2542Thorax 1993;48:254-259 Forced oscillation technique and in provocation tests cold air Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from

G J Wesseling, I M L Vanderhoven-Augustin, E F M Wouters

Abstract Bronchial hyperresponsiveness is one of the Background Impedance measurements key elements in the pathogenesis of , by the forced pseudo random noise oscil- and the assessment of bronchial hyper- lation technique can be used to study the responsiveness has become an important mechanical characteristics of the respi- diagnostic tool in the function laborato- ratory system. The objective of this study ry. Bronchial hyperresponsiveness can be was to analyse the changes in impedance assessed using a variety of methods. The to a cold air provocation test in patients forced expiratory volume in one second with asthma, and to correlate these (FEV,) is generally used as an index of the changes with those in the forced expira- response in bronchial challenge tests.' tory volume in one second (FEVy). Spirometry, however, is dependent on effort, Methods The response to isocapnic and requires a full inspiratory manoeuvre hyperventilation with cold air was which may influence bronchial tone2 and assessed by respiratory impedance mea- hence affect the outcome of bronchial provo- surements and spirometry in 60 patients cation tests. with bronchial asthma in whom the The measurement of the impedance of the provocative dose of histamine resulting with the technique of in a 20% fall in FEV, (PD20) was forced oscillations3 has the benefit of being < 8 umol. independent of effort, and it requires little or Results Cold air provocation resulted no cooperation from the patient. The method in a mean(SD) fall in FEV, from may therefore be well suited to provocation 3.75(0.85) litres to 3-10(0-90) litres. The

testing. With computerisation, the technique http://thorax.bmj.com/ mean(SD) decrease in FEV, as a per- can easily be implemented, and the imped- centage of predicted was 15-4(3.8)%. The ance of the respiratory system can be deter- oscillatory resistance at 8 Hz increased mined over a wide frequency range in a short from a mean(SD) of 0.367(0.108) kPall/s period of time. The technique has been used to 0.613(0.213) kPa/lIs and at 28 Hz the in bronchial challenge tests by several investi- resistance increased from 0.348(0.089) to gators.4-10 Only a few studies have compared 0.403(0-099) kPaIlIs. Frequency depen- absolute changes in spirometric values with dence of resistance became significantly in impedance data induced bronchoconstric- on September 28, 2021 by guest. Protected copyright. more negative. The reactance at 8 Hz tion.4s7 11 12 decreased from a mean(SD) of -0-035 The purpose of the present study was to (0-041) kPallls to 0.234(0-199) kPa/lls, evaluate the data obtained with the technique and the resonant frequency increased of forced oscillations in a provocation test from 12.5(4.9) Hz to 25.7(9.1) Hz. with isocapnic hyperventilation with cold air Significant correlations were calculated in patients with bronchial asthma with docu- between the decrease in FEV, and mented bronchial hyperresponsiveness, and changes in the various impedance para- to correlate these data with spirometric meters, especially between the decrease indices. in FEV, and the increase in resistance at 8 Hz (r = -0.66), and the decrease in FEV, and the increase in the resonant Methods frequency (r = - 0.63). SUBJECTS Conclusion Cold air provocation in We studied 60 asthmatic subjects (35 male) asthmatic subjects results in changes in with a mean (SD) age of 27-9(10-7) years. All the impedance of the respiratory system subjects had a characteristic history of recur- Department of that correlate well with the changes in of with Pulmonary Diseases, rent attacks dyspnoea perceptible University Hospital FEV,. These changes in impedance wheezing. Mean (SD) forced expiratory vol- Maastricht, PO Box reflect ventilatory inhomogeneities in the ume in one second (FEV,) was 3 7(0 9) litres 5800, 6202 AZ peripheral compartment of the bronchial (97-2(14-6)% of predicted). All patients had Maastricht, The show the value Netherlands tree. These observations evidence of bronchial hyperresponsiveness, G J Wesseling of this technique in the evaluation of reflected by a provocative dose of histamine I M L Vanderhoven- induced , as both a resulting in a 20% fall in FEV, (PD20) of <8 Augustin and a of M quantitative qualitative analysis ,umol. Before the study all medication was E F Wouters the response is possible. inhaled bron- Reprint requests to: withheld and short acting Dr G J Wesseling chodilators were stopped at least eight hours Accepted 26 August 1992 (Thorax 1993;48:254-259) before the provocation test. Before provoca- Forced oscillation technique and spirometry in cold air provocation tests 255

tion all subjects had to have an FEV, >70% tions of these various frequencies were of the reference values.'3 applied in succession at the mouth or the chest. Originally, the measurements were per-

EXPERIMENTAL DESIGN formed during voluntary relaxation at the end Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from Cold air challenge tests were performed using of a normal expiration. Mead'5 demonstrated a heat exchanger (Jaeger GmbH, Wurzburg, that the forced oscillations can be superim- Germany). The subjects inhaled dry air deliv- posed on the normal breathing pattern. ered from a cylinder. The temperature of the The technique of forced oscillation used in air leaving the cooling system was -20°C. The this study is similar to the method described flow of air could be adjusted by a needle valve by Landser et al.'6 The equipment consists of and was measured by a rotameter. The a loudspeaker which amplifies a signal gener- patients were instructed to breathe at a prede- ated by an oscillator, a high impedance side termined ventilation rate of 60% of the pre- tube which enables the subject to breath dicted indirect maximal breathing capacity'4 spontaneously and a screen type pneumo- by maintaining the size of a guide balloon. To tachograph (fig 1). In this technique a com- avoid hypocapnia, CO2 was added to the sys- plex pseudo random noise oscillation signal is tem at a rate of 5% of the predetermined used, and various frequencies ranging from 4 minute ventilation. Hyperventilation was sus- to 52 Hz are applied simultaneously. Each tained for three minutes, after quiet breathing frequency starts at a different randomly into the system for one minute. FEV1 was selected moment. This results in a small over- determined with a wet spirometer (Gould all peak to peak size of the signal to improve Pulmonet III). The best value of three suc- the signal to noise ratio. The signal is applied cessive measurements was used in the statisti- at the mouth during spontaneous quiet cal analysis. breathing. Mouth pressure and flow are The impedance of the respiratory system recorded by transducers with identical fre- was measured by the technique of forced quency characteristics (Validyne MP45). The oscillations. recorded signals are fed directly without fil- Three successive impedance and spiromet- tering into a Fourier analysing system, yield- ric measurements were performed before and ing impedance values for each of the one minute after the cold air challenge, with investigated frequencies by means of spectral the impedance measurements always preced- analysis. An ensemble averaging is performed ing forced expirations. over a time interval of eight seconds to filter out the disturbing signals produced by the FORCED OSCILLATION: TECHNICAL breathing of the subject. A coherence func- CONSIDERATIONS

tion is calculated for each of the frequencies http://thorax.bmj.com/ The impedance of the respiratory system was as a criterion for the validity of the measure- measured with the forced pseudo random ments. A perfect coherence is indicated by noise oscillation technique. This technique l 0, which means a complete absence of noise was originally developed by Dubois et al.3 It and alinearities in the obtained signals. Only determines the frequency characteristics of those values with a coherence function t 0 95 the respiratory system measuring the force are retained. Under these conditions the error velocity response to pressure variations pro- of the measurements is smaller than 10%.16 duced by a sine wave pump at frequencies The relationship between pressure and ranging from 1 to 35 Hz. Sinusoidal oscilla- flow is called the impedance. The impedance on September 28, 2021 by guest. Protected copyright. is divided into a resistance (R) and a reac- tance (X). The resistance corresponds with the total resistance in a resistance-induc- tance-capacitance (R-I-C) circuit. The total resistance of the respiratory system is the sum of three resistances in series: the resistance of the central airways, of the peripheral airways, and of the chest wall. The reactance depends on the compliant and inertia properties of the system: a negative reactance is found at lower frequencies as here the reactance is mainly determined by the capacitance of the system. V Pao2 At higher frequencies the reactance is influ- enced predominantly by the inertia qualities of the air within the airways. ' The reactance then becomes positive. The frequency at which the reactance equals zero is called the resonant frequency. With the technique used in this study the input impedance is measured, indicating that pressure variations and flow measurements occur at the same site. An alternative approach is to measure the transfer imped- ance, in which case the pressure variations Figure I Schematic diagram of the apparatus. I = loudspeaker; 2 = side tube; 3 = and flow measurements occur at different pneunzotachograph; 4 = pressure transducer; 5 = mouthpiece; 6 = bias flow. sites. 256 Wesseling, Vanderhoven-Augustin, Wouters

INTERPRETATION OF FORCED OSCILLOMETRY tends to underestimate the frequency depen- DATA dence of the resistance and decreases the Impedance data are influenced by the upper reactance. Therefore, the cheeks and the floor

extrathoracic airways, the intrathoracic air- of the mouth are supported with the palms of Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from ways, alveolar gas, parenchymal lung tissue, the hands during the measurements.'8 and chest wall tissue. The mechanical proper- Thus the observations in patients with air- ties of each of these components, their struc- flow obstruction of higher resistance values tural interactions, and the frequency range (especially at lower frequencies), a decrease over which impedance measurements are in resistance with increasing frequency, obtained, determine to what extent these decreased reactance values, and a high reso- components influence impedance data. nant frequency, can be explained by a high Michaelson et al'8 showed that in patients peripheral resistance in parallel with the com- with chronic obstructive airways disease pliance of the airways. In cases of high (COPD), the impedance of the respiratory peripheral resistance, the resonant frequency system is relatively high at low frequencies is determined predominantly by airway com- and decreases to a minimum at higher fre- pliance and inertia. quencies when compared with normal sub- jects. Clement et al'9 compared the frequency dependence of the total respiratory resistance DATA ANALYSIS and reactance in patients with airflow With the forced pseudo random noise oscilla- obstruction with those in healthy subjects and tion technique, the frequency dependent reported that resistance decreases with behaviour of the respiratory system can be increasing frequency and that the reactance is measured simultaneously at different frequen- more negative in patients, resulting in cies. The differences between the response of increased values for resonant frequency. the system to low and high frequencies allow Similar findings in respiratory impedance the division of the mechanical characteristics have been described in induced bronchocon- into a central and a peripheral compartment. striction.5 8 1' As a representation of low frequencies 8 The increase in resistance (especially at Hz was chosen. The impedance at 4 Hz lower frequencies), the decrease in resistance could not be used in our analysis as at this with increasing frequency, and the more neg- frequency the coherence coefficient was too ative values of reactance, can be explained by often below 0 95. Snashall et al'I showed that airway obstruction extending to the peripher- in this way the error of the measurements is al airways according to Mead's two compart- about 10%. Other investigators have used ment lung model where two parallel units are impedance values with a coherence function represented by the expansible airways and the as low as 0.8829 or 0 93° in their analysis. Van http://thorax.bmj.com/ air spaces.20 In the presence of an increase in Noord et a16 concluded from a study on hista- peripheral airway resistance, inclusion of air- mine provocation in patients with asthma that way compliance into the lung model will the reciprocal value of the resistance at 6 Hz result in negative frequency dependence of was the most suitable index of the technique resistance. In patients with peripheral airway of forced oscillations, and Lebecque et al31 obstruction, the total respiratory resistance showed that the concentration of histamine decreases with increasing frequency. resulting in a 50% increase in the oscillatory Patients with obstructive lung disease who resistance at 6 Hz had a sensitivity and speci- on September 28, 2021 by guest. Protected copyright. exhibit frequency dependence of compliance ficity of 100% to separate groups of normal also exhibit frequency dependence of resis- and asthmatic children. Wouters et al5 found tance.2' This was interpreted as the effect of a highly significant difference in the recipro- uneven distribution of the mechanical proper- cal value of the resistance at 8 Hz between ties of the . Nagels et al22 measured the normal subjects and patients with asthma resistance and reactance of the respiratory after histamine provocation. system in healthy subjects and in patients To represent higher frequencies 28 Hz was with COPD. They found that in healthy sub- chosen. Several investigators have demon- jects, as well as in patients, the chest wall had strated that at frequencies above 24-28 Hz a low resistance which decreased with fre- the negative frequency dependence of resis- quency and increased with decreasing lung tance disappears. volume. They concluded that the observed Thus, the resistance at low (8 Hz) and high frequency dependence of resistance and the (28 Hz) frequencies, the reciprocal value of simultaneous increase in resonant frequency the resistance at 8 Hz, the reactance at 8 Hz can be simulated satisfactorily by Mead's two and the resonant frequency (frequency at compartment model20 assuming a large which the reactance equals zero) were stud- increase in peripheral airway resistance. ied. The slope of the resistance versus fre- Furthermore, increasing the central airway quency curve is represented by the equation: resistance twofold to threefold by narrowing Frequency dependence of resistance (FD) the does not result in frequency = R28-R8/20. dependence of resistance,23 and a two com- Values of FEV, and impedance before and partment model explains the changes in after provocation were compared by the impedance.24 Student's paired t test, and Spearman's The shunt properties of the upper airways coefficients of correlation between FEV, as a may result in a loss of forced flow percentage of predicted and the various oscillations.25 28 This upper airway artefact impedance measures were calculated. p Forced oscillation technique and spirometry in cold air provocation tests 257

Meatn (SD) values ofFEV, and impedance data before and after cold air challenge tests resonant frequency (r = - 0-630, p < 0 001). Before IHCA After IHCA Correlations between AFEV, and the increase in the resistance at 28 Hz (r = - 0-458, FEV, (litres) 3-75 (0 85) 3 10 (0 90) p < 0 and between and the 001), AFEV, Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from FEV, (% predicted) 97-2 (14-6) 81-8 (19-3) at = Resistance at 8 Hz (kPa/l/s) 0-367 (0-108) 0-613 (0-213) decrease in the reactance 8 Hz (r 0-538, Resistance at 28 Hz (kPa/l/s) 0-348 (0 089) 0 403 (0 099) p < 0-001) were also significant. There was a Reactance at 8 Hz (kPa/l/s) -0 035 (0-041) -0-234 (0 199) significant correlation between the decrease Resonant frequency (Hz) 12-5 (4-9) 25-7 (9-1) in the of resistance Frequency dependence (kPa/l/s) -0 00095 (0 0037) -0 010 (0 0077) frequency dependence and the decrease in FEV, (r = 0-596, IHCA-isocapnic hyperventilation with cold air; FEV,-forced expiratory volume in one p < o O1). second. All comparisons p < 0 001. Discussion values below 0 05 were considered signifi- Respiratory impedance measurements form a cant. unique, non-invasive method, which is inde- pendent of effort, for the assessment of the response to bronchial provocation stimuli, Results providing insight into their pathophysiological The values for FEV,, both absolute and as a effects on the respiratory system. An impor- percentage of predicted, and the values for tant advantage of the technique of forced the various impedance data used in the analy- oscillations is the fact that no forced respira- sis, before and after the cold air challenge tory manoeuvres are necessary for the mea- tests, are given in the table. Mean (SD) FEV, surements, so possible influences on decreased from 3-75 (0 85) litres to 3 10 bronchial tone are avoided.2 In a recent study (0 90) litres (p < 0-001). The mean decrease by Wilson et al,"2 the effects of forced expira- in FEV, as a percentage of predicted was tory manoeuvres on the outcome of bronchial 15A4%, and the mean decrease as a percent- provocation testing have been clearly shown. age of the baseline values was 16-8% These authors compared the response to (p < 0-001). methacholine challenge in normal subjects on Significant increases were observed in the two separate days; on one day impedance and mean (SD) resistance at 8 Hz from 0-367 FEV, were measured, while on the second (0 108) kPa/l/s to 0-613 (0-213) kPa/l/s, and day only impedance measurements were per- at 28 Hz from 0-348 (0089) kPa/l/s to 0403 formed. No plateau was seen on the non- (0 099) kPa/l/s (p < 0-001). Frequency FEV, day, despite a mean fall in FEV, of dependence of resistance (FD) decreased 46%. On the non-FEV, day the increase in from -0 00095 (0-0037) kPa/l/s to -0-010 the resistance at 6 Hz was far greater than on http://thorax.bmj.com/ (0-0077) kPa/l/s (p < 0-001). The reactance the FEVy day. It was concluded from this at 8 Hz decreased from - 0035 (0-041) study that forced expiratory manoeuvres as kPa/l/s to - 0.234(0.199) kPa/l/s (p < 0.001), used in spirometry persistently reduce the with an increase in resonant frequency from bronchoconstrictor effect of methacholine. 12-5 (4.9) Hz to 25-7 (9 1) Hz (p < 0-001). This could explain, in part, the plateau seen Figures 2-5 show the relation between the in other studies on bronchial challenge test- changes in FEV, as a percentage of predicted ing. (AFEVI), and in the various impedance The sensitivity of the technique of forced on September 28, 2021 by guest. Protected copyright. parameters. Significant inverse correlations oscillations in detecting induced bronchocon- were found between the decrease in FEV, striction has been evaluated by several and the increase in the resistance at 8 Hz authors.5 681 3334 Van Noord et a16 concluded (r=-0-656, p < 0-001) and between the that the forced oscillation technique is a sen- decrease in FEV, and the increase in sitive indicator of induced changes in airway calibre. The reciprocal of the oscillatory resis- tance at 6 Hz was found to be a suitable 0-80 index with a sensitivity intermediate between -+ 0-70 >_+ + that of specific airway conductance using + body plethysmography, and FEV,. Response 0-60 evaluation measuring specific airway conduc- 0-50 + + tance, however, allows only a quantitative Z- Cu + + assessment of the response, whereas the tech- 0-40 + + + ++ + nique of forced oscillations provides not only -tCC. 0-30 + + + + + a sensitive method for diagnosing induced + + + bronchoconstriction, but also for a qualitative 0-20 -+ + 4 + t+ +++ ++ analysis of the response. 0-10 _+++ t + In our study, provocation with cold air ++ hyperventilation resulted in an increase in the 0-00 + resistance of the respiratory system, especially 0-10 l at lower frequencies, and thus frequency 50 -40 -30 -20 -10 0 10 dependence of resistance became highly neg- AFEV, ( ative. Reactance also decreased, resulting in a Figure 2 Relationship between the increase in the resistance at 8 Hz (AR8) and the marked increase in resonant frequency. These decrease i,n FEV, (AFEV) as a percentagefrom baseline after cold air provocation in 60 changes in the impedance of the respiratory patients w)ith asthma (r = - 0656, p < 0-001). system are consistent with the findings of 258 Wesseling, Vanderhoven-Augustin, Wouters

0.801 Clement et al 19 in patients with airflow + obstruction. 0-60 Our results are in agreement with the find- ings of Decramer et al.7 Analogous changes in Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from 0-401 impedance have been reported after provoca- -a 0-20 tion with various other stimuli, both in children and in adults, in particular hista-

- 6 9-11 1 6-38 0- 0.001 + +++. f++ + + mine methacholine,"3 carbachol,8 |-~ ~~ + + ++ ++ + exercise,39 and after .440 + +t+4f+ allergen provocation Io -0-20 + + + + + ++ This observation suggests that the response is + +++++ + independent of the type of stimulus used. -0-40 + + Cold air hyperventilation leads to cooling + + of the mucosa of the airways and hyperosmo- -0-60 ++ larity of the periciliary fluid. It is known that -0-80 beyond the 14th airway generation the sur- 50 -40 -30 -20 -10 0 10 face area of the respiratory mucosa is thought AFEV, (%) to be sufficient to humidify the inspired air in Figure 3 Relationship between the increase in the reactance at 8 Hz (AX8) and the cold air hyperventilation.4' 42 It is therefore decrease in FEV, (AFEV) (r = - 0-538, p < 0001). easy to understand how this stimulus results in obstruction extending to the peripheral compartment of the bronchial tree.43 In our study significant correlations were found between the changes in impedance and the changes in FEV,. Significant correlations between forced expiratory flow and oscillo- 030 metric impedance values have been reported _ + 0 25 by various investigators. Wouters et a14 found correlation coefficients between frequency _ 020 dependence of resistance and resonant fre- quency on the one hand, and the forced vital Z-C', 0 15 + capacity and FEV, on the other, ranging from + + to Similar values were 0- 010 + 0+492+ 0O668. reported ~ ~ + + + + * + by Peslinetal.4 CO ~~~+ + + cc + ++ 4++ In histamine challenge tests in children, ++ ++ ++ + even stronger correlations between FEV, and 000o_ + + + + http://thorax.bmj.com/ + ++ impedance were reported by Lebecque et al,3 0$00 + + + especially for resistance at lower frequencies -0.05 + + and for frequency dependence of resistance. A explanation for the somewhat 0 possible -50 -40 -30 -20 -10 0 lo weaker correlations between the changes in (%) FEV, and in frequency dependence of resis- AFEV, tance and resonant frequency found in our

Figure 4 Relationship between the increase in the resistance at 28 Hz (AR28) and the study may be that provocation results in air =

rease on September 28, 2021 by guest. Protected copyright. deci in FEV, (AFEV,) (r 0458, p < 0001). trapping and thus in an increase in the func- tional residual capacity. Nagels et a122 showed that at higher lung volumes the resistance decreases and the reactance increases, result- ing in a decrease in resonant frequency and lessening of the frequency dependence of resistance. In a study by Van den Elshout et - 30 al39 on exercise induced bronchoconstriction, + + correlations ranging from 0O46 to 0O89 were + 25 + + + found between the changes in impedance and + + + + + + + in flow volume data. In contrast to the find- + 61 20 of + + ings others,6 reciprocal + the resistance at 8 Hz did not result in - + 5 + + ++ + stronger correlations between the changes in 1++: impedance and in FEV,. 0 - 10 + ++ + In this study, patients with bronchial asth- -.1 + X ma of wide ranging severity were challenged

+ with cold air. 5 -,+ + + + by isocapnic hyperventilation The same provocative dose was used in all $ o+0 + + subjects. In view of the moderate response in + terms of the decrease in FEV,, isocapnic 5 hyperventilation with cold air can be consid- -50 -40 -30 -20 -10 10 0 ered a safe method in provocation studies. AFEV,(%) We conclude that isocapnic hyperventila- tion with cold air in asthma patients results

Fiagure5 Relationship between the increase in resonant frequency (AfO) and the decrease in a decrease in FEV, and an increase in in (r = p < 0001). especially at lower 0-630,- , I oscillatory resistance, FEV,I %-(AFEV) Al I Forced oscillation technique and spirometry in cold air provocation tests 259

frequencies, a decrease in reactance at 8 Hz, 1969;26:670-3. 21 Grimby G, Takishima T, Graham W, Macklem P, Mead and an increase in resonant frequency of the J. Frequency dependence of flow resistance in patients as measured the tech- with obstructive lung disease. Clin Invest 1968;47: respiratory system by 1455-65. nique of forced oscillations. The changes in 22 Nagels J, Landser FJ, Van der Linden L, Clement J, Van Thorax: first published as 10.1136/thx.48.3.254 on 1 March 1993. Downloaded from the impedance of the respiratory system rep- de Woestijne KP. Mechanical properties of lung and chest wall during spontaneous breathing. Jf Appl Physiol resent an inhomogeneity in the peripheral 1980;49:408-16. compartment of the bronchial tree. These 23 Harf A, Decramer M, Zin W, Milic-Emili J, Chang HK. Respiratory resistance in dogs by the single-breath and observations demonstrate the value of adding the forced oscillation methods. 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