Effects of preinsipiratory volume on the nitrogen closing volume test

Respiration Physiology (1980) 40, 241 251 © Elsevier/North-Holland Biomedical Press

EFFECTS OF P R E I N S P I R A T O R Y V O L U M E ON THE NITROGEN CLOSING VOLUME TEST

BERTIL HOLTZ, R U N E SIXT a n d B J O R N B A K E j Departments of Clinical Physiology and Anaesthesia, University 9["G6teborg, Sahlgrenska sjukhuset, G6teborg, Sweden

Abstract. The effect of varying the preinspiratory volume (Vlair; range: 0-75°4 vital capacity, VC) on the nitrogen closing volume (CV) test was studied in twelve seated subjects, aged 24-62 years. When Vlair was increased from 0 to about 121~oVC, the height of phase IV, the amplitude of the cardiogenic oscillations, CV and the slope of phase III increased. The height of phase IV and the amplitude of the cardiogenic oscillations showed a maximum at VIair = 12~% VC, although the average CV was about 18~(,VC. While the height of phase IV and the amplitude of the cardiogenic oscillations decreased when Vlair was increased above 12~/0VC, CV did not change and the slope of phase III increased consistently. These results cannot be explained solely by the regional lung volume model of Sutherland et al. (1968). However, if that model is extended to include the assumption that within a region alveoli behind closed airways may be differently expanded, we predict CV to be underestimated at low Vlair, independently of the upper to lower nitrogen concentration difference, in agreement with present findings. This assumption would also explain why the maximal height of phase IV can be obtained at a Vmir lower than CV. Airways Cardiogenic oscillation

Closing volume Nitrogen washout

C l o s i n g v o l u m e (CV), as assessed by the single breath n i t r o g e n test ( A n t h o n i s e n et al., 1969/70), has been shown to increase in the presence of an a d d e d a p p a r a t u s dead space, i.e. after increasing the p r e i n s p i r a t o r y v o l u m e (Mansell et al., 1972; K a n e k o et al., 1975; Craig et al., 1976; Stanescu et al., 1977). The a p p a r e n t increase in CV has been explained by the i m p r o v e d resolution of the inflection p o i n t at the onset of phase IV related to the increased u p p e r to lower n i t r o g e n c o n c e n t r a t i o n difference as a result of increased p r e i n s p i r a t o r y l u n g v o l u m e ( K a n e k o et al., 1975 ; Craig et al., 1976; S u t h e r l a n d et al., 1968). K a n e k o et al. (1975) predicted that m a x i m a l upper A ccepted/br publication 28 December 1979 I Address for reprint requests. 24l

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to lower concentration difference, and consequently also CV, would be obtained at a tSreinspiratory volume equivalent to CV. In the present investigation the effect of systemic increase of the preinspiratory volume on the expired nitrogen curve was studied in an attempt to test whether CV is largest and whether the inflection point is most evident at a preinspiratory volume equivalent to CV and whether the change in CV and the slope of phase III, i.e. the alveolar plateau could be explained satisfactorily by the change in upper to lower concentration difference.

Subjects and methods Twelve volunteers with no signs or symptoms of cardiopulmonary disease were studied in the seated position. General characteristics and spirometric results are given in table l. Five subjects were smokers and four ex-smokers (had not been smoking for at least one year before the study). Closing volume curves were obtained with the resident gas method (Anthonisen et al., 1969/1970) using equipment previously described in detail (Oxh6j and Bake, 1974). Volumes were obtained with a water-sealed spirometer with electrical output and the nitrogen concentration with an N2-analyzer (Med. Science Nitralyzer 505) with a 95 per cent response time of less than 200 ms and a linear output in the range 0-Q~°J,','/oN~. The signals were recorded on an X - Y - Y recorder (Bryans 26000). By means of a pneumotachograph and an integrator, t.he flow rates and the volume history were obtained. The flow rates were displayed in front of the subject and during the expiration from the total lung capacity (TLC) also recorded on the X-Y Y-recorder. The volume signal from the integrator was recorded on an X-t-recorder (Goertz RE 520) which facilitated the guidance of the subject during the breathing manoeuvres. The subject first breathed tYeely through the tube, and after the end-expiratory level had been obtained on the X-t-recorder, he expired to residual volume (RV). During the following inspiration the level at which the subject was switched to the oxygen supply was varied between 0 and 75 ~, VC (preinspiratory volume: Vlair).

TABLE 1 General and spirometric characteristics of the subjects No. of subjects Male/ Female

Age (yr)

Height (cm)

Weight (kg)

TLC C,; pred)

VC ('), pred)

FEV l (",~; pred)

9/3

36 (24-62)

172 (160-182)

65 (51-.76)

94 (81-105)

103 (94-113)

ll0 (95 118)

Mean values with range within parentheses. Predicted normal values of TLC calculated according to Grimby and S6derholm (1963) and of VC and FEV 1 according to Berglund et al. (1963).

NITROGEN CLOSING VOLUME

243

To eliminate the apparatus dead space (= 150 ml) tracings with Vlair = 0 were obtained by inspiration of oxygen from a separate bag. The inspiratory flow rate was kept below 0.5 1/s and the expiratory flow rate between 0.15 and 0.2 l/s. On average 25 accepted tracings were obtained in each subject. Tracings were obtained with a time interval of at least five minutes. In addition, three tracings in each subject were obtained after inspiration of oxygen from the functional residual capacity (FRC), excluding previous expiration to RV, according to the method of Craig et al. (1976). Only tracings with an expired volume of at least 95 per cent of the maximal VC were accepted. The tracings were mixed, copied and read blindly by two observers and the mean values were analyzed. The beginning of phase IV was defined as the first convincing, permanent, upward sloping departure from the slope of phase III. The height of phase IV and CV were measured. The slope of phase III was obtained by dividing the difference between nitrogen concentrations at the onset of phase IV and a point 0.75 1 ATP'S from TLC by the corresponding difference in volumes (Oxh6j and Bake, 1974). The average height of the 3-5 largest consecutive cardiogenic oscillations during phase III was also measured.

Results

Figure 1 shows original tracings from one subject at various preinspiratory volumes. The height of phase IV and the amplitude of the cardiogenic oscillations were maximal at a preinspiratory volume of about 12~o VC, whereas the slope of phase Iii increased continuously with increasing Vlair. CV appeared to be smaller when oxygen was inspired from RV (Vlair = 0) than at higher preinspiratory volumes. In each subject, the height of phase IV, amplitude of the cardiogenic oscillations, CV and the slope of phase III were plotted against VIair. One such graph is shown in fig. 2, were the height of phase IV is plotted against VIair. The best fitting line was drawn by eye. This method of analysis enabled us to read values on the Y-axis corresponding to specific preinspiratory volumes so that subjects could be compared. Thus, a mean plot for each variable was calculated, as shown in fig. 3. Although there were differences between subjects, these mean curves represent patterns clearly visible in most subjects. The height of phase IV (fig. 3, upper left panel) increased rapidly as the preinspiratory volume was increased above RV and became maximal at a Vlair of about 12~,i VC, which is lower than the average CV (fig. 3, lower right panel). With further increase of Vlair, the height of phase IV gradually decreased. The amplitude of the cardiogenic oscillations (fig. 3, upper right panel) shows a pattern which is very similar to that of the height of phase IV. In addition, the individual VIair (range 10-14~o VC) corresponding to the maximal height of phase IV appeared to be independent of CV.

244

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Fig. 1. Examples of CV-tracings in one subject illustrating the effects of increased preinspiratory volume (Vmir).

CV (fig. 3, lower right panel) increased from about 14~ VC when oxygen was inspired from RV to about 18~ VC at a VIair of about 10~ VC and did not change as VIair increased further, despite the accompanying decrease in the height of phase IV.

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Fig. 3. Height of phase IV, cardiogenic oscillations, slope of phase llI and CV in relation to preinspiratory volume. Results from twelve subjects. Mean values _+SEM.

The slope of phase III (fig. 3, lower left panel) increased consistently with increasing VIair and the increase was most pronounced when VIair increased from RV to about 20~o VC.

Discussion

Based on knowledge of regional lung expansion (Milic-Emili et al., 1966; Sutherland et al., 1968), the effect of preinspiratory volume on the upper to lower nitrogen concentration difference at TLC may be predicted. Within an individual, the height of phase IV may be regarded as an index of the upper to lower concentration difference (Engel et al., 1976). The nitrogen concentration at the onset of phase IV will be a mean value of the whole lung, weighted towards the concentrations in the lower regions, whereas the final nitrogen concentration at RV will be a mean value of the non-occluded upper regions. The pattern of change of the height of phase IV with VIair was therefore apparently in accordance with predictions. However, the lung volume at which the height of phase IV was maximal appeared to be lower than and independent of CV. This is at variance with the predictions of Kaneko et al. (1975), based on the lung model of Sutherland et al. (1968), in which the difference in regional

246

B. H O L T Z et al.

lung volumes and therefore the upper to lower nitrogen concentration difference is greatest at CV. The amplitude of the cardiogenic oscillations has also been considered dependent on the upper to lower concentration difference (Fowler and Read, 1961). Our findings show that the pattern of change of the amplitude of the cardiogenic oscillations was similar to that of the height of phase IV. This suggests that they have originating factors in common, presumably the upper to lower nitrogen concentration difference. On the other hand, Cormier et al. (1979) found a clear separation between the amplitude of the cardiogenic oscillations and the height of phase 1V when tracings were obtained after three consecutive VC of pure oxygen followed by one VC of air. No mechanism was suggested in their report. Our results for CV confirm previous observations that CV appeared to be larger if the preinspiratory volume was increased above RV (Mansell et et al., 1972; Kaneko et al., 1975; Craig et al., 1976; Stanescu et al., 1977). As shown in table 2, when Vlair = FRC all measured variables increased compared to when Vlair = RV, in agreement with the results of Craig et al. (1976). Expiration to RV before the inhalation of oxygen from FRC did not significantly affect these results. The pronounced effect when Vlair was increased by only 150 ml (=apparatus dead space) above RV was unexpected. Furthermore, if the assessment of CV were influenced by the upper to lower nitrogen concentration difference through the quality of the inflection point, as previously suggested (Kaneko et al., 1975; Craig et al., 1976; Stanescu et al., 1977), then CV should presumably decrease in parallel to the reduction of the height of phase 1V and the amplitude of the cardiogenic oscillations as Vlair is increased above CV. Our findings (fig. 3) show that CV does not decrease at high Vlair although the height of phase "IV and the amplitude of the cardiogenic oscillations clearly decrease. Thus, it seems unlikely that the upper to lower nitrogen concentration difference can alone explain the observed change in CV. We have considered the following factors as possible explanations for the difference between the predictions and the experimental results: opening versus TABLE 2 N 2 CV-test variables after inspiration of oxygen from RV and F R C and from F R C after expiration to RV (FRCmv))

RV FRC FRCIRvi

Height of phase IV (i'0 N2)

Cardiogenic oscillations ("L N2)

Slope of phase llI (",, N2/I )

CV ('~ VC)

3.73 +0.59 4.25 _+0.77 4~76 -+0.85"

0.60 -+0.11 0.88 _+0.08* 0.91 _ + 0 . 1 1

0.98 -+0.09 1.66 -+0.11"** 1.58_+0.12"**

14.1 -+2.3 16.5 _+2.7 17.9_+2.5"**

Mean ± S E M . Twelve subjects. * P < 0.05: * * P < 0.01: * * * P < 0.001. Significance levels denote differences compared to measurements after inspiration of oxygen from RV.

NITROGEN CLOSING VOLUME

247

closing volume, effect of volume history on CV and effect of intraregional dispersion of alveolar expansion behind closed airways. Opening versus closing volume. If the lung volume at which airways open were considerably less than CV~ particularly when CV was high, our resul~ts could partly be explained. However, Holland et al. (1968) showed that opening volume and CV were quite similar and Sutherland et al. (1968) found similar regional lung expansion on inflation and deflation. In excised dog lungs opening volume was found to exceed closing volume (Glaister et al., 1973). Thus, available data lend no support to this mechanism. Effi~ct o f volume history on CV. In previous studies we showed that airways closed at higher lung volume after inspiration to TLC compared to e.q. tidal breathing (Holtz et al., 1976, 1979). In this study the subject initially breathed normally and then expired to RV. It seems likely, therefore, that airways closed at a lower lung volume during the initial expiration to RV than during the subsequent expiration from TLC. On this basis we may expect the maximal apico-basal concentration difference, and consequently height of phase IV and amplitude of the cardiogenic oscillations, to occur at a lower lung volume than CV, as obtained after expiration from TLC. We have not measured CV at a reduced inspired volume in our subjects but knowledge of CV after expiration from TLC allows a reasonably accurate prediction (Holtz et al., 1979). About 50 per cent of the difference between CV and the volume at which the height of phase IV was maximal may be accounted for by this ~correction' of CV. Intraregional dispersion o f alveolar expansion behind closed airways. In an effort to explain the effect of Vlair on CV, and possibly also the unexpectedly low VIair at which the height of phase IV and the amplitude of the cardiogenic oscillations were maximal, we considered the possibility that within a region alveoli behind closed airways may not be equally expanded. We adopted a lung model presented by Kaneko et al. (1975, table 1) to make quantitative predictions. For the sake of simplicity, we divided the lung into an apical region (0 15 cm from the top of the lung, with TLC r = 2880 ml) and a basal region (15-25 cm from the top of the lung, with TLCr = 3120 ml) and allowed these regions to change volume according to the model. We assumed that within the basal region one-third of the alveoli were closed off at an expansion of 251~o TLCr, i.e. the minimal volume (MV) of these alveoli is 25)/o TLCr (MV25), and two-thirds at an expansion of 15~o TLCr, i.e. MV~5. Furthermore, over-all RV was assumed to be 22.5°,o TLC. Under these circumstances one-third of the basal airways will start to close at 13.5~o VC (=CV) and the rest of the airways in the basal region will close at 5.2~,] VC. At RV about 5o"/v,, of the alveoli will be closed off, which is in agreement with the predictions by Sutherland et al. (1968). Figure 4, upper left panel, illustrates the model. The change in slope of the regional

248

B. HOETZ et al. ioo.

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Fig. 4. Upper panels. Two-compartment models of regional lung volumes assuming two levels of alveolar expansion behind closed airways. Vertical arrows indicate when airways start to close. The dashed line is the line of identity and represents the average regional expansion at any over-all lung volume. (L~J~) Young lung: I/3 of the alveoli in the lower region becomes closed off at 25'~, T L C r and 2/3 at 151~i TLCr, RV = 22.5,,~ T L C and CV = 13.5'~, VC (CV + RV = 33'!~i TLC). (Right) Older lung: 1/3 of the atveoli in the lower region becomes closed off at 35'~,, TLC r and 2/3 at 25'~,, TLC,.. RV = 30?;, T L C and CV = 23.5".i, VC (CV + RV ~ 46°~, TLC). The change in slope of the curves when a given a m o u n t of alveoli became closed off was calculated according to Sutherland et al. (1968), such that the volume change of the alveoli with remaining patent airways, on extrapolation. converges to a point defined by the coordinates: regional lung volume = 1001~; T L C r, over-all lung volume = volume of remaining ventilating alveoli at TLC plus closed-off volume. Lower panels. Expired nitrogen concentration versus volume• Effects of increased preinspiratory volume (Vlair) are illustrated for a young lung (left) corresponding to the regional lung volumes of upper left panel and for an old lung (right) corresponding to the regional lung volumes of upper right panel. At low Vlair the onset of phase IV occurs at lower lung volume than the onset of airways closure (compare fig. 1). The model predicts stepwise concentration changes as airways close but to illustrate the results we have chosen linear increase or decrease or the nitrogen concentration to the calculated level•

v e r s u s over-all lung volume when some alveoli became closed off was calculated according to the method of Sutherland e t a l . (1968). On inspection it will be

NITROGEN CLOSING VOLUME

249

appreciated that when oxygen is inspired from RV the upper alveoli and the lower alveoli with MV25 will have quite similar nitrogen concentrations at TLC, whereas lower alveoli with MV~5 will have lower concentrations. Thus, at the following expiration from TLC, the nitrogen concentration at the mouth will in fact decrease when airways start to close (see fig. 4, lower panels, bottom curves corresponding to Vlair = 0). We calculated the regional nitrogen concentrations at TLC following various VIair and then the expected concentrations at the mouth at some points during the expiration to RV. The results of these calculations are illustrated in fig. 4, lower left panel. It will be seen that when Vlair = 0 and 5~o VC the onset of phase IV occurs at a lower lung volume than airway closure and thus CV is underestimated. Furthermore, CV is adequately assessed at high VI air although the upper to lower nitrogen concentration difference and height of phase IV decrease. In this model with the properties of a young lung, the VIair at which phase IV is maximal coincides with CV. To explain our finding that in subjects with large CV the maximal height of phase IV was obtained at VIair lower than CV, we extended the analysis to a model with elastic properties of a 60-year-old lung (fig. 4, right panels). In this model we assumed an over-all RV of 30~ TLC and minimal volumes of 35 and 25~o TLCr. Once again CV is underestimated at low VIair (fig. 4, lower right panel). In addition, the height of phase IV became maximal at a lung volume lower than CV. Thus, if we assume that within a certain region there is dispersion of alveolar expansion behind closed airways, our findings regarding the change of CV, and perhaps also change of height of phase IV and amplitude of the cardiogenic oscillations, can be adequately explained. Furthermore, this mechanism is consistent with previous reports on effects ofpreinspiratory lung volume (Mansell et al., 1972; Kaneko et al., 1975; Craig et al., 1976; Stanescu et al., 1977). Measurements of intraregional ventilation have shown considerable inhomogeneities to exist also within small segments of the lungs (Young and Martin, 1966; Engel et al., 1974), which generally appear consistent with our hypothesis. Differently expanded alveoli behind closed airways is one potential mechanism for intraregional inhomogeneity. In agreement with the findings of Engel et al. (1974) and Anthonisen et al. (1970, 1978), we found that the slope of phase III cannot be adequately explained solely by the upper to lower nitrogen concentration difference and that intra regional concentration differences and emptying patterns must also be of importance. The time available for gas mixing varies systematically in these experiments. The time is longest at VIair = 0 and successively shorter at high VIair. It has been demonstrated that breath-holding tends to reduce the slope of phase III (Buist and Ross, 1974). It, therefore, seems likely that the time factor contributed to the results. The difference in time available for gas mixing between manoeuvres with VIair = 0 and 70~o VC may amount to about 10 s. However, in two of the subjects about 30 s breath-holding at TLC at a VIair of about 70}~o VC did not alter the slope to

250

B. HOLTZ et al.

c o r r e s p o n d to VIair = 0. The time factor therefore does n o t a p p e a r to fully explain the effect o f Vlair on the slope o f p h a s e III. F r o m the p a t t e r n o f c h a n g e o f the slope o f phase I I I a g a i n s t VIair (fig. 3, lower left panel), it is t e m p t i n g to c o n c l u d e that with low VIair the u p p e r to lower nitrogen c o n c e n t r a t i o n difference is an i m p o r t a n t d e t e r m i n a n t but as VIair rises the i m p o r t a n c e o f i n t r a r e g i o n a l i n h o m o g e n e i t y increases since the u p p e r to lower n i t r o g e n conc e n t r a t i o n difference diminishes. In conclusion, o u r results c o n f i r m p r e v i o u s r e p o r t s t h a t CV, as m e a s u r e d with the resident gas m e t h o d , m a y be u n d e r e s t i m a t e d with low p r e i n s p i r a t o r y volumes. O u r results do not, however, s u p p o r t the earlier suggestion that this u n d e r e s t i m a t i o n o f CV is caused by a small u p p e r to lower nitrogen c o n c e n t r a t i o n difference a n d a c c o m p a n y i n g less distinct inflection p o i n t with low Vlair since at high VIair, when the u p p e r to lower nitrogen c o n c e n t r a t i o n difference is also small a n d the inflection p o i n t is again vague, we notice no t e n d e n c y t o w a r d s u n d e r e s t i m a t i o n o f CV. F u r t h e r m o r e , the results indicate that the m a x i m a l t o p b o t t o m n i t r o g e n difference, as reflected by the height o f phase IV, is n o t necessarily o b t a i n e d with Vlair equal to CV. A possible e x p l a n a t i o n for this as well as for the u n d e r e s t i m a t i o n o f CV at low Vlair c o u l d be a dispersion o f a l v e o l a r v o l u m e s in the c l o s e d - o f f regions o f the lung.

Acknowledgements This s t u d y has been s u p p o r t e d b y g r a n t s f r o m the Swedish M e d i c a l R e s e a r c h C o u n c i l (project No. 04959), the Swedish N a t i o n a l A s s o c i a t i o n against H e a r t a n d Chest Diseases a n d the Swedish T o b a c c o C o m p a n y .

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