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Brit. J. Anaesth. (1969), 41, 751: Measurement of Volume Displacement: Indicator Dilution Methods
Brit. J. Anaesth. (1969), 41, 751: Measurement of Volume Displacement: Indicator Dilution Methods
"It is a source of regret that the measurement of flow is so much more difficult than the measure-
ment of pressure. This has led to an undue interest in the blood pressure manometer. Most
organs, however, require flow rather than pressure. . ."
Jarisch, 1928
". . . variations in pressure could be due to two factors, power and resistance, and in the absence
of a criterion which allows one to decide with complete surety, many physiologists have chosen
the hypothesis which accords best with their preconceived ideas."
Etienne Jules Marey, 1881
V ml
max
the measured gas contents of the arterial and from the corresponding movements of oxygen and
mixed venous blood samples are representative carbon dioxide, so the nitrogen balance method
of the same period. Therefore we must assume [iv] for estimating the inspired minute volume
that a steady state exists during such a period, cannot be applied. This problem may be over-
the duration of which depends on the method come by using box-bag spirometry (Nunn and
employed for measuring gas uptake or elimination Pouliot, 1962), a technique which has been suc-
(Visscher and Johnson, 1953). The method cessfully applied during uptake and elimination
commonly used when the subject breathes room of nitrous oxide (Bay, Nunn and Prys-Roberts,
air consists of collecting a timed sample of expired 1968). A steady state for tissue production and
gas in a suitable container such as a Douglas lung elimination of carbon dioxide is more difficult
bag or Tissot spirometer, accurately measuring to obtain than that for oxygen because of large
the volume (VE) and reducing it to STPD and carbon dioxide stores, but during prolonged
measuring the fractional concentrations (or partial artificial ventilation, the "direct" Fick procedure
pressures) of oxygen ( F E 0 2 ) and carbon dioxide may be applied using directly measured CO 2
(FE C O 2 ) in the sample. To allow reasonable contents of arterial and mixed blood samples.
accuracy in measuring the gas volume, the
sampling period is usually between one and three
Inert diffusible gases may be used in preference
minutes. The inspired fractional concentration of
to the respiratory gases and were introduced in
oxygen (Fi 02 ) is either measured or assumed.
principle by Krogh and Lindhard (1912) who
Oxygen uptake (VO2 ml/min, standard tempera-
used a single-breath method using nitrous oxide
ture and pressure dry: STPD) is calculated from
as indicator. By measuring the uptake of an inert
the difference between the volume of oxygen
gas from the lungs, and knowing its mean alveolar
inspired and that expired:
concentration and its solubility in whole blood at
body temperature, pulmonary blood flow can be
Vo, = ( v i . Fi O 2 )-(VE . F E 0 2 ) estimated by the general method described by
Correcting for differences between inspired and Lee and Dubois (1955). These authors developed
expired minute volumes by assuming that there a particularly valuable application using the body
is no net volume exchange of nitrogen: plethysmograph to estimate the uptake of nitrous
oxide from the lungs, and their technique has
been further modified to estimate pulmonary
V i-Fio capillary blood flow and stroke volume on a beat-
-(VE.FI02) • • • [iv] by-beat basis in man (Bosman et al., 1964). The
cumbersome body plethysmograph limits the use-
where
fulness of the method, and of course it is par-
VI = inspired minute volume ticularly inapplicable during nitrous oxide anaes-
VE=expired minute volume both at STPD thesia. Acetylene has also been used as an inert
Samples of blood simultaneously withdrawn from gas (Grollman, 1929) but following a brief period
a peripheral artery and the pulmonary artery or of popularity, the method was shown to be
right ventricle are analyzed for oxygen content systematically in error (Hamilton et al., 1932).
(ml/litre blood at STPD), and cardiac output can
be calculated from equation [iii].
SUDDEN INJECTION OF INDICATOR
This method, when correctly applied either
during spontaneous or artificial ventilation, can Let us return to the model system and consider
produce reproducible results in conscious man the decay of indicator concentration from the
(Cournand et al., 1945, 1948; Visscher and time at which addition of indicator to the system
Johnson, 1953). Difficulties arise however, if the is stopped (fig. la). At any time after this event,
direct Fick method is applied during anaesthesia the concentration of indicator (Q) will bear some
with gaseous or volatile agents (Prime and Gray, relationship to the maximum concentration Cm**
1952). Uptake or elimination of anaesthetic agents as a function of the relevant time interval (t).
or nitrogen exchange are difficult to distinguish This relationship was found empirically to be an
754 BRITISH JOURNAL OF ANAESTHESIA
exponential decay (Kinsman, Moore and chamber (the heart) can be detected and quantified
Hamilton, 1929) and can be expressed: instantaneously. A number of indicators can
Ct=C m a i e- k t . . . [v] satisfy these criteria, notably dyes, electrolytes,
acids, cold, heat and radioactive tracers. At the
where: present time, dye dilution, thermodilution (cold)
e=2.718 (the Naperian logarithm base); and radioactive tracer dilution seem to have stood
k is the decay constant of the exponential. the test of time and each method has both
If we consider a further situation where, rather advantages and disadvantages.
than using a constant rate infusion of indicator, a
bolus containing a known mass of indicator is Application of the sudden-injection of dye dilution
suddenly introduced into the flow at the inlet of method in man.
the system, we can visualize that the concentra- Credit for the first application of dye dilution
tion of indicator at the outflow will follow some for the measurement of cardiac output in man
curvilinear function with time C (t) to reach a is due to Hamilton and his colleagues (1932)
peak concentration, and thereafter decay according although Stewart (1897) applied the same
to equation [v]. At any given moment in time, principle, but using an electrolyte as indicator
denoted by the infinitely small time interval (dt), and electrical conductivity of blood as the method
the rate at which indicator leaves the system is of detection. The dye used by Hamilton was
given by the product of the flow (Q) and its Brilliant Red, and he measured its concentration
concentration at that time C (t) dt. Since all the in individual timed samples of arterial blood by
indicator must leave the system eventually, if the visual colorimetry. The advent of transmission
products of Q and C (t) dt are summated by oximetry and its quantification by Matthes (1936)
mathematical integration, this must equal the led to the development of the oximeter to deter-
amount (M) of indicator injected. mine the change in optical density of blood by
addition of dye (Wood, 1950). This application
is based on the Lambert-Beer Law:
M=<> c (t) dt [vi]
I = I 0 e - Ecd . . . . [viii]
Rearranged we thus have an expression for volume where: I and I o are the amounts of transmitted
displacement (flow) which is the basis of all the and impingent light respectively, E is the extinc-
dilution methods involving sudden injection of tion coefficient, c the concentration of the light
indicator: transmitting fluid, and d is the layer thickness
M of the light pathway. Converting and taking
. . . . [vii] logarithms of both sides of [viii]:
log, (I/I 0 ) = E.c.d. . . . [ix]
Since E and d are constant for any given system,
and Io can be kept constant, it follows that the
The integral term 1 c (t) dt is the product of amount of transmitted light is proportional to
o-J the concentration of the specific transmitting
concentration and time, and thus represents the medium. The amount of light is detected by
area beneath the curve in figure lc. photosensitive cells whose current output is thus
This principle may be applied to the measure- proportional to the concentration of dye in blood.
ment of cardiac output using a sudden injection Choice of dye. Most of the dyes which have
of a suitable indicator. The criteria for such an been introduced for this purpose have been
indicator used in man are that it should be non- "blue" dyes which have their peak spectral
toxic even in large doses, that it should not diffuse absorption in the red region of the visual
out of the intravascular space during its first spectrum, that is between 600 and 700 nano-
circulation, that a known quantity can be intro- metres (nm) wavelength. In this range there is
duced into the venous segment, and that its a marked difference between the spectral absorp-
concentration downstream from the mixing tion of oxyhaemoglobin (HbO2) and that of
THE MEASUREMENT OF CARDIAC OUTPUT 755
FIG. 2
Spectral absorption of oxygenated and reduced haemo-
globin, and the peak absorption wavelengths of some
dyes used in the measurement of cardiac output.
tance between injection and detection, the greater may be withdrawn at a constant rate, and a filter
the chance that significant recirculation occurs and double photocell assembly (fig. 3g). This
before the downslope of the first dye curve is type of densitometer (XC-302, Waters Co.,
complete, particularly at low cardiac outputs Rochester, Minn., U.S.A.) is dichromatic, in that
(Oriol, Sekelj and McGregor, 1967) and in the transmitted light is split into two beams, one
patients with chronic lung disease (Oriol, of specifically 805 nm, and the other containing
Anthonisen and McGregor, 1968). To obtain the full light spectrum emitted by the lamp. The
consistent dosage with repeated injection, a self- outputs of the two photocells are balanced to
loading syringe with an adjustable stop should give zero current when blood is withdrawn
be used (fig. 3) to displace dye through a catheter through the cuvette prior to dye injection. The
filled with the same dye solution. The dose may extravascular circuit between the blood vessel used
be predetermined and checked by weighing for sampling and the cuvette densitometer must
aliquots of ejected fluid. be kept to an absolute minimum in order to avoid
Detection of dye. The photoelectric device com- catheter distortion effects (Scheel, Langill and
monly used for detecting the change in optical Millhorn, 1966), but if these are unavoidable, an
density of blood is a cuvette densitometer which on-line analogue electronic device may be used
consists of a variable light source, a light path- to correct the dye curve according to the physical
way through which blood from an arterial source characteristics of the system (Melbin, 1967).
100
50-
2.303
C 3 6 9 12 time in sees.
12 18 time in sees.
FIG. 4
Dye dilution curve obtained after injection of 3.5 mg Indocyanine Green into human pulmonary
artery, sampling from aortic root (left).
Replotting of the downslops of the same curve on semi-logarithmic paper (right), with method
of estimating the decay constant of the exponential function.
THE MEASUREMENT OF CARDIAC OUTPUT 757
Analysis of dye curves. Figure 4 shows a con- although potentially inaccurate, is the method
centration/time curve recorded from a Waters commonly used. Dynamic calibration is achieved
XC-302 densitometer and amplifier and inscribed by injecting a known mass of dye (ML) into the
on a potentiometric chart recorder (Model M.R., subject's blood withdrawn through a mixing loop
E. H. Sargent & Co., Chicago, 111., U.S.A.). The (fig. 3) at a constant rate (QL), thus inscribing a
curve has the acceptable criteria of a flat stable non-recirculating dye curve having a known area
baseline before and after injection of dye, a (AL). Thus from the mixing loop: QL = M L / A L .
smooth contour including a sharp peak, and the When a known mass of dye (MP) is injected into
obvious recirculation peak occurs after the down- the patient having an unknown cardiac output
slope has fallen below 20 psr cent of the peak (QP) and using the same system a dye curve is
height of the curve. inscribed having an area (AP), then the ratio of
The methods available for estimating the area the flows
under the inscribed dye curve are numerous, and QP/QL=MP.AJML.AP. . . [x]
have been assessed and their accuracy defined by (Shinebourne, Fleming and Hamer, 1967)
Kelman (1965). The method described below has
the merit not only of accuracy in determining this Since QL, ML, M P , AL are constant, the unknown
area but also of being quick and simple. Measur- cardiac output can be calculated from the above
ing the area under a function such as that in expression. This relationship is particularly useful
figure lc is relatively simple, but the area under if the relevant dye curve areas can be calculated
the curve in figure 4 is complicated by the recir- by an analogue computer (Hara and Bellville,
culation peak, the effect of which has to be 1963; Glassman, Bailiff and Herrera, 1967; Taylor
eliminated. This is achieved by replotting the et al., 1967).
downslope on semilogarithmic paper, thus pro- THERMODILUTION
ducing a function linear with time up to the
point of recirculation (Kinsman, Moore and The principle of thermodilution methods is
Hamilton, 1929). It has been traditional to identical to that described for dye dilution, the
extrapolate the line beyond this point to zero con- indicator being either hot or cold injected fluid,
centration and then transpose the relevant values and the sensor of temperature change being an
to the original plot before estimating the total area intravascular thermistor probe. Various techniques
under extrapolated curve. have been described in animals (Fegler, 1954;
The method of manual analysis of dye curves Evonuk et al., 1961; Hosie, 1962) and in man
is to divide the curve into two areas as in figure 4, (Branthwaite and Bradley, 1968). In this last
the dividing line being arbitrarily determined by method, a miniature cardiac catheter carrying a
the point C* which is the last point on the thermistor at its tip is floated into the pulmonary
originally inscribed curve which is included in artery, its location being determined by visualiza-
the exponential decay. This ordinate is used to tion of the pressure waveform at its tip (Bradley,
calculate the area A2 by the expression: A2 = C*/k, 1964). Saline or dextrose at room temperature is
where k is the decay constant of the previously injected through a separate catheter into the
determined exponential (Appendix I). The area right atrium, and the change of temperature in
under the preceding part of the curve (Aj) is the pulmonary artery is inscribed as a tempera-
determined by application of the trapezoid rule ture/time dilution curve. Cardiac output is calcu-
(Kelman, 1965) as in Appendix I. This method is lated from the expression in the footnote below.
particularly suitable for digital computerization, Branthwaite and Bradley (1968) found that this
either on a large multi-purpose computer, or a method agreed well with tie direct Fick method,
small desk-top computer (Wang Laboratories, V. D x . Sx . C T B - T I ) = Q . dT . t . D B . S B (1000/60)
Model 370, Tewksbury, Mass., U.S.A.) as used in [xi]
the author's laboratory. where: Q is the cardiac output, Dj, D B are the
Calibration. Static calibration of dye curves is densities, S r , SB the specific heats, and T x and T B the
temperatures of the injected fluid and blood respectively.
achieved by drawing blood containing known V is the volume of injected fluid, dT the mean tem-
dye concentrations through the densitometer, and perature change and t its duration.
758 BRITISH JOURNAL OF ANAESTHESIA
and stress that frequently repeated injections of of pressure in the region of the ascending aorta,
indicator are relatively innocuous and no blood it might seem that these methods would be ideal
sampling is required. for continuous measurement of stroke volume
and cardiac output in intact man. There has been
RADIOACTIVE TRACER DILUTION
a fairly general inability on the part of workers
(RADIOCARDIOGRAPHY)
other than the original authors to validate the
Continuous recording of radioactivity using methods, which accounts in some way for the
external counting apparatus has been used in an lack of acceptance in the clinical field, and the
attempt to avoid sampling of blood (Huff et al., number of alternative methods. The stringent
1955). The indicator used by these authors was requirements for fidelity in reproduction of the
radioiodinated (I131) human serum albumin (RISA) pressure waveform can now be more easily met,
injected intravenously and detected with a colli- and the application of on-line digital computation
mated beam scintillation counter placed over an to calculate stroke volumes on a beat-to-beat basis
intercostal space to one side of the sternum. This in real time, makes this "Philosopher's stone" of
application has been extended by Cournand and cardiovascular physiology almost tangible (Warner,
his colleagues (1960) who, using a highly volatile Gardner and Toronto, 1968; Kouchoukos et al.,
radioactive indicator (KrS5) injected in the right 1968). All these methods are empirical and the
atrium, obtained a dilution curve for the right computed values of stroke volume are in arbitrary
heart alone, and by injection of RISA into the units which have to be multiplied by an appro-
pulmonary artery, were able to obtain a similar priate proportionality constant determined from
curve for the left ventricle. The limitations of simultaneous dye dilution measurements.
radioactive tracer methods in general are mainly
concerned with the calibration techniques, the APPENDIX I
inadvisability of repeated estimations and the Calculation of area under inscribed dye-dilution curve
radiation hazard, particularly to the thyroid when in figure 4.
I 131 labelled indicators are used. Area A, is calculated by the trapezoid rule (Kelman,
1965):
MEASUREMENT OF FLOW VELOCITY fc=n fc=n _
Methods which measure mean flow velocity in c(t)dt= (c,+c2 + c, + ...+ ^ ) At
either pulmonary artery or the ascending aorta c=o-) c=oJ L
Oriol, A., Sekelj, P., and McGregor, M. (1967). Limi- Taylor, S. H., McDonald, H. R., Robinson, M. C , and
tations of indicator-dilution methods in experi- Sapru, R. B. (1967). Computers in cardiovascular
mental shock. J. appl. Physiol., 23, 605. investigation. Brit. Heart J., 29, 352.
Thorp, J. M (1959). Properties and biological
Anthonisen, N., and McGregor, M. (1968). behaviour of Coomassie blue. Brit. Heart J., 21,
Limitations of indicator dilution methods in esti- 492.
mation of cardiac output in chronic lung disease. Visscher, M. B., and Johnson, J. A. (1953). Fick prin-
Amer. Heart J., 75, 589. ciple: analysts of potential errors in its conven-
Prime, F. J., and Gray, T. C. (1952). Difficulties in the tional application. J appl. Physiol., 5, 635.
application of Fick principle to determine cardiac Warner, H. R., Swan, H. J. C , Connolly, D., Tomp-
output in anesthesia. Curr. Res. Anesth., 31, 347. kins, R. G., and Wood, E. H. (1953). Quantitation
of beat-to-beat changes in stroke volume from the
Remington, J. W., Hamilton, W. F., and Dow, P. aortic pulse contour. J. appl. Physiol., 5, 495.
(1945). Some difficulties involved in the prediction Gardner, R. M., and Toronto, A. F. (1968).
of the stroke volume from pulse wave velocity. Computer-based monitoring of cardiovascular
Amer. J. Physiol., 144, 536. functions in post-operative patients. Circulation,
Scheel, K. W., Langill, A. W., and Millhorn, H. T. jr. 37-38, Suppl. II, 68
Womersley, J. R. (1955). Method for the calculation of
(1966). Correction of catheter distortion effects on
mean transit time-dye-dilution method. J. appl. velocity, rate of flow and viscous drag in arteries
when the pressure gradient is known. J. Physiol.
Physiol, 21, 1637. (Lond), 127, 553.
Shincbourne, E., Fleming, J., and Hamer, J. (1967). Wood, E. H. (1950). Special instrumentation problems
Calibration of indicator dilution curves in man by encountered in physiological research concerning
the dynamic method. Brit. Heart J., 29, 920. the heart and circulation in man. Science, 112, 717.
Zierler, K. L. (1962). Circulation times and the theory
Stewart, G. N. (1897). Researches on the circulation of indicator-dilution methods for determining
time and on the influences which affect it. IV: blood flow and volume; in Handbook of Physio-
The output of the heart. J. Physiol. (JLond.), 22, logy: Circulation, Sect. 2, Vol. I, Chap. 18, pp.
159. 585-615. Washington, D.C.: Amer. Physiol. Soc.
Applications are invited by the Royal Society of Medicine, Section of Anaesthetics, for
a prize of £50 provided by Messrs. May & Baker Ltd., for a paper written by a medical
practitioner of Senior Registrar or Registrar status, holding an appointment in anaes-
thesia in a department or hospital, or in the armed forces of the Commonwealth or of
the Republic of South Africa or Eire. Fellowship of the Royal Society of Medicine is
not necessary for entry. The subject will be of the author's choice, but must be connected
with anaesthesia. All papers for the 1970 award must be submitted in triplicate oy
1 January, 1970.