)
and extravascular water content using the mean transit time difference
between both indicators. These methods are well grounded by mathematical
analysis of the processes of non-steady-state transfer of indicators in
the fluid stream and its exchange with surrounding tissues. There are
different mathematical and technical approaches to performing the
measurements and calculating the results. Such details as injection site
and form, methods of indicator collection and detection, as well as the
site of collection may substantially influence the results. Adequate
measurements require appropriate mixing of indicator at the entrance and
exit of the lung, correction for the delay imposed by the collection
catheter and the position of the collection catheter. In the ideal
situation the collection catheter would be located in the left atrium, but
that involves additional technical problems in positioning the catheter.
The principal theoretical limitation of the method is the
perfusion-dependant distribution of the extravascular indicator. If some
portions of the lungs are poorly perfused, as is often true in lung
diseases, it is difficult to obtain correct mean transit times due to
incomplete recovery of tracer (flow limited). Recirculation of indicator
is another serious problem because the slowly perfused portions of the
lung may empty during the period of recirculation. Improper extrapolation
of the indicator-dilution curve downslope is the reason why standard
indicator dilution curves measure only a fraction of 40-90% of the lung
thermal mass. Since lung tissue is composed of different types of organic
materials, the solubility of indicators in water and lipids is important.
For example, different permeable indicators yield different extravascular
volumes (diffusion limited).
Further, the main problem preventing its wide clinical use is the
invasiveness of the procedure. Most techniques require positioning of
catheters for indicator injection and collection in the pulmonary artery
and aorta respectively. Catheterization of the heart, especially
puncturing of a large artery are complicated procedures, often accompanied
by various complications - clotting, embolism etc., and can not be
recommended as routine procedures. Positioning of the probes outside the
chest without direct contact with the arterial bloodstream significantly
decreases the accuracy of the measurements.
The above-mentioned drawbacks can be eliminated by using high-energy
indicators and external scanning over the chest. Scanning procedures may
permit more accurate evaluation of poorly perfused regions and retention
of the indicator, as well as measurements of regional water content. Such
determinations of lung water with the gamma-indicator .sup.22 -Na were
used by Weidner in 1956, and by Kety's (1949) measurements of tissue
perfusion. This procedure never became clinically popular because of
considerable exposure to radioactivity and uncertainty regarding tracer
distribution in cells. Others indicators, such as .sup.99 Tc-DTPA are
being currently used. As this indicator is extracellular, it is not
possible to distinguish between the plasma and interstitial water volumes.
Uncertainty regarding the contribution of thoracic wall activity exists.
The method also requires employing of expensive and sophisticated
apparatus.
A different approach is used in methods utilizing soluble gas absorption by
the lung tissue. Such measurements of lung tissue volume have been
studied, since Cander and Forster used the inert gas acetylene for this
purpose in 1959. The method is based on measuring the concentration of
exhaled soluble gas after inhalation of a gas mixture with known
concentration of the test gas. The soluble gas disappears from the airways
and alveolar spaces due to its solution in lung tissues and blood.
Constant blood flow via the lungs provides continuous extraction of the
test gas from the lungs, so that pulmonary blood flow is also determined
in these measurements. The solubility of the gas is of critical importance
for the determination of lung water.
One of the main limitations of the soluble gas technique involves the back
extrapolation of the disappearance curve to zero time of the soluble gas
following multiple breathholds of the test-gas mixture. These
back-extrapolation calculations are sensitive to a variety of measurement
errors. Some factors which might occasion systematic errors are: cardiac
output changes during the breathhold maneuvers, inhomogenities in the lung
ventilation/perfusion ratios an inhomogenities of the lung deflation
pattern. Also the method is sensitive to alterations in ventilation
distribution which can be critical in pulmonary edema due to airway
closure.
Application of the technique demands expensive and accurate apparatus for
precisely measuring the gas concentration such as a mass spectrometer.
Also the method is not useful in very sick patients, because the procedure
requires rather complicated breathing procedures with the special gas
mixture.
Although this method is capable of providing accurate enough measurement of
lung water and cardiac output, the complexity and expense of the related
gas concentration processing apparatus has significantly limited its
widespread commercial application.
Various methods have been proposed for the measurement of cardiac output or
pulmonary blood flow alone, without measuring lung water content. Most of
them are also invasive, employing intravascular catheters or probes. The
pioneering method was by Fick (1870), which was based on the measurement
of oxygen consumption and the arterial-venous O.sub.2 concentration
difference. But the method requires obtaining arterial and mixed venous
blood samples. Single indicator dilution methods are also used for blood
flow determination. These are referred, for example, to U.S. Pat. Nos.
4,024,873, Antoshkiw et al., 4,329,993, Lieber et al.
Other invasive methods use different principles of fluid flow
measurement--measurement of the differential temperature that results from
localized heating of the blood (U.S. Pat. Nos. 3,359,974, Khalil,
3,798,967,Gieles et al.), electromagnetic energy (U.S. Pat. No. 3,347,224,
Adams) or ultrasonic devices (U.S. Pat. No. 4,802,490, Johnston), or local
heating or cooling of the tissue itself (U.S. Pat. No. 4,802,489, Nitzan
). All these methods tend to be invasive, which is their main
disadvantage.
It is therefore, the principal object of the new invention to provide a
non-invasive method for pulmonary blood flow rate determination and
pulmonary tissue volume determination, using heat as the permeable
indicator of lung tissue volume and permitting non-invasiveness of the
measurement. The method depends upon the lung'ability to humidify and heat
the inspired air to the lung's own temperature over a wide range of
breathing conditions, and upon easily performed measurements on expired
air.
SUMMARY OF THE INVENTION
This invention provides a method (hereafter reffered to as airway thermal
volume) for carrying out pulmonary tissue volume and pulmonary blood flow
measurements, comprising the steps of:
1. Providing a probe for simultaneous measurement of temperature, humidity
and volume flow of inspired and expired air and adapted to produce a
signal indicative of temperature, humidity and gas flow at the entrance to
the upper respiratory tract;
2. Measuring the temperature of the body;
3. Measuring the above mentioned variables in steady-state period of
spontaneous or artificially-provided breathing, then changing the rate of
breathing and/or temperature and humidity of inspired air, following the
changes in temperature and humidity of expired air until new steady-state
conditions are established under the new constant state of ventilation
pattern;
4. Calculating pulmonary blood flow and airway thermal volume by
integration of the differential equation of lung heat exchange with the
environment by the known parameters of inspired gas temperature and
humidity, measured expired gas temperature and humidity and taking
mean-integrated temperature of the lung tissue as linearly proportional to
the expired air temperature with a coefficient of proportionality that
equals to the ratio of body temperature to the expired gas temperature at
the beginning of the measurement.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in connection with certain preferred
embodiments with reference to the following illustrations so that it may
be more fully understood.
With specific reference to the figures in detail, it is stressed that the
particulars shown are by way of example and for purposes of illustrative
discussion of the preferred embodiments of the present invention only and
are presented in the course of providing what is believed to be most
useful and readily understood description of the principles and conceptual
aspects of the invention. In this regard no attempt is made to show
structural details of the invention in more detail than is necessary for a
fundamental understanding of the invention; the description taken with the
drawings making apparent to those skilled in art how the several forms of
the invention may be embodied in practice.
In the drawings
FIG. 1 represents the scheme of heat exchange in the lung;
FIG. 2 represents a typical temperature-time curve of the expired air
during lung ventilation with dry air at a ventilation rate three times
greater than baseline;
FIG. 3 represents curves of the expired air temperature-time in ventilatory
loading for various lung tissue mass;
FIG. 4 represents curves of the expired air temperature-time in ventilatory
loading for various pulmonary blood flow;
FIG. 5 represents the method of analysing of the parameters of the curve;
FIG. 6 represents a general set up of the probes for measuring temperature,
humidity and ventilation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The temperature and water vapor concentration of the inflowing airstream
differ from those at the mucosal surface of the respiratory tract. The
respiratory tract adjusts the inspired air temperature and humidity as it
conditions the inspired air nearly to body temperature and full
humidification. As a result of this process the respiratory tract surface
loses heat and water to the inspired air. Some part of the losses is
recovered during expiration because condensation of water vapor occurs on
the cooled surface of the bronchial tree. The amount of heat and water
recovered is dependent on lowering of the temperature and water vapor
concentration of the expired air. Due to heat exchange between the
bronchial walls and the inspired air the walls of the bronchial tree and
lung tissue are cooled. At the same time, a temperature gradient develops
between the airway surfaces and blood vessels, so that heat streams from
the blood to the tissues. In this manner pulmonary blood flow plays the
role of an inner heat source for the lungs.
Referring now to the drawings, the scheme of heat fluxes in the lung tissue
is given in FIG. 1, for inspiration and expiration. An element of lung
tissue of volume, dV, and related to the contact with air surface area
element, dS, having temperature, T.sub.t, provides two different heat
fluxes into the incoming airstream with air temperature, T.sub.Go, and
water vapor concentration, C.sub.o, during inspiration. The first one, jT,
is the convectional and dissipative heat flux, associated with water vapor
transfer, jC, from the bronchial surface into the airstream, and the
latter can be given as:
jC=U.sub.z,(dC/dx)/r.sub.z =2 b(C.sub.w -C), (1)
where U.sub.z is the linear air velocity at a given point of the bronchial
tree, C is the water vapor concentration, x is the length coordinate of
the bronchial tree, r.sub.z is the radius of the bronchus, b is the
coefficient of water vapor mass transfer from the wall, C.sub.t is the
concentration of totally saturated water vapor at the wall, and depends on
the wall temperature.
Total convectional and dissipative heat flux can be given as:
jT=.rho..sub.G C.sub.pG U.sub.z (dT/dx)r.sub.z =2(T.sub.t -T)
(a+jCC.sub.pw), (2)
where .rho..sub.G is the gas density, T is the gas temperature, C.sub.pG is
the heat capacity of gas, T.sub.t is the tissue temperature, a is the
coefficient of heat transfer, C.sub.pw is the heat capacity of water.
The second heat stream, jH, is associated with the evaporative heat losses
and is given as:
jH=jCH, (3)
where H is the heat of water vaporization.
The equation for the specific instantaneous heat transfer to the lung
tissues from the pulmonary circulation (the inner heat source) is given:
jB/S=K.sub.t .rho..sub.W C.sub.pt q(T.sub.B -T.sub.w)+C.sub.pw T.sub.B
q.sub.o .rho..sub.w, (4)
where jB is the heat flux to the lung tissue from the pulmonary blood flow,
K.sub.T is the coefficient of lung tissue heat conductivity, .rho..sub.w
is the density of lung tissue, q is the pulmonary blood flow, T.sub.B is
the temperature of blood, q.sub.o is the net fluid flux of water
evaporated into the airstream.
The differential equation for the temperature balance of the lung tissue is
given as the sum of these fluxes:
dV.rho..sub.w C.sub.Pt (dT.sub.t /dt)=.intg.(jB-jT-jH) dS, (5)
where t is the time.
The above equations represent the mathematical model of lung heat exchange
with the inspired air during breathing. They were used as a basis for the
development of the method of pulmonary blood flow and airway thermal
volume measurements.
Experimentally the amount of heat lost by the lungs during a certain period
of breathing (Q.sub.o) can be measured knowing temperatures and humidities
of inspired and expired air and the total amount of the air that enters
the lungs. It can be presented as:
Q.sub.o =.intg.dt.intg.dS (jT+jH),
For practical purposes it can be given as the sum of a finit-difference
elements as:
-Q.sub.o =V.sub.G ((T.sub.GO -T) .rho..sub.G C.sub.PG +(T.sub.GO C.sub.pw
C.sub.o -TC.sub.pw C)+(C.sub.o -C)H), (6)
where V.sub.G is the volume of gas that entered the lungs over the time t,
Te.sub.Go and T are the mean temperatures of inspired and expired gas,
C.sub.o and C are the mean mass concentration of water vapor in inspired
and expired air, respectively (here "mean" relates to the average value
during one breathing cycle). All the above-mentioned parameters can be
easily measured so that Q.sub.o can be determined explicitly.
During ventilatory loading of the lungs and/or changes in temperature and
humidity of expired air, Q.sub.o will be changing as well as T. Q.sub.o
and T will be the functions of time due to the cooling of the lung caused
by increased outward heat flux until a new steady-state condition between
heat loss into the environment and inner heat source (pulmonary blood
flow) will be achieved. The corresponding equation of lung tissue cooling,
taking into account eq. (5), can be given as:
V.rho..sub.w C.sub.pt (dt.sub.t /dt)=q.rho..sub.w C.sub.pt (T.sub.B
-T.sub.t)-Q, (7)
where Q is net heat flux.
In order to determine the airway thermal volume, V, and pulmonary blood
flow, q, we need to know the relationship between temperature of expired
air, T, and actual mean-integrated temperature of lung tissue, T.sub.t.
This relationship can be given as a linear one:
T.sub.t =K.sub.R T, (8)
where K.sub.R is the coefficient of proportionality and it is derived as:
K.sub.R =T.sub.B /T.sub.o, (9)
where T.sub.B is body temperature and T.sub.o is the temperature of expired
air at the beginning of the ventilatory loading. In ventilatory loading
the temperature of the expired air T will decrease to some steady-state
value. In this new steady-state condition the heat losses to the expired
air will equal the heat transfered from the pulmonary blood flow to the
lung tissue:
(jT+jH) .intg.dS=jB .intg.dS=Q. (10)
Eq. (10) allows one to calculate pulmonary blood flow in steady-state
conditions.
A typical curve of the expired air temperature-time curve during
hyperventilation of a experimental animal is given in FIG. 2. The
temperature of the expired air decreases monoexponentially during loading,
reaching some steady-state condition of heat exchange.
The developed model of lung heat exchange was analyzed to obtain predicted
expired air temperature dynamics in situations where lung tissue volume or
pulmonary blood flow change. In FIG. 3 the calculated values of the
expired air temperature-time curve are given for different lung tissue
masses, while the external heat losses and pulmonary blood flow were hold
constant. Expired air temperature is given in relative values (actual
temperature is related to initial temperature at the beginning of
loading). As can be seen from the figure, increasing lung tissue mass is
associated with distinct changes in the dynamics of the expired air
temperature. The curve becomes smooth as V increases.
In FIG. 4 the expired temperature-time curve is analyzed in terms of
pulmonary blood flow, while lung tissue mass and ventilation are constant.
In this case the temperature of the final steady-state condition is
markedly affected.
Convenient for practical purposes is the solution of eq. (7), which, by its
analytical integration, enables one to obtain values of pulmonary blood
flow, q, and airway thermal volume, V.
Practically the expired air from the lungs is always fully saturated at its
temperature. This special case means that one does not have to measure
both temperature and humidity of expired air but permits one to use only
temperature for calculating heat loss, including evaporative heat losses,
by calculating water vapor mass from the measured temperature of air.
For this purpose a linear approximation of the mass concentration of
saturated water vapour in the air is used:
C(T)=0.016+0.0018(T-20), (11 )
where C is water vapor mass concentration (kg/M.sup.3) and T is the
temperature in degrees Centigrade. This linear approximation is valid for
the temperature interval 20.degree. to 38.degree. C.
For this case eq. (7) can be given as:
dT/dt+AT+B=0, (12)
where the constants A and B are:
A=qK.sub.T /V+V.sub.G x.sub.1 /VK.sub.R +yH0.0018V.sub.G /V.rho..sub.w
Cp.sub.w K.sub.R, (13)
B=(qT.sub.B K.sub.T /K.sub.R V+V.sub.G x.sub.1 T.sub.GO /VK.sub.R
+0.02yHV.sub.G /V.rho..sub.w Cp.sub.w K.sub.R) (-1), (14)
where y is equals unity with dimension kg*m.sup.-3 *K.sup.-1, x.sub.1 is a
dimensionless parameter=(.rho..sub.G C.sub.pG +.rho..sub.w
C.sub.GO)/.rho..sub.w C.sub.pW.
The density and heat capacity of lung tissue were taken as those of water
(.rho..sub.w and C.sub.pw respectively).
The solution of eq. (12) can be easily obtained as:
T(t)=T.sub.o exp(-At)(1+B/AT.sub.o)-B/A. (15)
Equation (15) can be solved for two different steady-state conditions in
terms of temperature fall, .DELTA.T-the difference of temperatures of
expired air in two steady-states, and the half-time of the temperature
fall, t.sub.0.5. The graphic method for the evaluating of these parameters
is given in FIG. 5.
Pulmonary blood flow, q, and airway thermal volume, V, are obtained from
the curve of temperature dynamics vs time as:
q=V.sub.G x.sub.2 (T.sub.o -T.sub.Go -.DELTA.T)/.DELTA.TK.sub.T K.sub.R,
(16)
V=t.sub.0.5 (qK.sub.T K.sub.R +V.sub.G x.sub.2)/0.69K.sub.R, (17)
where x.sub.2 =x.sub.1 +0.0018yH/.rho..sub.w C.sub.pw.
In order to get particular values of pulmonary blood flow, q, and airway
thermal volume, V, it is necessary to measure expired air temperature and
humidity, body temperature during normal breathing and during ventilatory
loading by changing the temperature and humidity of inspired, air and the
following parameters or variables:
Temperature (T.sub.Go) and humidity (C.sub.Go) of inspired air
Temperature of the body (T.sub.B)
Volume ventilation (V.sub.G)
Initial temperature of expired air (T.sub.o) and temperature fall
(.DELTA.T) after reaching new steady-state
Half-time of temperature fall (t.sub.0.5)
The other variables can be calculated from the above definitions and the
relative coefficient of lung thermal conductivity, K.sub.T, equals 0.2
(dimensionless).
In FIG. 6 the general set-up of the probe for measurement of airway thermal
volume is shown. The temperature probe for the expired air measurements
should be positioned in the middle of the airstream. The probe should have
a response time less than 0.05 sec and minimal mass to provide for
accuracy of the airstream temperature measurement. The humidity probe
should also be located in the middle of the airstream but should be
positioned downstream to the temperature probe. For accurate measurements
and to prevent water vapor condensation, the humidity probe is heated.
Positioning of the humidity probe before the temperature probe may alter
the temperature measurement. In most cases measurements of the expired air
humidity is not necessary, assuming that the expired air is fully
humidified. Although measuring this variable provides slightly more
accurate measurements, it is associated with technical difficulties.
The ventilation measurement can be made at any point of the respiratory
circuit, whereas the temperature and humidity probes should be located as
close as possible to the upper respiratory tract entrance. Intubation
tubing or tracheostomy can be succesfully used for this purposes in
anesthetized humans or experimental animals.
The method and probe, according to the invention, are eminently suitable
for automatic monitoring by connection to an analog-digital converter.
Data can be stored in buffer memory and analyzed by a person or computer
to obtain the variables needed for calculation of pulmonary blood flow and
airway thermal volume.
For ventilatory loading, increasing the ventilation rate with a tidal
volume of 22 ml/kg of body weight appends to optimal. Also
hyperventilation ca be combined with using cold dry air which increases
the heat loss. Either artificial ventilation or spontaneous breathing with
air-CO.sub.2 mixtures is satisfactory. The duration of altered ventilation
depends on the subject and the rate of respiratory heat loss, ranging
between 100-500 sec.
It will be evident to those skilled in the art that the invention is not
limited to the details of the foregoing illustrative embodiments and that
the present invention may be embodied in other specific forms without
departing from the spirit or essential attributes thereof. The present
description is therefore to be considered in all respects as illustrative
and not restrictive, the scope of the invention being indicated by the
appendant claims rather than by the foregoing description, and all changes
which come within the meaning and range of equivalency of the claims are
therefore intended to be embraced therein.
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