Pflfigers Archiv
PfIiigers Arct:. 375, 2t3-217 (1978)
EuropeanJournal of Physiology 9 by Springer-Verlag 1978
A Non-Invasive Determination of Lung Perfusion Compared with the Direct Fick Method A a r t Z w a r t 1, Jan M. B o g a a r d 2, Jos R. C. Jansen 2, a n d A d r i a a n Versprille 2 ] Institute of Medical Physics TNO, Department of Cardiovascular Physics, 45, Da Costakade, Utrecht 2 Pathophysiological Laboratory, Department of Pulmonary Diseases, University HospitaI Dijkzigt, Rotterdam, The Netherlands
In 5 y o u n g pigs ( 7 - 9 kg each) d a t a on effective lung p e r f u s i o n were o b t a i n e d using a sinusoidal forcing function in the inspired h a l o t h a n e c o n c e n t r a t i o n . These d a t a were c o m p a r e d with the c a r d i a c o u t p u t m e a s u r e d by the direct F i c k m e t h o d for oxygen, c o r r e c t e d for v e n o u s a d m i x t u r e . T o p r o d u c e different levels o f c a r d i a c o u t p u t d u r i n g each e x p e r i m e n t the r e s p i r a t o r y a n d c i r c u l a t o r y conditions were changed. F o r the 5 e x p e r i m e n t s t a k e n together, the m e a n o f the ratios between the noninvasively o b t a i n e d effective lung p e r f u s i o n a n d the venous a d m i x t u r e c o r r e c t e d F i c k d a t a was 1.01 (SD 0.14, n = 55) with r = 0.92. Abstract.
Key words: L u n g p e r f u s i o n - N o n - i n v a s i v e techniques - Inert gas techniques.
Riley a n d C o u r n a n d [9]. This m o d e l consists o f a d e a d space c o m p a r t m e n t , a h o m o g e n e o u s a l v e o l a r c o m p a r t m e n t a n d a lung shunt, H e n c e the lung perfusion, which is n o n - i n v a s i v e l y d e t e r m i n e d , is the p e r f u s i o n o f this alveolar c o m p a r t m e n t (QA). As an alveolar a m p l i t u d e response technique is used, we d e n o t e this p e r f u s i o n as Qa ( A A R T ) . This investigation was carried o u t d u r i n g a current research p r o g r a m investigating the c i r c u l a t o r y effects o f positive e n d - e x p i r a t o r y pressure (PEEP). In this p r o g r a m the direct "Eick m e t h o d for oxygen was r o u t i n e l y used to d e t e r m i n e c a r d i a c o u t p u t . The n o n invasive technique c o u l d be a d d e d w i t h o u t c h a n g i n g the e x p e r i m e n t a l p r o t o c o l .
Methods
An#rials and Preparation_ Five pigs, 5 - 7 weeks old, ranging in weight Introduction
N o n - i n v a s i v e , q u a n t i t a t i v e m e t h o d s to o b t a i n card i o r e s p i r a t o r y variables are o f g r e a t i m p o r t a n c e , n o t only for p h y s i o l o g i c a l studies, b u t also in the clinical fields o f p a t i e n t m o n i t o r i n g , intensive care, a n d screening p r o g r a m s . In the past, several techniques to m e a sure p u l m o n a r y b l o o d flow using soluble gas methods, have been p r o p o s e d . N o a c c e p t a b l e way to correct for the influence o f the venous c o n c e n t r a t i o n was given in these m e t h o d s , as discussed b y Butler [2]. Recently Z w a r t et al. [13,14] r e p o r t e d a n o n - i n v a s i v e technique to o b t a i n the v e n t i l a t i o n - p e r f u s i o n ratio from the endexpired h a l o t h a n e tension, using a sinusoidal forcing function in the inspired tension at a harmless level o f 0.02 v o l u m e ~ . T h e y s h o w e d t h a t with a sinusoidal forcing function the influence o f i n d i c a t o r gas in the venous b l o o d can be neglected. The m e t h o d to o b t a i n the lung p e r f u s i o n f r o m the v e n t i l a t i o n - p e r f u s i o n r a t i o is based on the 3 c o m p a r t m e n t m o d e l as described by
between 7 and 9 kg were ventilated through a tracheal cannula at a frequency of 10 rain-1 with intermittent or continuous positive pressure (IPPV and CPPV respectively) under pentobarbital anesthesia (initial dose 30 mg kg- ] intraperitoneally). The animals were heparinised (10000 IU) as soon as a catheter for measuring blood pressure was introduced. A continuous infusion of heparin sodium (300 IU kg- 1 h 1) and of pentobarbital sodium (7.5 nag kg 1 h- 1) into the right femoral vein was started about 1 - 1.5 h after the initial pentobarbital dose and was maintained until the end of the experiment. Except in situations of hyper- and hypoventilation the ventilatory volume (V~) was adjusted to the endexpiratory CO 2 fraction (FEEcO2), which was measured during the period of spontaneous breathing before the artificial ventilation, In the calculations F~Eco~was assumed to be equal to the alveolar COz fraction (FAco_,). The animals were ventilated with a piston pump (BraunMelsungen). The inflation lasted 44 ~ of the cycle period and was followed by a spontaneous expiration against a water-seal from 0 up to 1.18 kPa (12 cm H20). Suppression of spontaneous breathing during artificial ventilation was achieved with intermittent doses of 0.2 mg tubocurarine intravenously. In one experiment the thorax was opened by rnidsternal cleavage and perforation of pericardium and pleura. FAc% was measured with a CO z analyscr (Beckman, LB2) by continuous sampling of gas from the nose during spontaneous breathing and from the tracheal cannula during artificial ventilation,
0031-6768/78/0375/0213/5 1.00
214
Pfliigers Arch. 375 (1978)
at a rate of about 100 ml m i n - ~. In the latter case the gas was led back into the expiration line in order to avoid lung volume changes during closure of the expiratory valve. Theintra-tracheal(P0 and intra-oesophageal pressure (P,,~) were measured with pressure transducers (HP model 270), Expiratory (~'E) and inspiratory (V,) flow were measured with a pneumotachometer (Fleisch model O, Godart) built into the tracheal cannula. Blood pressure catheters were introduced into the right atrium (P~) and pulmonary artery (Pp.) through the right external jugular vein and into the aorta (P.o) through the right femoral artery. The pressure was measured with Statham lransducers (model PD23e), ECG was derived from two needle elect vodes under the skin o f the right foreleg and the abdominal wall ncur the sternum. Blood gases, pH, Hb-concentration and oxygen saturation (Sao) were analysed intermittently with an automatic blood gas analyser (Radiometer, model A B L ]) and a CO-oximeter (Instr. Laboratories, model IL182) after sampling of 1.5 ml venous and arterial blood from the pulmonary artery and the aorta.
Lung Perfusion. Lurig perfusion ( ~ ) was measured by the direct Fick method for oxygen [61. A description of the possible systematic errors with this method is given a m o n g others by Stow [11]. Mixed expired air was obtained from a mixing box with a volume of 400 ml, placed in the expiratory line of the pump. In the calculation of the oxygen consumption a correction was made for the difference in volume of in- and expired air [3]. Oxygen content of blood from the pulmonary artery and the aorta was calculated from the directly measured oxygen saturation and Hb values, and from the physically dissolved oxygen as determined by the Po~ values. As oxygen binding capacity the value 1.39 ml O z per g Hb was used. The alveolar lung perfusion ~)A (Fick) was calculated from Oeby multiplying this value with 1-Fs, were Fs is the fraction of the venous admixture (shunt fraction). Fs was calculated from the arterial, the mixed venous and the end capillary oxygen content. The end capillary oxygen tension (/'co:) was assumed to be equal to the ideal alveolar oxygen tension and calculated with the alveolar gas equation [12]. The end capillary oxygen saturation was determined from P~o, with help of the Severinghaus n o m o g r a m for h u m a n blood assuming p H and base excess to equal those of arterial blood. Alveolar Amplitude Response Technique. Two variants of this technique have been described by Zwart et al. [13,14]. Both techniques are based on exactly the same model and hence they are fully compatible. In this study the technique described in Ref. [13] was used. The lung is described with the Riley-Cournand model [9] and consists of a dead space compartment, a homogeneous alveolar compartment and venous admixture. The mass balance for the gas exchange in the alveolar compartment (the Fick principle) yields:
Fig. 1. Actual recording of the inspired and expired halothane tension which is made to vary in an alternating fashion by drawing a continuous sample of 4 ml/min from.the m.outh piece. P~, PA, T and zt t are used to calculate the ratio of )~Q to V. For explanation see text
(1) can be neglected if halothane is used as tracer gas. In the further derivations it was assumed that these conditions also hold for the pigs in this study and that the term Pv in Eq. (1) can be neglected. Rearranging Eq. (1) then yields:
with VA . +V ~'QA - ~ and using the Fourier transform eq. (2) yields:
PA (1 q- icoz) =
VA ' PI v~+~OA .
or
Pa/P~ = (1 + ).QA/I)A) 1. (1 + icoz) -1 i=
(
(3)
1) 1/2 .
The ratio of the variation in the end-expired tension to the variation in the inspired tension then becomes
IPAIIIPII
= (1 + 2QA/I)A) -x (1 + COZY2)-1/2.
(4)
Because tg~ = --cot eq. (4) can also be written as
dPa
IPAI/IPll = COS ~ (1 -- ;tQA/VA)-1
(5)
dt in which : P~ = the tension of the tracer in the inspired mixture PA = the tension of the tracer in the alveolar compartment P~ = the tension of the tracer in the mixed venous blood V = total absorbing volume of the alveolar compartment (alveolar air + lung tissue + blood) (1) CA = alveolar ventilation (1/min) QA = alveolar perfusion (1/min) 2 = blood gas partition coefficient of the tracer. If the inspired tension is changed sinusoidally with angular c0. in frequency co [P1(t) = Pi sin co t], then PA (0 = Pa sin (co t which ~ represents a phase shift. Zwart et al. [14] have described in detail that under normal conditions (standard m a n 75 kg) P~ in Eq.
The terms coz and cos c~ are related to the influence of the absorbing capacity of the lung. The technique using Eq. (5) was used during this investigation. In Figure 1 is shown how the ratio Qa/I)A can be determined when IPAI and IPll can be measured directly and c~ = 360 x zlt/T. In this investigation halothane was used as tracer. The inspired tension was varied in a sinusoidal fashion around a m e a n tension corresponding to 0.02 volume ~o. The halothane tension was measured with an analyzer as described by Cramer and Trimbos [4]. This analyzer gave a step response with a time constant o f 0.2 s at a continuous sample rate of 4 ml/min. The blood gas partition coefficient ()~) of halothane was assumed to be 2.3. The alveolar ventilation (VA) was obtained from the total ventilation (Fz) using the Bohr equation. The lung perfusion QA was calculated from PA and the ratio QA/NA from Eq. (5).
A. Zwart et al.: Non-Invasive Determination of Lung Perfusion
Results The relationship between the individual values o f the simultaneous measurements o f Qa is presented in Figure 2. In Table 1 a specification o f the ventilatory and circulatory conditions for each experiment is given together with the statistical properties o f the data. In 4 out o f 5 experiments P E E P was the independent variable. In one o f these experiments (7602) the last 4 determinations were obtained with open thorax. In one experiment (7607) the effects of P E E P were not studied because o f severe hypoxia occurring early in
(~A(AART} 04F~ck) t3 x
12
x
o _ _ _ _ _
o x
x--'~-
x
1.1
o &
1.0
9
o
o
9 9
09
x
x
9
oOe 9 •
e
O
0.8
215 the experiment. Conditions were then changed by hyper- and hypoventilation and hyper- and hypovolaemia. In 2 experiments (7603 and 7607) a change o f only 40 % in lung perfusion was observed. Also in the other experiments the range was limited. Therefore, the use o f regression lines o f the functional relationship between the two lung perfusion estimates in the individual experiments does not give valuable statistical information. We used the mean o f the quotients between the corresponding individual data points, this being a meaningful statistical parameter. The composite standard deviation o f the individual quotients, either derived f r o m the variance o f the c o m p o n e n t s or calculated f r o m the pooled data, lead to virtually the same numerical value. Therefore, the results o f all groups were lumped, although analysis o f variance showed significant differences between the g r o u p means (P > 0.05). The venous admixture varied between 0.00 and 0.15 except for the open thorax situation, during which the venous admixture increased to 0.25.
9 9 r
oe
a a
Discussion
0.7
{~A(Fick)m/Vs
Fig.2. Comparison of lung perfusion as obtained with the alveolar amplitude response technique Oa (AART) with lung perfusion as simultaneously obtained using the direct Fick method for oxygen. Data were obtained during 5 experiments. The dashed lines show the ,+ I SD, the dotted dashed lines show the _+ 2 SD. Further statistical information is given in Table 1. Experiment codes are as follows: 9 7602, 9 7603, 9 7604, ~ 7606, x 7607
Factors influencing the accuracy o f the measurements are discussed in the following 3 sections : correction for venous admixture, variability o f the blood gas partition coefficient, simplifications o f the lung model.
Correction for Venous Admixture The alveolar amplitude response technique measures the part o f the cardiac o u t p u t which is involved in the
Table 1. Ventilatory and circulatory conditions and statistical properties of the data Experiment code
7602 7603 7604 7606
Conditions
Correlation coefficient
Qa (AART) .....
Number of determinations
QA (AART)/Qa (Fick) mean
sd
Closed thorax, open thorax PEEP 0-l.18 kPa (0-12 cm H20) Closed thorax PEEP 0-0.98 kPa (0-10 cm H 2 0 )
10
1.06
0.09
0.93
2.5
10
0.91
0.06
0.88
1.,4
Closed thorax PEEP 0-0.98 kPa (0-10 cm H20)
12
0.94
0.13
0.85
1.9
Closed thorax PEEP
]0
0.96
0.12
0.68
1.4
13
1,11
0.14
0.82
2.0
55
1.01
0.14
0.92
3.9
QA (AART)m,,~
0-0.98 kPa (0-10 cm H 2 0 ) 7607
7602- 7607
Closed thorax/hypo-, hyperventilation/hypo-, hypervolaemia
216
gas exchange. In order to be able to compare the data obtained with this technique, (~A (AART), with cardiac output measurements, QL (Fick), a correction for the venous admixture has to be made to obtain (~A (Fick). This correction adds an extra random error, and possibly also systematic error, to the comparison of the ~)A values obtained with the two methods. In order to minimize the systematic error the following procedure was used. The model of Riley and Cournand [9] postulates an end-capillary oxygen tension which is equal to the ideal alveolar oxygen tension, obtained from the alveolar gas equation. The end-capillary oxygen saturation was calculated from this ideal alveolar oxygen tension with the Severinghaus nomogram for human blood. Bartels and Harms [1] have shown that the oxygen dissociation curve of pig blood differs considerably from that of human blood. In the region of 12.0-14.6 kPa ( 9 0 - 110 mm Hg) which was found during this investigation, there is only a small influence of this difference. This can be illustrated with a representative example. Assuming Sao~ = 95 ~ , Svo_, = 60~o, pH~ = 7.40, T = 38~ PcQ = 13.3 kPa (100 mm Hg) and Hb = 6.21 mmol/1 (10.0 g- dl 1), an Fs of 0.068 would be obtained with the saturation curve of Bartels instead of 0.073 with the Severinghaus homogram. Another reason not to use Bartel's data was that the number of data in his communication in the range of 12.0-14.6 kPa was only four. An estimate of the influence of errors in the venous admixture on the overall standard deviation is difficult to make. Comparison of QA (AART) with QL (Fick) resulted in the same standard deviation as that of Qa (AART) vs. ~)A (Fick). The correlation coefficient between the estimates for venous admixture and the ratios of QA (AART) and QA (Eick) values was 0.01 for the 55 experiments..Thus, the estimate of the alveolar lung perfusion by QA (AART) is independent of the level of this flow as well as of the amount of venous admixture. The largest correction of 25 ~ for venous admixture was found with IPPV in the open thorax situation. This value is in agreement with previously published data by Zwart et al. [13] who found a ratio of 0.7 of QA (AART) and the flow through the ascending aorta determined with an electromagnetic flow probe.
Variability of the Blood Gas Partition Coefficient The blood gas partition coefficient of halothane was assumed to be 2.3. Mapleson et al. [8] have shown that the partition coefficient of halothane for different species may vary over a considerable range (2.3 for humans, 3.2 for dogs). Thus, assuming a value of 2.3 may introduce a systematic error. Moreover, within one species an individual variation in the partition coefficient of halothane with a standard deviation of
Pfliigers Arch. 375 (1978)
about 10 ~ has been reported by Ellis and Stoelting [5], Gibbs et al. [7], Mapleson et al. [8] and Steward et al. [10]. The individual variation in the partition coefficient will also add a systematic error to the mean of the ratio QA (AART) and QA (Fick) in each experiment. Therefore, it might be assumed that combination of the different experiments results in an increase of the standard deviation and very probably in a decrease of the corresponding correlation coefficients of the combined data. Table 1 shows that the ratio QA (AART)/QA (Fick) varies around unity with variations in the mean of the separate experiments which are in agreement with the above-mentioned individual variations in the blood gas partition coefficients of halothane. The influence of the variation in blood gas partition coefficients could be avoided by determination of the individual blood gas partition coefficients. The method then looses its non-invasive character. This variation can also be avoided by the choice of another tracer agent of which the solubility is less dependent on the proteins and lipids of the blood than halothane. The use of acetylene with its low lipid solubility shows a very small variation in the blood gas partition coefficient (), = 0.96 ___ 0.02). Zwart et al. [14] suggested that the use of tracers with a high lipid solubility was preferable because this would result in a larger time constant of the body compartments (v.i.), which makes it possible to neglect the venous return. Comparison of simultaneous measurements of QA (AART) with acetylene and halothane, with measurement of the solubility of both tracers, in a recent study (L@endijk, unpublished data) have not shown evidence of a larger influence of venous return in the case of acetylene.
Simplifications of the Lung Model The lung was described with the model of Riley and Cournand, in which the pulsatile character of both the ventilation and perfusion is neglected and the gas exchanging parts of the lung are considered to be homogeneous. The influence of the venous return was neglected. The period of the sinusoidal change in the inspired tension of the tracer has to be large enough to neglect the pulsatile character of the respiration, but should be short enough to neglect the pulsatile character of the respiration, but should be short enough to neglect the influence of the venous return, which can be estimated as follows. The steady state of Eq. (1) gives
J
A. Zwart et al. : Non-Invasive Determination of Lung Perfusion
217
F o r sinusoidaI c h a n g i n g tensions this e q u a t i o n becomes
the c a r d i a c o u t p u t which is involved in gas exchange in a h o m o g e n e o u s lung.
Q=([PI]-IPA])coscz (
Acknowledgement.A. van Dieren, A. Drop and J. J. Schreuder are
tPa
IPA[ ]PAl -- [P~P sin
)2
1.(7)
fi
Hence Eq, (7) shows t h a t the influence o f the v e n o u s r e t u r n is d e p e n d e n t on the v a r i a t i o n o f the tension in the m i x e d venous o f b l o o d a n d a p h a s e shift ft. The p h a s e shift fi is d e t e r m i n e d by the time c o n s t a n t o f the b o d y c o m p a r t m e n t s a n d the recirculation time o f the b l o o d . Pv is d e t e r m i n e d m a i n l y by the highly perfused b o d y c o m p a r t m e n t s (kidney, a d r e n a l glands) which have a time c o n s t a n t o f a b o u t 90 s a n d which receive a p p r o x i m a t e l y 30 ~ o f the total c a r d i a c o u t p u t . F o r a sinusoidal change with a p e r i o d o f 3 rain we have an a n g u l a r frequency co = 2 ~z/3. Both effects result in [P~,] = 0.3[PA[ (1 § CO2 "C2) 1/2 = 0.09[PAl ' T h e e r r o r i n t r o d u c e d by the v a r i a t i o n o f the v e n o u s r e t u r n is then 9 ~ m u l t i p l i e d by sin ft. The errors resulting f r o m i n h o m o g e n e i t y o f the lung consist o f 2 factors : the v a r i a t i o n o f the time c o n s t a n t in different lung regions a n d the v a r i a t i o n o f the Q / l ? in different lung regions. The v a r i a t i o n o f the time c o n s t a n t in different lung regions can be neglected for lungs w i t h o u t o b s t r u c t i v e lung disease. I n h o m o g e n e i t y o f the v e n t i l a t i o n perfusion d i s t r i b u t i o n m a y influence the m e a s u r e m e n t s . The e r r o r in QA/I?A resulting f r o m a functional d e a d space t o g e t h e r with a h o m o g e n e o u s alveolar c o m p a r t m e n t will be fully c o m p e n s a t e d by the error m a d e in the e s t i m a t i o n o f 1?A with the B o h r formula. O t h e r types o f i n h o m o g e n e i t y will i n t r o d u c e errors in the ~)A/I'~Awhich are n o t fully c o m p e n s a t e d by the e r r o r in the estimate o f 1~.
Conclusion The a l v e o l a r a m p l i t u d e response technique offers the possibility to o b t a i n the lung perfusion in situations w i t h o u t o b s t r u c t i v e lung disease. The s t a n d a r d deviation which was f o u n d in this study is o f the same o r d e r as is generally f o u n d if two i n d e p e n d e n t invasive c a r d i a c o u t p u t m e a s u r e m e n t s are c o m p a r e d . W e have to keep in m i n d that this n o n - i n v a s i v e technique only m e a s u r e s lung p e r f u s i o n or, in o t h e r words, t h a t p a r t o f
gratefully acknowledged for their assistance and R. van Strik of the Dept. of Biostatics, Erasmus University, Rotterdam, for his statistical advice. S.C.M. L@endijk from the Dept. of Physiology of the State University, Utrecht, is acknowledged for the information on the comparison of acetylene and halothane.
References 1. Bartels, H., Harms, H.: Sauerstoff-Dissoziationskurven des Blutes yon Sfiugetieren. Pflfigers Arch. 268, 334-365 (1959) 2. Butler, J.: Measurement of cardiac output using soluble gases. In : Handbook of Physiology, Section 3 : Respiration, Vol. II, Ch. 61 (1965) 3. Carpenter, T. M.: Tables, factors and formulas for computing respiratory exchange and biological transformatious of energy. Carnegie Institution of Washington, Publication 3036, Washington D.C. 1964 4. Cramers, C. A., Trimbos, H. F.: Development of an on-line analyzer for organic anesthetics in inspiratory and-tidal gases. J. Chromatog. 119, 71 - 84 (/976) 5. Ellis, D. E., Stoelting, R. K. : Individual variations in flurocene, halothane and methoxyflurane blood gas partition coefficients and the effect of anemia. Anesthesiology 42-6, 748- 750 (1975) 6. Fick, A.: fiber die Messung des Blutquantums in den Herzventrikeln. Sitzungsberichte der physikalisch-medimediziniscben Gesellschaft zu W/irzburg, 16 (1870) 7. Gibbs, C. P., Munson, E. S., Tham. M. K. : Anesthetic solubility coefficients for maternal and fetal blood. Anesthesiology 43-1, i00-103 (1975) 8. Mapleson, W. W., Allot, P. R., Steward, A. : The variability of partition coefficients for halothane in the rabbit. Br. J. Anesth. 44, 656-661 (1972) 9. Riley, R. L., Cournand, A. : Ideal alveolar air and the analysis of ventilation-perfusion relationships in the lung. J. Appl. Physiol. 1, 825-847 (1949) 10. Steward, A , Allott, P. R., CowIes, A. L., Mapleson, W. W.: Solubility coefficients for inhaled anesthetics for water, oil and biological media. Br. J. Anesth. 45, 282 293 (1973) 11. Stow, R. W. : Systematic errors in flow determinations by the Fick method. Minn. Med. 37, 30 (1954) 12. West, J B.: Ventilation/blood flow and gas exchange. Oxford: Blackwell Scientific Publications 1972 13. Zwart, A., van Dieren, A. : A simple and non-invasive method to determine the ventilation-perfusion ratio of the lung and the effective lung perfusion. Acta Anaesth. Belg. 26, Suppl. 53 - 64 (1975) 14. Zwart, A., Seagrave, R. C., van Dieren, A.: Ventilationperfusion ratio obtained by a non-invasive frequency response technique. J. Appl. Physiol. 41,419-424 (1976)
ReceivedMarch1, 1978
PfIiigers Arct:. 375, 2t3-217 (1978)
EuropeanJournal of Physiology 9 by Springer-Verlag 1978
A Non-Invasive Determination of Lung Perfusion Compared with the Direct Fick Method A a r t Z w a r t 1, Jan M. B o g a a r d 2, Jos R. C. Jansen 2, a n d A d r i a a n Versprille 2 ] Institute of Medical Physics TNO, Department of Cardiovascular Physics, 45, Da Costakade, Utrecht 2 Pathophysiological Laboratory, Department of Pulmonary Diseases, University HospitaI Dijkzigt, Rotterdam, The Netherlands
In 5 y o u n g pigs ( 7 - 9 kg each) d a t a on effective lung p e r f u s i o n were o b t a i n e d using a sinusoidal forcing function in the inspired h a l o t h a n e c o n c e n t r a t i o n . These d a t a were c o m p a r e d with the c a r d i a c o u t p u t m e a s u r e d by the direct F i c k m e t h o d for oxygen, c o r r e c t e d for v e n o u s a d m i x t u r e . T o p r o d u c e different levels o f c a r d i a c o u t p u t d u r i n g each e x p e r i m e n t the r e s p i r a t o r y a n d c i r c u l a t o r y conditions were changed. F o r the 5 e x p e r i m e n t s t a k e n together, the m e a n o f the ratios between the noninvasively o b t a i n e d effective lung p e r f u s i o n a n d the venous a d m i x t u r e c o r r e c t e d F i c k d a t a was 1.01 (SD 0.14, n = 55) with r = 0.92. Abstract.
Key words: L u n g p e r f u s i o n - N o n - i n v a s i v e techniques - Inert gas techniques.
Riley a n d C o u r n a n d [9]. This m o d e l consists o f a d e a d space c o m p a r t m e n t , a h o m o g e n e o u s a l v e o l a r c o m p a r t m e n t a n d a lung shunt, H e n c e the lung perfusion, which is n o n - i n v a s i v e l y d e t e r m i n e d , is the p e r f u s i o n o f this alveolar c o m p a r t m e n t (QA). As an alveolar a m p l i t u d e response technique is used, we d e n o t e this p e r f u s i o n as Qa ( A A R T ) . This investigation was carried o u t d u r i n g a current research p r o g r a m investigating the c i r c u l a t o r y effects o f positive e n d - e x p i r a t o r y pressure (PEEP). In this p r o g r a m the direct "Eick m e t h o d for oxygen was r o u t i n e l y used to d e t e r m i n e c a r d i a c o u t p u t . The n o n invasive technique c o u l d be a d d e d w i t h o u t c h a n g i n g the e x p e r i m e n t a l p r o t o c o l .
Methods
An#rials and Preparation_ Five pigs, 5 - 7 weeks old, ranging in weight Introduction
N o n - i n v a s i v e , q u a n t i t a t i v e m e t h o d s to o b t a i n card i o r e s p i r a t o r y variables are o f g r e a t i m p o r t a n c e , n o t only for p h y s i o l o g i c a l studies, b u t also in the clinical fields o f p a t i e n t m o n i t o r i n g , intensive care, a n d screening p r o g r a m s . In the past, several techniques to m e a sure p u l m o n a r y b l o o d flow using soluble gas methods, have been p r o p o s e d . N o a c c e p t a b l e way to correct for the influence o f the venous c o n c e n t r a t i o n was given in these m e t h o d s , as discussed b y Butler [2]. Recently Z w a r t et al. [13,14] r e p o r t e d a n o n - i n v a s i v e technique to o b t a i n the v e n t i l a t i o n - p e r f u s i o n ratio from the endexpired h a l o t h a n e tension, using a sinusoidal forcing function in the inspired tension at a harmless level o f 0.02 v o l u m e ~ . T h e y s h o w e d t h a t with a sinusoidal forcing function the influence o f i n d i c a t o r gas in the venous b l o o d can be neglected. The m e t h o d to o b t a i n the lung p e r f u s i o n f r o m the v e n t i l a t i o n - p e r f u s i o n r a t i o is based on the 3 c o m p a r t m e n t m o d e l as described by
between 7 and 9 kg were ventilated through a tracheal cannula at a frequency of 10 rain-1 with intermittent or continuous positive pressure (IPPV and CPPV respectively) under pentobarbital anesthesia (initial dose 30 mg kg- ] intraperitoneally). The animals were heparinised (10000 IU) as soon as a catheter for measuring blood pressure was introduced. A continuous infusion of heparin sodium (300 IU kg- 1 h 1) and of pentobarbital sodium (7.5 nag kg 1 h- 1) into the right femoral vein was started about 1 - 1.5 h after the initial pentobarbital dose and was maintained until the end of the experiment. Except in situations of hyper- and hypoventilation the ventilatory volume (V~) was adjusted to the endexpiratory CO 2 fraction (FEEcO2), which was measured during the period of spontaneous breathing before the artificial ventilation, In the calculations F~Eco~was assumed to be equal to the alveolar COz fraction (FAco_,). The animals were ventilated with a piston pump (BraunMelsungen). The inflation lasted 44 ~ of the cycle period and was followed by a spontaneous expiration against a water-seal from 0 up to 1.18 kPa (12 cm H20). Suppression of spontaneous breathing during artificial ventilation was achieved with intermittent doses of 0.2 mg tubocurarine intravenously. In one experiment the thorax was opened by rnidsternal cleavage and perforation of pericardium and pleura. FAc% was measured with a CO z analyscr (Beckman, LB2) by continuous sampling of gas from the nose during spontaneous breathing and from the tracheal cannula during artificial ventilation,
0031-6768/78/0375/0213/5 1.00
214
Pfliigers Arch. 375 (1978)
at a rate of about 100 ml m i n - ~. In the latter case the gas was led back into the expiration line in order to avoid lung volume changes during closure of the expiratory valve. Theintra-tracheal(P0 and intra-oesophageal pressure (P,,~) were measured with pressure transducers (HP model 270), Expiratory (~'E) and inspiratory (V,) flow were measured with a pneumotachometer (Fleisch model O, Godart) built into the tracheal cannula. Blood pressure catheters were introduced into the right atrium (P~) and pulmonary artery (Pp.) through the right external jugular vein and into the aorta (P.o) through the right femoral artery. The pressure was measured with Statham lransducers (model PD23e), ECG was derived from two needle elect vodes under the skin o f the right foreleg and the abdominal wall ncur the sternum. Blood gases, pH, Hb-concentration and oxygen saturation (Sao) were analysed intermittently with an automatic blood gas analyser (Radiometer, model A B L ]) and a CO-oximeter (Instr. Laboratories, model IL182) after sampling of 1.5 ml venous and arterial blood from the pulmonary artery and the aorta.
Lung Perfusion. Lurig perfusion ( ~ ) was measured by the direct Fick method for oxygen [61. A description of the possible systematic errors with this method is given a m o n g others by Stow [11]. Mixed expired air was obtained from a mixing box with a volume of 400 ml, placed in the expiratory line of the pump. In the calculation of the oxygen consumption a correction was made for the difference in volume of in- and expired air [3]. Oxygen content of blood from the pulmonary artery and the aorta was calculated from the directly measured oxygen saturation and Hb values, and from the physically dissolved oxygen as determined by the Po~ values. As oxygen binding capacity the value 1.39 ml O z per g Hb was used. The alveolar lung perfusion ~)A (Fick) was calculated from Oeby multiplying this value with 1-Fs, were Fs is the fraction of the venous admixture (shunt fraction). Fs was calculated from the arterial, the mixed venous and the end capillary oxygen content. The end capillary oxygen tension (/'co:) was assumed to be equal to the ideal alveolar oxygen tension and calculated with the alveolar gas equation [12]. The end capillary oxygen saturation was determined from P~o, with help of the Severinghaus n o m o g r a m for h u m a n blood assuming p H and base excess to equal those of arterial blood. Alveolar Amplitude Response Technique. Two variants of this technique have been described by Zwart et al. [13,14]. Both techniques are based on exactly the same model and hence they are fully compatible. In this study the technique described in Ref. [13] was used. The lung is described with the Riley-Cournand model [9] and consists of a dead space compartment, a homogeneous alveolar compartment and venous admixture. The mass balance for the gas exchange in the alveolar compartment (the Fick principle) yields:
Fig. 1. Actual recording of the inspired and expired halothane tension which is made to vary in an alternating fashion by drawing a continuous sample of 4 ml/min from.the m.outh piece. P~, PA, T and zt t are used to calculate the ratio of )~Q to V. For explanation see text
(1) can be neglected if halothane is used as tracer gas. In the further derivations it was assumed that these conditions also hold for the pigs in this study and that the term Pv in Eq. (1) can be neglected. Rearranging Eq. (1) then yields:
with VA . +V ~'QA - ~ and using the Fourier transform eq. (2) yields:
PA (1 q- icoz) =
VA ' PI v~+~OA .
or
Pa/P~ = (1 + ).QA/I)A) 1. (1 + icoz) -1 i=
(
(3)
1) 1/2 .
The ratio of the variation in the end-expired tension to the variation in the inspired tension then becomes
IPAIIIPII
= (1 + 2QA/I)A) -x (1 + COZY2)-1/2.
(4)
Because tg~ = --cot eq. (4) can also be written as
dPa
IPAI/IPll = COS ~ (1 -- ;tQA/VA)-1
(5)
dt in which : P~ = the tension of the tracer in the inspired mixture PA = the tension of the tracer in the alveolar compartment P~ = the tension of the tracer in the mixed venous blood V = total absorbing volume of the alveolar compartment (alveolar air + lung tissue + blood) (1) CA = alveolar ventilation (1/min) QA = alveolar perfusion (1/min) 2 = blood gas partition coefficient of the tracer. If the inspired tension is changed sinusoidally with angular c0. in frequency co [P1(t) = Pi sin co t], then PA (0 = Pa sin (co t which ~ represents a phase shift. Zwart et al. [14] have described in detail that under normal conditions (standard m a n 75 kg) P~ in Eq.
The terms coz and cos c~ are related to the influence of the absorbing capacity of the lung. The technique using Eq. (5) was used during this investigation. In Figure 1 is shown how the ratio Qa/I)A can be determined when IPAI and IPll can be measured directly and c~ = 360 x zlt/T. In this investigation halothane was used as tracer. The inspired tension was varied in a sinusoidal fashion around a m e a n tension corresponding to 0.02 volume ~o. The halothane tension was measured with an analyzer as described by Cramer and Trimbos [4]. This analyzer gave a step response with a time constant o f 0.2 s at a continuous sample rate of 4 ml/min. The blood gas partition coefficient ()~) of halothane was assumed to be 2.3. The alveolar ventilation (VA) was obtained from the total ventilation (Fz) using the Bohr equation. The lung perfusion QA was calculated from PA and the ratio QA/NA from Eq. (5).
A. Zwart et al.: Non-Invasive Determination of Lung Perfusion
Results The relationship between the individual values o f the simultaneous measurements o f Qa is presented in Figure 2. In Table 1 a specification o f the ventilatory and circulatory conditions for each experiment is given together with the statistical properties o f the data. In 4 out o f 5 experiments P E E P was the independent variable. In one o f these experiments (7602) the last 4 determinations were obtained with open thorax. In one experiment (7607) the effects of P E E P were not studied because o f severe hypoxia occurring early in
(~A(AART} 04F~ck) t3 x
12
x
o _ _ _ _ _
o x
x--'~-
x
1.1
o &
1.0
9
o
o
9 9
09
x
x
9
oOe 9 •
e
O
0.8
215 the experiment. Conditions were then changed by hyper- and hypoventilation and hyper- and hypovolaemia. In 2 experiments (7603 and 7607) a change o f only 40 % in lung perfusion was observed. Also in the other experiments the range was limited. Therefore, the use o f regression lines o f the functional relationship between the two lung perfusion estimates in the individual experiments does not give valuable statistical information. We used the mean o f the quotients between the corresponding individual data points, this being a meaningful statistical parameter. The composite standard deviation o f the individual quotients, either derived f r o m the variance o f the c o m p o n e n t s or calculated f r o m the pooled data, lead to virtually the same numerical value. Therefore, the results o f all groups were lumped, although analysis o f variance showed significant differences between the g r o u p means (P > 0.05). The venous admixture varied between 0.00 and 0.15 except for the open thorax situation, during which the venous admixture increased to 0.25.
9 9 r
oe
a a
Discussion
0.7
{~A(Fick)m/Vs
Fig.2. Comparison of lung perfusion as obtained with the alveolar amplitude response technique Oa (AART) with lung perfusion as simultaneously obtained using the direct Fick method for oxygen. Data were obtained during 5 experiments. The dashed lines show the ,+ I SD, the dotted dashed lines show the _+ 2 SD. Further statistical information is given in Table 1. Experiment codes are as follows: 9 7602, 9 7603, 9 7604, ~ 7606, x 7607
Factors influencing the accuracy o f the measurements are discussed in the following 3 sections : correction for venous admixture, variability o f the blood gas partition coefficient, simplifications o f the lung model.
Correction for Venous Admixture The alveolar amplitude response technique measures the part o f the cardiac o u t p u t which is involved in the
Table 1. Ventilatory and circulatory conditions and statistical properties of the data Experiment code
7602 7603 7604 7606
Conditions
Correlation coefficient
Qa (AART) .....
Number of determinations
QA (AART)/Qa (Fick) mean
sd
Closed thorax, open thorax PEEP 0-l.18 kPa (0-12 cm H20) Closed thorax PEEP 0-0.98 kPa (0-10 cm H 2 0 )
10
1.06
0.09
0.93
2.5
10
0.91
0.06
0.88
1.,4
Closed thorax PEEP 0-0.98 kPa (0-10 cm H20)
12
0.94
0.13
0.85
1.9
Closed thorax PEEP
]0
0.96
0.12
0.68
1.4
13
1,11
0.14
0.82
2.0
55
1.01
0.14
0.92
3.9
QA (AART)m,,~
0-0.98 kPa (0-10 cm H 2 0 ) 7607
7602- 7607
Closed thorax/hypo-, hyperventilation/hypo-, hypervolaemia
216
gas exchange. In order to be able to compare the data obtained with this technique, (~A (AART), with cardiac output measurements, QL (Fick), a correction for the venous admixture has to be made to obtain (~A (Fick). This correction adds an extra random error, and possibly also systematic error, to the comparison of the ~)A values obtained with the two methods. In order to minimize the systematic error the following procedure was used. The model of Riley and Cournand [9] postulates an end-capillary oxygen tension which is equal to the ideal alveolar oxygen tension, obtained from the alveolar gas equation. The end-capillary oxygen saturation was calculated from this ideal alveolar oxygen tension with the Severinghaus nomogram for human blood. Bartels and Harms [1] have shown that the oxygen dissociation curve of pig blood differs considerably from that of human blood. In the region of 12.0-14.6 kPa ( 9 0 - 110 mm Hg) which was found during this investigation, there is only a small influence of this difference. This can be illustrated with a representative example. Assuming Sao~ = 95 ~ , Svo_, = 60~o, pH~ = 7.40, T = 38~ PcQ = 13.3 kPa (100 mm Hg) and Hb = 6.21 mmol/1 (10.0 g- dl 1), an Fs of 0.068 would be obtained with the saturation curve of Bartels instead of 0.073 with the Severinghaus homogram. Another reason not to use Bartel's data was that the number of data in his communication in the range of 12.0-14.6 kPa was only four. An estimate of the influence of errors in the venous admixture on the overall standard deviation is difficult to make. Comparison of QA (AART) with QL (Fick) resulted in the same standard deviation as that of Qa (AART) vs. ~)A (Fick). The correlation coefficient between the estimates for venous admixture and the ratios of QA (AART) and QA (Eick) values was 0.01 for the 55 experiments..Thus, the estimate of the alveolar lung perfusion by QA (AART) is independent of the level of this flow as well as of the amount of venous admixture. The largest correction of 25 ~ for venous admixture was found with IPPV in the open thorax situation. This value is in agreement with previously published data by Zwart et al. [13] who found a ratio of 0.7 of QA (AART) and the flow through the ascending aorta determined with an electromagnetic flow probe.
Variability of the Blood Gas Partition Coefficient The blood gas partition coefficient of halothane was assumed to be 2.3. Mapleson et al. [8] have shown that the partition coefficient of halothane for different species may vary over a considerable range (2.3 for humans, 3.2 for dogs). Thus, assuming a value of 2.3 may introduce a systematic error. Moreover, within one species an individual variation in the partition coefficient of halothane with a standard deviation of
Pfliigers Arch. 375 (1978)
about 10 ~ has been reported by Ellis and Stoelting [5], Gibbs et al. [7], Mapleson et al. [8] and Steward et al. [10]. The individual variation in the partition coefficient will also add a systematic error to the mean of the ratio QA (AART) and QA (Fick) in each experiment. Therefore, it might be assumed that combination of the different experiments results in an increase of the standard deviation and very probably in a decrease of the corresponding correlation coefficients of the combined data. Table 1 shows that the ratio QA (AART)/QA (Fick) varies around unity with variations in the mean of the separate experiments which are in agreement with the above-mentioned individual variations in the blood gas partition coefficients of halothane. The influence of the variation in blood gas partition coefficients could be avoided by determination of the individual blood gas partition coefficients. The method then looses its non-invasive character. This variation can also be avoided by the choice of another tracer agent of which the solubility is less dependent on the proteins and lipids of the blood than halothane. The use of acetylene with its low lipid solubility shows a very small variation in the blood gas partition coefficient (), = 0.96 ___ 0.02). Zwart et al. [14] suggested that the use of tracers with a high lipid solubility was preferable because this would result in a larger time constant of the body compartments (v.i.), which makes it possible to neglect the venous return. Comparison of simultaneous measurements of QA (AART) with acetylene and halothane, with measurement of the solubility of both tracers, in a recent study (L@endijk, unpublished data) have not shown evidence of a larger influence of venous return in the case of acetylene.
Simplifications of the Lung Model The lung was described with the model of Riley and Cournand, in which the pulsatile character of both the ventilation and perfusion is neglected and the gas exchanging parts of the lung are considered to be homogeneous. The influence of the venous return was neglected. The period of the sinusoidal change in the inspired tension of the tracer has to be large enough to neglect the pulsatile character of the respiration, but should be short enough to neglect the pulsatile character of the respiration, but should be short enough to neglect the influence of the venous return, which can be estimated as follows. The steady state of Eq. (1) gives
J
A. Zwart et al. : Non-Invasive Determination of Lung Perfusion
217
F o r sinusoidaI c h a n g i n g tensions this e q u a t i o n becomes
the c a r d i a c o u t p u t which is involved in gas exchange in a h o m o g e n e o u s lung.
Q=([PI]-IPA])coscz (
Acknowledgement.A. van Dieren, A. Drop and J. J. Schreuder are
tPa
IPA[ ]PAl -- [P~P sin
)2
1.(7)
fi
Hence Eq, (7) shows t h a t the influence o f the v e n o u s r e t u r n is d e p e n d e n t on the v a r i a t i o n o f the tension in the m i x e d venous o f b l o o d a n d a p h a s e shift ft. The p h a s e shift fi is d e t e r m i n e d by the time c o n s t a n t o f the b o d y c o m p a r t m e n t s a n d the recirculation time o f the b l o o d . Pv is d e t e r m i n e d m a i n l y by the highly perfused b o d y c o m p a r t m e n t s (kidney, a d r e n a l glands) which have a time c o n s t a n t o f a b o u t 90 s a n d which receive a p p r o x i m a t e l y 30 ~ o f the total c a r d i a c o u t p u t . F o r a sinusoidal change with a p e r i o d o f 3 rain we have an a n g u l a r frequency co = 2 ~z/3. Both effects result in [P~,] = 0.3[PA[ (1 § CO2 "C2) 1/2 = 0.09[PAl ' T h e e r r o r i n t r o d u c e d by the v a r i a t i o n o f the v e n o u s r e t u r n is then 9 ~ m u l t i p l i e d by sin ft. The errors resulting f r o m i n h o m o g e n e i t y o f the lung consist o f 2 factors : the v a r i a t i o n o f the time c o n s t a n t in different lung regions a n d the v a r i a t i o n o f the Q / l ? in different lung regions. The v a r i a t i o n o f the time c o n s t a n t in different lung regions can be neglected for lungs w i t h o u t o b s t r u c t i v e lung disease. I n h o m o g e n e i t y o f the v e n t i l a t i o n perfusion d i s t r i b u t i o n m a y influence the m e a s u r e m e n t s . The e r r o r in QA/I?A resulting f r o m a functional d e a d space t o g e t h e r with a h o m o g e n e o u s alveolar c o m p a r t m e n t will be fully c o m p e n s a t e d by the error m a d e in the e s t i m a t i o n o f 1?A with the B o h r formula. O t h e r types o f i n h o m o g e n e i t y will i n t r o d u c e errors in the ~)A/I'~Awhich are n o t fully c o m p e n s a t e d by the e r r o r in the estimate o f 1~.
Conclusion The a l v e o l a r a m p l i t u d e response technique offers the possibility to o b t a i n the lung perfusion in situations w i t h o u t o b s t r u c t i v e lung disease. The s t a n d a r d deviation which was f o u n d in this study is o f the same o r d e r as is generally f o u n d if two i n d e p e n d e n t invasive c a r d i a c o u t p u t m e a s u r e m e n t s are c o m p a r e d . W e have to keep in m i n d that this n o n - i n v a s i v e technique only m e a s u r e s lung p e r f u s i o n or, in o t h e r words, t h a t p a r t o f
gratefully acknowledged for their assistance and R. van Strik of the Dept. of Biostatics, Erasmus University, Rotterdam, for his statistical advice. S.C.M. L@endijk from the Dept. of Physiology of the State University, Utrecht, is acknowledged for the information on the comparison of acetylene and halothane.
References 1. Bartels, H., Harms, H.: Sauerstoff-Dissoziationskurven des Blutes yon Sfiugetieren. Pflfigers Arch. 268, 334-365 (1959) 2. Butler, J.: Measurement of cardiac output using soluble gases. In : Handbook of Physiology, Section 3 : Respiration, Vol. II, Ch. 61 (1965) 3. Carpenter, T. M.: Tables, factors and formulas for computing respiratory exchange and biological transformatious of energy. Carnegie Institution of Washington, Publication 3036, Washington D.C. 1964 4. Cramers, C. A., Trimbos, H. F.: Development of an on-line analyzer for organic anesthetics in inspiratory and-tidal gases. J. Chromatog. 119, 71 - 84 (/976) 5. Ellis, D. E., Stoelting, R. K. : Individual variations in flurocene, halothane and methoxyflurane blood gas partition coefficients and the effect of anemia. Anesthesiology 42-6, 748- 750 (1975) 6. Fick, A.: fiber die Messung des Blutquantums in den Herzventrikeln. Sitzungsberichte der physikalisch-medimediziniscben Gesellschaft zu W/irzburg, 16 (1870) 7. Gibbs, C. P., Munson, E. S., Tham. M. K. : Anesthetic solubility coefficients for maternal and fetal blood. Anesthesiology 43-1, i00-103 (1975) 8. Mapleson, W. W., Allot, P. R., Steward, A. : The variability of partition coefficients for halothane in the rabbit. Br. J. Anesth. 44, 656-661 (1972) 9. Riley, R. L., Cournand, A. : Ideal alveolar air and the analysis of ventilation-perfusion relationships in the lung. J. Appl. Physiol. 1, 825-847 (1949) 10. Steward, A , Allott, P. R., CowIes, A. L., Mapleson, W. W.: Solubility coefficients for inhaled anesthetics for water, oil and biological media. Br. J. Anesth. 45, 282 293 (1973) 11. Stow, R. W. : Systematic errors in flow determinations by the Fick method. Minn. Med. 37, 30 (1954) 12. West, J B.: Ventilation/blood flow and gas exchange. Oxford: Blackwell Scientific Publications 1972 13. Zwart, A., van Dieren, A. : A simple and non-invasive method to determine the ventilation-perfusion ratio of the lung and the effective lung perfusion. Acta Anaesth. Belg. 26, Suppl. 53 - 64 (1975) 14. Zwart, A., Seagrave, R. C., van Dieren, A.: Ventilationperfusion ratio obtained by a non-invasive frequency response technique. J. Appl. Physiol. 41,419-424 (1976)
ReceivedMarch1, 1978
