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1School of Information Technology and Engineering, University of Ottawa, Ontario, Canada K1N 6N5; 2Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892; and 3Vermont Lung Center, University of Vermont, Burlington, Vermont 05405
Submitted 4 August 2003 ; accepted in final form 16 March 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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enhanced pause; airway resistance; lung mechanics
However, recent studies suggest there are serious problems with this approach. Albertine et al. (1) and Petak et al. (27) have shown an inconsistent relationship between Penh and invasive measurements, especially in C57BL/6 mice. Mitzner and colleagues (21, 22), Lundblad et al. (19), and Enhorning et al. (8) have shown that the relationship between Pb and airway mechanics is limited. Pb changes are caused by the heating and humidification, and compression and decompression, of inspired gas. Although only compression is physically related to bronchoconstriction, the signal is largely dominated by the heating and humidification effect. Although these theoretical and experimental problems are significant, we believed that the potential usefulness of this technique warranted further investigation. After all, many times in the past, parameters without solid theoretical support have been shown to be very useful (e.g., forced expiratory volume in 1 s). In this study, we began our consideration with the premise that barometric plethysmographical parameters are related to mechanical ones, even though these theoretical studies (19, 22) suggest the link is tenuous. We sought to answer these questions: 1) How do the changes in Penh compare with changes in traditional UP and lung mechanical parameters? 2) How well do UP parameters perform in two different but widely used mouse strains?
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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UP measurements were made using a 181-ml cylindrical Plexiglas chamber. The chamber had a small controlled leak with a time constant of 1.8 s and a port into which aerosolized MCh could be pumped. Pb was measured with a pressure transducer (Validyne, Northridge, CA) and recorded with an analog-to-digital converter (NB-MIO16x, National Instruments, Austin, TX) at a sampling frequency of 100 Hz after filtering with an appropriate antialiasing filter.
Mice were placed into the chamber and allowed to move freely. Saline and MCh solutions were aerosolized (Aerosonic Nebulizer, DeVilbiss Heath Care, Somerset, PA) and pumped into the chamber at a flow of 1.9 l/min for 2 min. The pump was then stopped, its connecting tube was occluded, and Pb was recorded continuously for 2 min. Measurements were made at concentrations of 0 (saline), 1.6, 3.1, 6.2, 12.5, 25, and 50 mg/ml MCh.
Twenty-four hours after the UP measurements, RL and compliance (CL) were measured in the same mice. The measurements were made under anesthesia while the animals were mechanically ventilated with a previously described plethysmographic method (20). RL and CL were determined after challenge with 10 breaths of MCh aerosol at concentrations of 0 (saline), 1.6, 3.1, 6.2, 12.5, 25, and 50 mg/ml. At the end of this protocol, bronchoalveolar lavage fluid (BAL) was collected to verify the inflammatory status of the animal. One control and one immunized C57BL/6 mouse and one control and four immunized BALB/c mice did not survive to the end of this protocol.
Data analysis. The 2-min Pb records obtained after each MCh exposure were analyzed to extract candidate end-expiration and end-inspiration points. Each breath was tested against acceptance criteria (see below), and the average plethysmography parameters were calculated for the first 30 s after each exposure. Signals were processed with the following algorithm. Low-frequency drift was removed by a Butterworth digital high-pass filter (cutoff frequency of 1.5 Hz). Candidate breath start points were identified from a low-pass-filtered signal (cutoff frequency of 15 Hz) at points where the slope began to exceed a threshold, which was selected to be 20% of the median slope magnitude. Candidate start points were then corrected with respect to the original, unfiltered signal. For each breath start point, the corresponding inspiratory and expiratory segments were identified, and the breath was compared with the following acceptance criterion: 1) inspiratory (TI) and expiratory times (TE) within 0.3–3.0 times the median times, 2) inspiratory and expiratory change in Pb within 0.3–3.0 times the median value, 3) spurious signal noise within the breath below a threshold, and 4) Pb below the candidate end-inspiratory point. For each accepted breath, TI, TE, pressure change during inspiration (PI), and pressure change during expiration were directly calculated. The parameter values for each dose level were calculated to be the average value for all accepted breaths.
VT was calculated from Pb with the approach of Epstein and Epstein (9) according to the equation
 | (1) |
We analyzed our records of Pb following the scheme outlined by Hamelmann et al. (14), even though their algorithm is proprietary, so its precise details were not given. Hamelmann et al. used a plethysmographic chamber with a large leak and thus an extremely low time constant (0.02 s). We simulated the effects of their apparatus by subjecting our measurements of Pb to a frequency-domain digital filter with a pole at frequency = 1/0.02 s and a zero at a frequency of 1/1.8 s. The following values were calculated from the filtered Pb (Fig. 1): the maximum change in Pb during expiration (PEP), the maximum change in Pb during inspiration (PIP), and the time interval that encompasses 63% of the integrated expiratory pressure signal (TR). Linear interpolation was used to estimate TR values that did not occur on sample boundaries. We also calculated the following additional parameters for each breath: TI + TE (Ttot), TI/Ttot, VT/TI, VT/TE, VT/Ttot, Pause, and Penh. Following Ref. 14, Pause and Penh are defined as
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 | (3) |
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Figure 1 shows representative Pb signals for immunized BALB/c (A) and C57BL/6 (B) mice at a MCh concentration of 25 mg/ml. The expiratory signal in the BALB/c mice shows a delay between the end of one expiration and the beginning of the next, whereas the C57BL/6 mice do not show any clear delay. As the MCh concentration increased, the ratio between TR and TE decreased, resulting in an increase in Pause (Eq. 2). This example shows how sensitive TR is to any variability in the identification of the end-expiratory point. If this point is erroneously identified 10 ms too early (B, dotted line), the baseline level is dramatically reduced with a commensurate increase in TR.
Figure 2 shows RL and CL as a function of inhaled MCh concentration. The BALB/c mouse shows large changes in both parameters with concentration, whereas the C57BL/6 mouse has relatively little response. Because not all BALB/c mice survived to the highest concentration (9 of 16 animals survived), the contribution from the most responsive animals is not seen at this concentration level.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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The purpose of our study was to determine how changes in Penh relate to changes in traditional invasive measures of lung mechanics and whether the nature of this relationship varies between mouse strains. We chose to study BALB/c and C57BL/6 mice because both strains are commonly used as models of lung disease; the BALB/c strain mounts a strong immune response with high IgE levels (16), whereas the C57BL/6 strain is largely used for environmental exposure and production of some types of transgenic animals, such as knockout and constitutive overproducers of cytokines. We chose to compare the parameters of UP to independent measurements of RL because this parameter has been widely used to characterize lung mechanical function in laboratory animals. The robustness of RL as a general measure of mechanics is supported by the fact that CL, another widely used index of lung mechanical function, exhibited a very similar relationship to the UP parameters (Table 1).
VT is calculated from Pb using the approach of Epstein et al. (10) (equation 1), which adds corrections for signal drift to the equations of Drorbough and Fenn (7). This approach assumes that Pb originates solely from heating and humidification of inspired gas. These formulas are widely used (9, 13, 17, 18, 22, 32), although they have been shown to be inaccurate under conditions of increased RL, where compressive changes in Pb may be significant (10, 19, 22, 30). This compressive contribution to Pb depends on alveolar pressure and absolute lung volume, variables we were unable to measure noninvasively. Thus, in our calculations, no correction has been made for compressive contributions to Pb, so VT may be overestimated at higher MCh concentrations. The contribution from this effect is small (19, 21, 22) and is commonly ignored (26, 32). Another potential inaccuracy in our calculation stems from the assumed values [from Jacky (18)] for nasal and alveolar temperature and humidity. These formulas assume complete heating and humidification of inspired air, which has been shown to be inaccurate for humans (25, 26), although it is probably a valid assumption in mice because of their much smaller lung volumes. Thus, although our estimated values of VT may be somewhat inaccurate, the observed trends are unlikely to be artifacts.
Figure 3 shows the response of TE and Penh to increasing concentrations of MCh. TE is significantly different for treatment groups for both strains, although the difference is reduced at the higher concentrations. Penh, on the other hand, is significantly different between treatment groups in the BALB/c but not in the C57BL/6 mice. These results are similar to those of Table 1, where Penh is the UP parameter with the highest correlation to lung mechanics in the BALB/c mouse but does not correlate to lung mechanics in the C57BL/6 mouse. On the other hand, other UP parameters, such as TE, have similar correlations in both strains. This strain difference in behavior of Penh has also been observed by other workers (S. Sur, J. Lee, and L. Lundblad, personal communications). The sensitivity of Penh at low MCh concentration originates largely in its dependence on TR, which shows a marked early response to agonist but returns to baseline values at the highest concentration (Fig. 5). TR also behaves very differently in the different strains and appears to account for most of the differences in Penh response between the C57BL/6 and BALB/c mice. The calculated value of Penh is sensitive to the value of TR, because TR is in the denominator of the Penh equation (Eq. 2), which becomes very small at the highest concentrations of MCh. TR is itself very sensitive to the value estimated for TE. For example, as shown in Fig. 1, if the end of expiration is identified to be 10 ms too early, the resulting increase in TR reduces Penh by a factor of four. Thus Penh shows important experimental problems, in addition to the theoretical ones mentioned previously, which indicate that it cannot be considered as a valid measure of airway mechanics.
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First, differences in UP parameters correspond to differences in physiology. VT parameters (and Penh) correlate well in BALB/c but not in C57BL/6 mice, whereas flow parameters show the reverse effect. This observation corresponds closely with known physiological differences between these strains, as Takeda et al. (31) showed that eophinophils are distributed in peribronchial and peripheral lung tissue in BALB/c mice but were distributed diffusely in peripheral lung tissue in C57BL/6 mice. This suggests that BALB/c mice largely have an airway response, and an adaptive response to the bronchoconstriction is to take slower and deeper breaths, as seen in the data (Fig. 3). In contrast, C57BL/6 mice largely have a tissue response to MCh and so change flow with little decrease in VT. The apparent decrease in responsiveness in the immunized C57BL/6 mouse (Fig. 2) may be reflective of this peripheral response, possibly due to the strain-dependent spectrum of inflammatory mediators such as IL-6 (6). Also, if our data are interpreted in terms of the change with respect to baseline value (such as in Ref. 31), then there is no decrease of responsiveness with immunization.
Second, it is known that, at least in larger mammals, part of the breathing pattern response to agonists such as MCh is due to reflex mechanisms. Phillipson and coworkers (11, 28, 29) have shown the importance of the vagal reflexes in the control of breathing pattern in dogs. For example, elimination of the stretch and vagal reflexes uncouples the mechanical response from the neural response and produces independent reductions in Ttot (28). In unsedated exercising dogs, inhalation of histamine increases RL, decreases CL, and induces rapid shallow breathing, whereas cooling the vagus nerve abolishes these responses (4). Sectioning the parasymphatic vagal pathway in the cat increases the response in RL to aerosolized MCh compared with sham, symathectomy, or section of both vagal pathways (2), demonstrating that MCh elicits a vagal reflex. Recently, Wagner and Jacoby (33) showed that MCh also causes reflex bronchoconstriction in sheep.
Third, UP parameters begin to diverge between treatment groups at lower concentrations of MCh than mechanical variables. RL shows a significant difference in response between treatment groups beginning at 6.2 mg/ml (Fig. 2), whereas Penh shows a significant difference at 3.1 mg/ml (Fig. 3). This is consistent with a nonmechanical (i.e., reflex) origin for the response at very low MCh concentrations.
In summary, although the technique of UP promises an easy-to-use, noninvasive index of lung mechanics in mice, there has been considerable concern over its validity. Theoretical studies (8, 21, 22, 24) have shown that only a small fraction of the Pb changes measured by UP reflects lung mechanics, and practical problems (1, 23, 27) in the interpretation of UP parameters have also been described. Our study supports these concerns. We show that, although Penh correlates with RL in the BALB/c mouse, there is no significant correlation in the C57BL/6 strain. Our data also suggest that Penh largely reflects effects from irritant receptors affecting the control of breathing. Furthermore, Penh does not even appear to be the most useful parameter that can be calculated from the UP signal. For example, TE correlates almost as well with RL as Penh does in the BALB/c mice and performs significantly better in the C57BL/6 strain. Additionally, the TE vs. RL relationship is similar for both strains, whereas the Penh vs. RL relationship is more variable between strains. We conclude, therefore, that Penh is not special compared with other more easily interpretable quantities derivable from Pb and that it is inappropriate to use UP parameters in general, and Penh specifically, as substitute variables for traditional, valid measures of lung mechanics.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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, Control BALB/c mice; 
, immunized BALB/c mice; 
, control C57BL/6 mice; 
, immunized C57BL/6 mice. *Significant difference (P < 0.05) between control and immunized animals at each dose.
