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2 LOST WORK DUE TO OBSTRUCTION IN HUMAN AIRWAYS DURING QUIET BREATHING W. С WILBERS

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4 Lost work due to obstruction in huan airways during quiet breathing

5 Preotor: Lector dr.h.h.beneken Koler.

6 LOST WORK DUE TO OBSTRUCTION IN HUMAN AIRWAYS DURING QUIET BREATHING PROEFSCHRIFT TER VERKRIJGING VAN DL GRAAD VAN DOCTOR IN DE GENEESKUNDE AAN DE KATHOLIEKE UNIVERSITEIT TE NIJMEGEN, OP GEZAG VAN DE RECTOR MAGNIF1CLS PROI. DR. A. J. H. VENDRIK VOLGENS BESLUIT VAN HET COLLEGE VAN DECANEN IN HET OPENBAAR TE VERDEDIGEN OP VRIJDAG 8 SEPTEMBER 1978 DES MIDDAGS TE 4 UUR DOOR WILLIBRORD CORNEÉIS WILBERS GEBOREN TE ROTTERDAM 1978 KRIPS REPRO MEPPEL

7 Want die clevgie -is so subbi 'I Daev ie o peynse lange wijl Dat vinden sy varino inder schrift Dit doet dat io et anxten dioht. Wille van Hildegaerdsberch (ostreeks 1409). Aan Julie,Arjen en Erik.

8 Dit proefschrift heb ik іюдеп bewerken in het Longfunctielaboratoriu (hoofd: dr. H.H.Beneken Kolraer) van de afdeling Anaesthesiologie (hoofd: Prof. dr. J.F.Crul) van het St Radboudziekenhuis te Nijegen. Technische adviezen zijn ij verstrekt door dr. M.J.M.Gielen en de instruéntele dienst (hoofd: ing. W.H.Theunissen) van de afdeling Anaesthesiologie. Drs. L.J.C.Hoofd,wetenschappelijk hoofdedewerker van de afdeling Fysiologie (hoofd:prof. dr. F.J.A.Kreuzer),is zo vriendelijk geweest de wiskundige basis van dit proefschrift te controleren. De longfunctieproeven zijn verricht door de hoofd-longfunctieassistente ej.h.j.m, van de Pluy. De statistische bewerking van de resultaten is verricht door ir.h.j.j. van Lier van de atheatisch-statistische afdeling van het Instituut voor Wiskundige Dienstverlening (hoofd:drs.ph. van Eiteren) van de Katholieke Universiteit. De tekeningen zijn vervaardigd door de afdeling van de Medische Illustratie (hoofd:j.j.m, de Bekker) en drukklaar geaakt door de afdeling Medische Fotografie(hoofd:A.Th.A.F. Reynen). Tenslotte dank ik allen die op enigerlei wijze hebben bijgedragen aan het tot stand koen van dit proefschrift.

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10 I CONTENTS. Sybols. IV I. Introduction: A. Historical review. 1 B. The body Plethysograph. 3 C. The use of the body Plethysograph easuring airway obstruction. 7 D. Suary 13 II. Purpose of investigation: A. The proble of airway resistance. 14 B. Lost work due to airway obstruction. 16 C. Purpose of investigation. 17 D. Sunary. III. The forula of W : к A. Introduction. 19 B. Substitution of ΔΡ by other factors. 20 С The forula of W. 21 D. Suary. 22 IV. Measureent of W R in a odel using the body plethyarograph : A. The body plethysnograph. 23 B. The odel in the Plethysograph. 25 C. Adaptation of forula for W R to the equipent used. 25 D. Measureents. 27 E. Results. 28 F. Discussion. 34 G. Suary. 35

11 II V. Measureent of W D in subjects using the body Plethysograph: A. Siilarities and differences in W К easureents between odel I and subjects. 36 B. Technique of the easureent of W С in subjects. Measureents. D. Results. E. Discussion. F. Sunary. VI. The significance of W_ as a clinical lung function test: A. Deterination of obstructive lung disease. 57 B. W R as a paraeter of airway obstruction. 58 C. W R forula of Matthys and Overrath. 60 D. Sunary. 63 к Suary. 64 Saenvatting. 67 References. 70 Appendix I. 82 Appendix II. 85

12 Ill SYMBOLS. DIMENSIONS. A A C,c с e F FEV. FIV 1 f f 0 κ ι к 2 к з К 4 к M in L N R Ρ ΔΡ Α = = = = = = = = = = = = = = = = = = = cross-section of a tube area of a diagra loop (ΔΡ - V ) J\ -L area of a diagra loop (Д ^ - V ) В 1 coefficient of proportionality cycles elastic odulus force forced expiratory volue after 1 s forced inspiratory volue after 1 s frequency function scale factor (V-) scale factor (Δν η ) scale factor (ΔΡ ) ( = 1) conversion factor (V ) exponent of Poisson's law ass inute length Reynolds nuber pressure alveolar pressure i.e. pressure gradient in the airways between alveolar space and environent of the subject L 2 L 2 L 2 M/L.T 2 M.L/T 2 L 3 L 3 1/T L 2 L 2 M/L 2.T 2 M Τ L M/L.T 2 M/L.T = pressure gradient between cylinder and end of the tube in a odel 2 M/L.T ΔΡ = sall pressure changes in outh 2 M/L.T ΔΡ = sall pressure changes in Plethysograph M/L.T P n = barorretric pressure M/L.T oar. R = airway resistance M/L.T r = radius of a tube L s = second Τ TC = total lung capacity 3 L

13 IV gas volue L gas volue displaceent through the wall of the 3 Plethysograph L vital capacity L gas volue in thorax at the end of expiration L gas volue of the Plethysograph containing a subject L stroke volue L tidal volue L gain or loss of gas volue due to copression or decopression inside thorax and abdoen,or inside cylinder in odel,during respiration L volue flow L /T work M.L 2 /T 2 lost мэгк due to resistance during one respira- 2 2 tory cycle M.L /T angle 3 between ΔΡ and Д П В dynaic viscosity M/L.T 3 density M/L

14 і.шгюоисгісм. A.Historical review. Measureents of airway resistance in hurran subjects have interested physiologists for nearly half a century.before that tie technical difficulties ipaired the easureent of airway resistance,although atheatical analysis of fluid echanics,facilitating the solution of probles concerning flow echanics of gases,started about three centuries ago. Torricelli(1644) described the flow velocity of a liquid through a sall orifice and was able to develop a forula for it: flow velocity is directly proportional to the square root of twice the product of acceleration of gravity and the height fro which the liquid flows.tvro centuries later Poiseuille (41) investigated the dynaics of blood flow through blood vessels. He discovered that flow velocity through a tube is directly proportional to the pressure gradient.osborne Reynolds(63) distinguished between lainar and turbulent flow patterns in coloured liquids. Rohrer (1915) was the first who applied the knowledge of fluid echanics to the easureents of airway resistance using an anatoical preparation of the huan lung. He divided the total airway into: - upper airways: outh larynx glottis - lower airways: trachea bronchus and bronchioli Rohrer supposed that gas flow through the lower airways was lainar, but turbulent in the upper airways.fro this assunption and che exact easureent of airway diensions in the different parts of the respiratory tract he was able to calculate airway resistance. It ust be stressed once irore that Rohrer' s conclusions concerning airway resistance resulted fro anatoical studies of the lung.

15 2 In 1927 von Neergaard and Wirz easured airway resistance directly in subjects. At that tie it was possible to easure flow velocity and volue flow. However, a direct easureent of the pressure gradient between alveolar space and environent, necessary to calculate airway resistance, was incessible. Therefore they developed the "airway interruption nethod". In this ethod alveolar pressure is supposed to be equal to outh pressure during interruption of the flow at the rrouth by a shutter for 0.1 s The value of the outh pressure at the oent of interruption is divided by the value of volue flow just before and after the rroent of interruption and so airway resistance can be calculated. The "airway interruption ethod" was corrected by Vuilleuier (1944) and Otis and Proctor (1948). Mead and Whittenberger (1954) criticized this ethod and proved that, although nouth pressure is about the sae as the dynaic coponent of ventilatory pressure (alveolar pressure) during interruption, the alveolar pressure just before interruption, at least theoretically, is not necessarily the sae as when airflow is stopped. DuBois, Botelho and Coroe (1956) introduced a new technique of easuring alveolar pressure by eans of a body Plethysograph. Since we also used this apparatus a description of this ethod will be given later (Section В of this chapter). Fisher, DuBois and Hyde (1968) published another technique of airway resistance easureent. They added to the gas flow of the spontaneous respiration a forced çscillation of 50 l of air with a sall pup. The pressure necessary to push this volue into the airways is known. The volue flow is easured with a pneuotachograph. The frequency of the pup has to be equal to the resonance frequency of the syste because only in this situation ipedance is equal to resistance. The resonance frequency, however, is hard to obtain and this is the difficulty of this ethod. In 1970 Sobol published a technique which to soe extent resebled the "airway interruption ethod" of von Neergaard and Wirz. The interruption tie was even shorter than that of von Neergaard and Wirz.

16 3 Vooren(1976) introduced a odification of the "airway interruption ethod" by neasuring the pressure in the outh at the end of the interruption period of s,and the volue flow just after the interruption. As a criticis of these different interruption techniques we like to point out the fact that pressure easured during interruption and volue flow easured iediately before or after interruption,are put together into a quotient representing the airway resistance which is according to the definition of DuBois et al.(1956):"...the ratio of alveolar pressure to airflow at a particular tie", i.e.the sae tie. The Plethysographie technique of DuBois et al.(1956) provides the opportunity to easure pressure gradient and volue flow at exactly the sane oent whereas a pressure equilibriu between pressures in alveoli and nouth is obtained during a relatively long period of about 2 seconds. B. The body Plethysograph. A Plethysograph is an apparatus that easures volue changes of a part of the body. The body Plethysograph easures volue changes of the whole body. It consists of an airtight box in which the subject is enclosed breathing air fre or into the Plethysograph. During respiration of the subject a pressure gradient between alveolar space and Plethysograph is necessary to ove gas into or out of the lungs. This pressure gradient is obtained by copression or deoorrpression of the gas volue in the thorax resulting in volue changes of the body. These volue changes of the body are easured by the body Plethysograph. One can distinguish two types of body Plethysographs: 1. The constant - volue Plethysograph. In this type changes of the body volue are easured as pressure changes in the Plethysograph (ΔΡ ). The gas volue of the Plethysograph is kept constant(figure 1).

17 4 2. The constant-pressure plethysnograph. In this type changes of the body volue are easured as gas volue displaceents out of or into the Plethysograph (AV).The pressure in the Plethysograph is kept constant. The gas volue displaceents can be easured with ( figure 2): a. a spiroeter: volue-displaceent body Plethysograph. (Mead,1960;Jaeger and Otis,1964). b. a pneuotachograph and integrator: flow-displaceent body Plethysograph. (Bosan et al.,1964;wasseran et al.,1966). ( Р АІ І ^ V Ppit inspiration expiration Fig. 1 Pressure changes in the alveolar space and plethysirograph during respiration. The lungs of the subject are represented as one single alveolus with an airway. Ρ sybolizes the alveolar pressure. Ρ, is the pressure inside the Plethysograph. (Gielen,1971.Published with perission of the author).

18 5 The easuring principle of the body Plethysograph can be sunarized as follows: Respiratory uscles in thoracic wall and diaphrag I Copression or deconpression of gas voluite in thorax I Changes in body volue Measured by body Plethysograph as pressure changes inside the Plethysograph (ΔΡ Π ). (Constant-volue Plethysograph) Measured by body Plethysograph as volue displaceent by a spiroeter or integration of volue flow (Л ). в (Constant-pressure Plethysograph). If teperature is constant inside the Plethysograph, pressure changes in the constant-volue Plethysograph and gas volue displaceent in the constant-pressure Plethysograph are ruled by Poisson's law: v k = (1) Ρ = pressure V = volue k. = quotient of specific heat at constant pressure and specific heat at constant volue С = constant

19 б 0 dp P' dvpl - integr^tor -^dv pl '4dvo / anoeter spiroeter pneuotachograph Fig. 2 Different types of plethysnidgraphs: a: constant - volurne Plethysograph. b: constant - pressure Plethysograph: Gas volue displaceents are easured by a spiroeter. c: constant - pressure Plethysograph: Gas volue displaceents are easured by integration of volue flow. (Gielen, Published with perission of the author)

20 7 С. The use of the body Plethysograph easuring airway resistance. The airway resistance (R) is the ratio of pressure gradient in the airways to volue flow (V) at a particular tie. The pressure gradient in the airways is the difference between alveolar pressure(p.) and pressure of the environent of the subject in which he is respiring (Varêne et al.,1966). Since the pressure gradient in the airways is obtained by copression or decopression of the gas volue in the thorax, the pressure gradient in the airways is equal to the changes of alveolar pressure (ЛР.). In 1956 DuBois and his colleagues used a constant-volue body Plethysograph for the easureent of airway resistance. The subject in the Plethysograph is breathing air into and fro the body Plethysograph through a tube which is provided with a pneuotachograph and a shutter. Between the outhpiece and the shutter a pressure transducer is located. Since the total aount of gas inside the plethysnograph-lung syste is constant, changes of alveolar pressure (АРд) ust cause changes of pressure inside the Plethysograph (ΔΡ η ) in the opposite sense. The relation between ΔΡ and AP R can be found if the subject perfors respiratory oveents with open glottis against a closed shutter. During closure, flow is zero and a pressure equilibriu between alveoli and outh is supposed to be achieved. If during closure of the shutter the pressure changes in the irouth (ΔΡ ) which are equal to the pressure changes in the alveolar space (ДР а ),are easured siultaneously with the pressure changes in the Plethysograph (ΔΡ η ), the relation between ΔΡ and ΔΡ η can be found. о ΰ The principle of the easureent of airway resistance is as follows: 1. During respiration V and ΔΡ_ are continuously plotted on a χ - у reti corder, V vertically, ΔΡ_ horizontally. In favourable cases a straight о line can be obtained which akes an angle with the x- axis. The tangent of this angle can be easured. 2. Then, respiration is interrupted by the shutter, while the subject continues to ake respiratory oveents. Pressure changes in the

21 8 Plethysograph (AP R ) and pressure changes at the irouth (ΔΡ = ΔΡ ) are plotted on the χ - y recorder, ΔΡ vertically, AP D horizontally. о Again a straight line is obtained, also aking an angle with the χ - axis fro which the tangent can be easured. The quotient of the tangents in both diagras gives the airway resistance: ΔΡ,/ΔΡ^ ΔΡ ΔΡ, _ÜL_1 = _E = -A = R (2) V/ΔΡ,, V V The ethod of DuBois has several disadvantages: a. DuBois claied that during respiration there should be a constant ratio between the gas volue of the thorax and the gas volue of the Plethysograph to get a constant relationship between alveolar pressure (ДРд) and changes of pressure inside the Plethysograph (ΔΡ^).The necessity of this assertion follows fro the elastic oduli (e) of both gas volues, which can be explained as follows: Supposing the ooposition and teperature of both gas volues to be equal, the elastic oduli of both gas volues are equal. The elastic odulus of a gas volue is the ratio of stress (ΔΡ) and the resulting strain (Л / ): ΔΡ e = (3) л / The elastic odulus of the gas volue in the thorax (e. ) is: e th = ^A ^th^th The elastic odulus of the gas volue inside the Plethysograph (eg) is: % ΔΡ Β AV B^B

22 9 Supposing e, = е_ gives: ΔΡ Α ^th^th ΔΡ Β Д В / в The оішге changes of thorax and Plethysograph are equal,so that: ΔΡ Α ΔΡ Β V B = 2- (4) V th ΔΡ can only be calculated fron ΔΡ if the quotient V /V, is kept constant.the subject,therefore,has to breathe very superficially with sall tidal volues to keep V/V ore or less constant. He has to pant with a high frequency,and in the literature this technique is called the "panting ethod of DuBois". In fact the coposition and condition of both gas volues differ. Therefore, the elastic oduli of both gas volues are not equal. With respect to this fact the relationship between др, and ΔΈ> is not constant,even if' there is a constant relationship between V D and V.,. th High flow velocity during panting results in a change of flow pattern (lainar,turbulent) in coparison with quiet breathing. This can lead to false conclusions as to airway resistance in quiet breathing. The proble whether a pressure equilibriu is achieved between alveolar space and outh during interruption of gas flow at the outh is not solved. During panting the subject tends to breathe at a higher level of lunginflation as copared with quiet breathing.this ay lead to an underestiation of airway resistance.due to this fact and the concoitant high flow velocity,airway resistance during panting ay be quite different fro airway resistance during quiet breathing.

23 10 DuBois' ethod has also advantages: a. If the air inhaled is not the sane as the air in the Ivgs, probles arise when woricing with the body Plethysograph which can be explained as follows. Inspiratory air expands due to an increase of teperature and saturation with water vapour. The reverse occurs during expiration. These volue changes are superiposed on the paraeter of interest,i.e.,the changes of thoracic gas volue, due to conpression or deoonpression. During panting this error cannot occur because the subject is rebreathing very sall tidal volues through the heated breathing tube and there is no difference in teperature and saturation with water vapour between inspiratory and expiratory air. Another ethod for solving this proble was described by Bargeton et al. in He used an electronic copensation for the error described above. b. Although the proble of equilibriu between alveolar pressure (АР Д ) and outh pressure (ΔΡ ) during interruption of the gas flow at the outh still exists in the Plethysographie technique, this technique has an iportant advantage above the "airway interruption ethod" of von Neergaard and Wirz. We ay, therefore, refer to the article of DuBois et al. (1956) by quoting their words: "The difference between this ethod (DuBois 1 ethod) and previous interrupter ethods is that the interruption of flow in the present ethod is erely the eans of calibrating the changes in plethysiragraph pressure in ters of alveolar pressure; the values for resistance are always obtained during uninterrupted airflow." In the so - called airway interruption ethod, however, alveolar pressure is deterined at interrupted gas flow. с Direct visualizing of the AP_/V curve gives an iediate irtpression of the resistance. The so-called "panting ethod" of DuBois has led to contradictory results between different authors.

24 11 Jaeger and Otis (1964) found that airway resistance during panting is higher if copared with resistance during quiet breathing. They attributed this phenoenon to turbulence in the upper airways. Hcwever/Peset (1969),Stanescu (1972) and Barter (1973) found experientally that airway resistance during panting is saller than during quiet breathing. The contradictory results between different authors can possibly be explained by the different conditions during the easuresnt of airway resistance. If flow velocity,tidal volue,breathing frequency and state of inflation are not standardized during the easureents,different results ay be expected. Bouhuys and Jonson (1966) easured the airway resistance in a constantvolue plethysrrograph at different states of lung inflation. They found that airway resistance is saller if the lungs are ore inflated. Uler (1965) introduced the "panting ethod" as a clinical lung function test. He found that especially in patients with obstructive lung disease, the (ΔΡ - V) diagra shows an ellipsoid fro (fig.3). At the side of expiration this ellipsoid has a caracteristic configuration. However, the tangents at several points of the curve have different slopes, so that resistance, the quotient of pressure gradient and volue flow, has different values. At the end of this chapter vre have to ention the rearks of Sidt and Muysers (1969) with respect to the body Plethysograph and the easureirent of airway resistance in particular. The rearks of Sidt and Muysers with respect to the body Plethysograph are: 1. The stability of the walls of the plethysrrograph has to be perfect with respect to pressure changes in the Plethysograph. 2. The respiratory quotient of the subject and the increase of teperature inside the Plethysograph induce a drift in the recording of 3. The value of exponent к in Poisson' s law,р.\л = С is unknown. This law fors the principle of the body plethysiragraph and will be discussed in chapter III-D.

25 12 ДРд(ст HjO) / Fig. 3 (ΔΡ - V) diagra in obstructive lung disease.several tangents are drawn to the curve. Uler used these tangents as paraeters to interpret the airway resistance. (Slightly nodifled after Uler,1965)

26 13 The rearks of Sidt and Muysers with respect to airway resistance are: 1. Due to the fact that,probably,the flow is not lainar as Jaeger and Matthys could deonstrate, there is no linear relationship between pressure gradient and volue flow. The airway resistance does not have a constant value. 2. There nay be a phase shift between pressure gradient and volue flow, so that the quotient between the cannot be deterined at every rroent of a respiratory cycle. 3. The diaeter of the airways varies during respiration leading to different values of airway resistance. The rearks of Sidt and Muysers with respect to airway resistance have such a fundaental character that the eaning of easuring airway resistance becoes questionable. In chapter II vie shall discuss airway resistance in ore detail. D. Surary. Measureent of airway resistance can be done by several techniques. The difference between various techniques resides in the deterination of ΔΡ. DuBois et al. (1956) introduced a new technique in which ΔΡ is deterined by a body Plethysograph. This technique is subject to soe objections which are described. Airway resistance defined as the quotient of pressure gradient between the alveolar space and the environnent and volue flow has no one single value during respiration.

27 14 II. PURTOSE OF INVESTICATION. The purpose of this investigation is to search for a paraeter of airway obstruction during quiet breathing. The only directly available paraeter until now is airway resistance (R).Airway resistance, however, has not a oonstant value during respiration. In this chapter we will try to find better inforation about the relationship between ΔΡ. and V. The iplications of this relationship with respect to airway resistance ay lead to another concept called " lost work due to obstruction". A. The proble of airway resistance. If a gas flow through a straight tube is governed by only four physical factors, for instance: a. pressure gradient per unit of length: ДР/ЛЬ b. viscosity: μ c. radius of tube: r d. volue flow: V it is possible to derive, using the Π - theore of Buckingha (1915), the forula: ΔΡ _ V.y.c ДЬ 4.П.Г 4,c\ с = a constant without diension. This forula which is well known as Hagen-Poiseuille's law for lainar flow shows that there is a linear relationship between pressure gradient and volue flow under these particular conditions. If, however, a gas flow through a tube is governed by ore than four physical factors,for instance if density (p) also plays a role, the application of the Π - theore gives a different result:

28 15 ΔΡ V^P-C-ÜNR) (б) AL 2.П 2.г 5 f(ν ) = function of Reynolds nuber. It is evident that in this case there is no linear relationship between pressure gradient and volue flow.it follows fro forulas (5) and (6)that for a particular syste under particular conditions the relationship between pressure gradient and volue flow can be described by the siple, general forula: Ρ = C.V a In this forula С is a constant which depends on the physical properties of the syste and the flowing gas. Exponent a varies fro 1 to 2 depending on the type of gas flow. If the flow is lainar a is equal to 1. If the flow pattern changes fre lainar to turbulent, a becoes greater than 1. АРд (c H 2 0) V (crnvs) Fig. 4 ΔΡ - V diagra. For explanation see text

29 16 In figure 4 this siple forula has been applied to huan airways (ΔΡ = ΔΡ ) and has been represented graphically. Two graphs are drawn, one when the gas flow is lainar (ΔΡ = C.V), the other when gas flow is turbulent (ΔΡ = C.V). Vie suppose that both curves intersect at point A. If starting fron point A the alveolar pressure (ΔΡ.) is increased and the flow reains lainar, the airway resistance rsnains constant (point B). If, however, the flow pattern becoes turbulent, point A is oving to point С and the airway resistance increases. This eans that, at the sae alveolar pressure,two or ore values of airway resistance can be calculated depending on the existing flow pattern. Moreover, it is very unlikely that the gas flow in huan airways is governed by only four physical factors, so it cannot be expected that a linear relationship between volue flow ( V) and pressure gradient exists. The usefulness of one single value of airway resistance is, therefore, doubtful, especially if a loop appears in the ΔΡ - V diagra as in the case of patients with obstructive lung disease. This eans that if we are interested in a paraeter of airway obstruction during respiration, we should better look for another easure. B. Lost здэгк due to airway obstruction. Let us assue that a force (F) is acting on a gas volue in a tube which has a cross section A. If this gas volue in the tube is displaced by a distance (dx),' the aount of work (dw) perfored is equal to: dw = F.dx (7) Because pressure (p) is equal to force per surface area it follows that F = A.P Cross section (A) tines sall distance (dx) is equal to the sall displaced volue (dv): dv = A.dx

30 17 So forula (7) ay be written as: dw = P.dV The total aount of югк (W) which has to be perfored during displaceent of gas volue (V) in the tube is: W = OJ ' V T P.dV (8) This vrork (W) is spent on oving a gas volue against resistances. We call this : lost work due to obstruction to gas flow. Applying forula (8) to the situation in huan airways the displaced gas volue is equal to the tidal volue (V,^). Pressure (P) corresponds to alveolar pressure (АР Д ) So the work lost due to obstruction in the airways during inspiration and expiration is : i V T W R = I AP A.dV (9) W can be considered as a paraeter of airway obstruction during the whole period of the respiratory cycle. In contrast to airway resistance (R),which fixes the attention to one arbitrarily chosen oent of the respiratory cycle, W covers the work of the whole inspiration and expiration. In our opinion, therefore, W R is a better paraeter of airway obstruction than airway resistance. C. Purpose of investigation. The purpose of this investigation is to introduce W as a paraeter of airway obstruction into clinical lung function testing. Although a forula for W can be derived, still a proble exists in the easureent of ΔΡ,,.Ιί alveolar pressure (ДР Д ) cannot be easured direct-

31 ly in subjects (for instance in a constant-pressure Plethysograph) ΔΡ should be replaced by other easurable factors. The following chapters are dealing with these probles, i.e.: 1. Replacing ΔΡ in forula (9) by other easurable factors: Chapter III. 2. Measureent of Vl, in a odel using the body Plethysograph: к Chapter IV. 3. Measureent of W in subjects: Chapter V. 4. Significance of W R in clinical lung function testing: Chapter VI. D. Sunary. The purpose of this investigation is to search for a paraeter of airway obstruction during quiet breathing. The value of airway resistance used as a paraeter of airway obstruction is subjected to discussion, bost яэгк (W ) due to obstruction is,in our opinion, a better paraeter of airway obstruction. This paraeter involves the entire respiratory cycle of inspiration and expiration. A forula for VL, is introduced.

32 19 III. THE FORMULA OF W_.. К A. Introduction. Since we have a constant-pressure Plethysograph in our laboratory in which a direct easureent of ΔΡ is ipossible, we have to replace ДРд in forula (9) by other easurable factors. Ihis replaceent gives rise to probles which we shall discuss using a nodel (fig. 5). The odel consists of a punp connected to a tube. At the end of the tube a shutter (S) is located. The gas volue displaced during an entire oveent of the piston in one direction is called the stroke volutte (V ). In analogy to subjects this stroke volue can also be called tidal volue (V_). The pressure difference between inside and outside the cylinder is (P - P2) = ΔΡ. Moveent of the piston to the right is expiration, to the left is inspiration. V is the gas volue in the odel at end - expiratory position and (V + V ) is the gas volue when the piston is at end-inspiratory position. P., is the baroetric Bar pressure. This pressure is equal to the pressure inside the cylinder when the shutter is open and the piston is at the end - expiratory or end - inspiratory position. (Рі-Рг) Fig. 5 A punp is rroving a gas volue through a tube. Pressure gradient is (P. - P 2 ) = ΔΡ, stroke volue is V, tidal volue is V-,.

33 20 В. Substitution of ΔΡ by other factors. The relationship between pressure and volue of an enclosed gas volue is ruled by Poisson's law: P.V 3^ = С (1) If according to Jaeger and Otis (1964) exponent к is supposed to be equal to 1, changes of pressure and vole are related as: ΔΡ =-^±1ν Δν Anticipating the experients on huan subjects we can say that the volue changes are very sall with respect to the original volue ( about 80 l to 3000 l).therefore, Д in the dencinator of this forula can be neglected,so: ΔΡ = - -. Д Applying this result to our odel or to huan subjects we get: AP A = -r^ v c (10) ΔΡ Α = the pressure gradient in our odel or the alveolar pressure in huan subjects. Pp. = the barostric pressure which is equal to the original pressure in our odel or in huan lungs. V = the change of gas volue due to copression or decorrpression of the original gas volue. This change of gas volue can be easured by a constant-pressure body Plethysograph.

34 21 V = the original gas volue The quotient Ρ /V in forula (10) is not constant during respiration Bar because the gas volue (V) varies between V and (V + V ), V being the end-expiratory gas volue and ( V + V T ) the end-inspiratory gas volue.we found a ean value of P., /V between the extrees P /V Bar Bar о and Ρ /( V + V ) (Appendix I) and introduced this ean value in forula (10), so this forula changed into: ΔΡ Α = Ρ ^. V c (11) ^ (V? + V.VJ In this forula (11) V needs further explanation. If for exaple the piston starts oving fro the end-inspiratory position the gas volune in the odel has to be oopressed before gas can flow out of the odel. The change in gas volue due to copression ( or deconpression in the reverse direction) which is aintained during the oveent of the piston is called V. As will'be seen in the next chapter this volue change can be neasured directly by a constant-pressure body Plethysograph. С. The forula of W 0. Replacing ΔΡ in forula (9) by the result of equation (11) we get: ρ Ял ν- W R =. i V.dV (12) /(v +v o.v T ) In this equation all factors are easurable by a constant-pressure plethysnograph. However, the forula of W is only correct if the exponent к in Poisson's law is equal to 1. The proof of this oondition will be given in the next chapter.

35 22 D. Sary. Using a odel consisting of a punp connected to a tube a forula for W_ has been derived in which all factors are easurable. A ean value к for Ρ /V during the oveent of the piston in the odel is calculated. Forula (12) can only be applied if exponent к in Poisson's law is equal to 1.

36 23 IV. MEASUREMENT OF W,, IN A MODEL USING THE BODY PLETHYSMOGRAPH. A. The body Plethysograph. Because Gielen (1971) has given a full description of our Plethysograph * it is sufficient to describe soe details which are iportant for our easureents. 1. In the front wall of the Plethysograph a Fleisch pneuotachograph connected to an integrator is inserted. In this way volue displaceent (Д -,) out of or into the Plethysograph can be easured. 2. In the breathing tube a Fleisch pneuotachograph is located connected to an integrator so that tidal volue (V T ) can be deterined. 3. Pressure changes (ΔΡ ) inside the breathing tube are easured by an electric differential anoneter. 4. Teperature inside the body Plethysograph can be easured. 5. An electroagnetic shutter is located inside the breathing tube vaiich can be controlled fre outside the Plethysograph. 6. All easureents can be recorded on an χ - y recorder. * Manufactured by Fenyves and Gut, Basel,Switzerland.

37 24 ГЦ. " HT 'V {EErîEl \' T D^= re ^ _ Harvard pup 'ocel 607) W= Fig. 6 Constant-pressure Plethysograph; a pup is placed inside the Plethysograph. Д,, : gas volue displaceent through the wall of the Plethysograph ΔΡ : pressure at the outhpiece S : shutter V- : tidal volue (Reproduced with odification by perission of Gielen, 1971),

38 25 B. Ihe odel in the Plethysograph. A Harvard pup (odel 607) is placed inside the Plethysograph (fig. 6). The outlet is connected by a wide - bore tube to the breathing tube inside the Plethysograph. The axial stroke volue of this puitp is about 1.1 litre The frequency of the puirp can be controlled fro outside. The frequency range of the pup can be varied fro zero to sixty per inute. To the wide - bore tube a 5-litre bottle can be connected, siulating a lung volue of 5 litres. Vfe used two odels in our experients: del I : with a 5-litre bottle. MDdel II : without a 5-litre bottle. The bottle is filled with aluinu pellets which are used in order to obtain isotheric conditions during copressing or deconpressing (Gielen, 1971). The oonnections of tubes and bottle are sealed with silicone grease.known resistances can be inserted into the tube at the outlet of the pup (R in figure 6). We used twd resistances, one being 4 c H 2 0/l/s,the other 2 c KO/l/s. C. Adaptation of forula for W R to the equipent used. In chapter III we have derived a forula for Wo (12) in viiich all factors are easurable. : is easured directly in Hg and converted into c H_0 by ultiplying by : tidal volue is easured at the outhpiece fro the integrated pneuotachogra. The absolute value of V is calculated fro i 3 the paper recording using a scale factor К (diension L /L). : In order to obtain a gas flow out of or into the cylinder of our odel, a pressure gradient has to be built up between

39 26 inside and outside the cylinder. This pressure gradient arises frorn the oonpression or deconpression of the gas voluine inside the cylinder by the piston. As we have seen in chapter III the volue changes vdiich acoopany oonpression or decopression are called V. These volue changes are equal to the gas volue displaceents out of or into a constant-pressure Plethysograph which can be easured and are called Д. The absolute value of Д _ can be calculated fro the paper 3 recordings using a scale factor K_ (diension L /L). 4. V : We have defined V as the original gas volue in the odel at the end-expiratory position of the piston. If the shutter is closed at this position and the piston is oving to and fro with a certain frequency the gas volue locked up in the cylinder and tube is conpressed or decopressed. As a result gas volue displaceent (AV R ) out of or into the Plethysograph takes place which can be easured. Pressure changes (ΔΡ ) are siultaneously easured proxial to the shutter during copression or decopression. Both easureents (volue displaceents and pressure changes) are recorded on an χ - y recorder, AV R on the y - axis, ΔΡ on the χ - axis. In this way a straight line is obtained, which akes an angle α with the χ - axis. If the original pressure in the odel is equal to Ρ and supposing that к = 1 (chapter III), we get with reference to chapter III: V 0 Л В = s. V ΔΡ Replacing Δν^/ΔΡ by tg α and two appropriate scale factors Κτ for Л,, (diension L /L) and K-, for ΛΡ_ (diension M /L /T ), ^ li J we get: V = tg a.k 2.K 3.P.1.36 (13) ^

40 27 5. V Τ ι V.dV с This integral cannot be solved atheatically. Hcwever,AV (= V ) and V can be easured siultaneously and recorded on an χ - у recorder (Д П on у - axis, V^, on χ - axis) resulting in a loop. If the surface of the loop is equal to A^., and using again the appropriate scale factors К get: rv, Τ and K-, we 'V r V c.dv = (i AVg.dV = b^.i^.ag (14) Using forulas (12) and (14) the following forula of VL can be derived for the odel in which all factors are easurable and W is expressed in Joule according to the S.I. syste R _7 (Visser, 1973) by ultiplying with Κ.,Κ,.Α.-.Ρ Ю -7 W = 1 2 "В Bar = я _ (ι5) / ( V Т.К 1 ) D. Measureents. The following iteasuretnents are perfored: 1. Measureent of tg a at different frequencies of the pp ( 14,,22, 26,30,34 and 38 c/in) in odel I (with bottle) and odel II (without bottle) in the way described before. During these easureents pressure changes are kept between the liits of + 30 c Н? 0 and - 30 c H? 0 because pressure changes also occur between these liits in subjects. 2. Measurenents of W D in odel I only (with bottle). As we have seen we need twd easureents (V and A^) for the calculation of Itf. During easureent of V the shutter is closed, but R о open during easureent of А_.

41 28 W is easured in three groups of experients: group I tidal volue (V ) about 400 l. pip frequencies (f) 10,14,,22,26,30 c/in resistance in the tube 4 c H 2 0/l/s. - group II - group III tidal volue (V ) pup frequencies (f) resistance in the tube tidal volue (V ) pup frequencies resistance in the tube about 850 l. 14,,22,26,30 c/in. 2 c H 2 0/l/s. about 850 l. 10,14,,22 c/in. 4 c H 2 0/l/s. During the easureents P is read off. Before and after each eatìar sûreent the scale factors K, and K 2 are deterined. E. Results. 1. The results of the easureents of tg α are shown in figure 7. It is clear that in odel I (with bottle) tg α is nearly constant at different frequencies of the pup in contrast to the easureents with odel II (without bottle). 2. The results of neasureents of Wj, are listed in table I and plotted к in figures 8 and 9. For each group of experients there are tvro curves which will be explained in the discussion. Anticipating this discussion we ay say that W frequency of the pup rises. IS. increases when the

42 29 tg α 07І З frequency Fig. 7 Measureent of tg α at different frequencies. Open circles : Model I,with bottle. Closed circles : Model II,without bottle.

43 30 Fig. 8 W is calculated at different frequencies of the pup к in group I. Open circles: W R calculated with forala (15). Closed circles: W D calculated with forula (9).

44 31 Fig. 9 W D is calculated at different frequencies of the pup in groups II and III. Open circles: W R calculated with forula (15). Closed circles: W R calculated with forula (9).

45 Table I: Data of W R easureents in odel I. The various groups are described in chapter IV-D. Group tga V o c f c/i_n v T c K l c ii K 2 3 c i h it A 2 i W R (15) Joule W R (9) Joule I ui Ν) II N (9) : Wp, calculated with forula (9). К к νΐ η (15): VL calculated with forula (15). R К

46 Table I: (continuation) Group tga V f v K 2 *B A W R (15) W R (9) an 3 / c/in c c n c 2 2 inn i i Joule Joule W 0 (9) : Vi, calculated with forula (9). VL(15) : VL calculated with forula (15).

47 34 F. Discussion. The derivation of forala W (12) in chapter III is based on the assurnption that during the easureents exponent к in Poisson's law ust be equal to 1. To support this assuption we tried to find out the influence of exponent к on the data of our experients. Applying Poisson's law to a gas volue with an original pressure Ρ and an original gas volue of V we get after differentiating: dp _ P Bar dv " K V о In our experients with odel I, tg α does not change at different frequencies of the ршр. This eans that dp/dv did not change at different frequencies of the pup. Assuing that Ρ and V are constant during the easureents it follows that к ast be constant at different frequecies of the pup. This eans that in odel I the theral conditions do not change at different frequencies and that changes of tenperature due to copression or decopression of the gas volue are iediately abolished by the aluinu pellets. This was also forced by Gielen (1971). What we have to prove now is that к is equal to 1. Therefore, we calculated W not only with forula (15) but also with forula (9). The latter forula can be used in odel experients only because in this case it is possible to easure ΔΡ directly which is ipossible in subjects. In the sae anner as we have described for the solution of the integral in forula (15) (chapter Г -С) we can solve the integral in forula (9): Pressure changes and tidal volues are plotted on an x-y recorder giving a loop,the surface of which (A) can be easured. The results of easureents using forula W (9) are listed in table I and іл. in figures 8 and 9. We see that the results obtained with forula

48 35 (9) agree quite well with the results obtained with forila (15) except in group III above 1.1 Joule. Fro the fact that the curves obtained fran two different forulas (9 and 15) practically ooincide,it ust be concluded that к is equal to 1. The conclusion fro our experients is that the forula for W (15) which we have derived atheatically gives reasonable results if it is applied to experients using a odel. In the next chapter we shall use this forula in subjects. G. Sary. Using a constant-pressure Plethysograph W is easured in a odel with an adapted forula. The odel, a Harvard pup odel 607, is placed inside the Plethysograph. The pup outlet is connected by a tube with the outhpiece. TWo odels are used: odel I with a 5-litre bottle filled with aluinu pellets and connected to the tube, and odel II without bottle. W is easured and calculated in odel I using tvro different forulas. The results of both forulas agree quite well until a value of 1.1 Joule is reached. If the odel is connected with a 5-litre bottle filled with aluinu pellets,it appears that copression or decopression of the gas volue occurs isother ally at different puitp frequencies. It is also concluded that the exponent к in Poisson' s law is equal to 1 if the odel with the 5-litre bottle filled with aluinu pellets is used.

49 36 V. MEASUREMENT OF W-, Ш SUBJECTS USING THE BODY PLETHYSMOGRAPH. R ' A. Siilarities and differences in W neasureraents between odel I and subjects. If we copare easureents of W_ in odel I (with bottle) with those к in huan subjects, we can distinguish siilarities and differences. Siilarities are: a. Gas volues susceptible to corrpression or decopression in odel I and in subjects are about the sae. b. Frequencies used in odel I correspond to breathing frequencies during W R easureents in subjects. c. Tidal volues in odel I and subjects are about the sae, although soa subjects ay breathe with an even larger tidal volue. Ad a. As entioned in chapter III, V is the total gas volue of the cylinder and bottle at the end-expiratory position of the piston. In huan lungs it is soeties difficult to easure V (= the intrathoracic gas volue at the end of expiration) due to its relation to trapped air which influences the agnitude of factor V. A hypothetic situation in the odel ay reveal the relation between V and trapped air. Let us iagine that an air-filled balloon is placed inside the cylinder. This situation is chosen in analogy to a gas volue cut off fro the rest of gas volue in thorax and abdoen. Now the question arises: Can the gas volue locked up inside the balloon be considered as a part of V or not? Vte ay also put the question in another way: Ίο what extent is the gas volue inside the balloon easured during the easureent of V? (figure 10.)

50 37 i Ô ΔΡη о I V, = Д о Fig. 10 Air-filled balloon inside the cylinder. For explanation see text. Two extree situations ay occur between which a gradual transition is possible: - The balloon wall is very stiff. Copression or deconpression of bhe gas volue in the balloon is ipossible. This gas volue is not easured in deterining V. - The balloon wall is very flaccid. The gas volue in the balloon is equally copressed or deconpressed in conparison with the rest of the gas volue inside the cylinder. Now the gas volue of the balloon is easured indeed in deterining V. Of these two extree situations, the forer ay gradually change into the latter and vice versa, so the gas volue inside the balloon is sasured only partially during the deterination of V. Fro this exaple it is clear that V is equal to the gas volue inside the cylinder at the end of expiration in so far as it is susceptible to copression or decopression. If an isolated part of this gas volue is

51 38 (partially) susceptible to oonpression or decopression it is (partially) easured during the easureent of V. In accordance to the odel, V in subjects is equal to the total copressible gas volue in the lungs, whether trapped or not, which ay be different fro the end-expiratory gas voluire deterined with the heliu dilution ethod. Differences between odel I and subjects are: 1. Fro experients the conclusion is deduced that the process of copression or decopression in odel I is isotheral (chapter IV-F). Notwithstanding the differences between the conditions of the gas volues in odel I and in subjects, this process is also supposed to be isotheral in subjects because tenperature changes are ruled out nrediately by blood flow, so exponent к in Poisson' s law (P.^ = C) ust be equal to 1 (DuBois et al.,1956; Gielen,1971). 2. The gas volue inside the body Plethysograph is wared up by the subject and expands. This expanding gas volue results in a drift of Д (Sidt and Muysers, 1968). This was also deonstrated experientally by Jaeger and Otis (1964). The drift is very sall after a period of 15 in (figure 11). However, waiting until this period is over in order to obtain a ore or less stationary zero line results in another drift of Д due to the respiratory quotient,which becces apparent after this period of 15 in (Bargeton et al.,1957). At the sae tie cooperation of the subject tends to diinish and the easureent of W 0 becoes irrpossible. The proble of a drift of Д can be solved as follows. An exponen- Б tially changing ter is added to Д _ resulting in a new base line. о The exponentially changing ter to the tie constant of the drift of Д should have a tie constant equal. In our Plethysograph exponentially changing ters with different tie constants can be added to the zero line of Д. The appropriate tie constant is chosen в by stabilizing the new zero line of ÄV R on the horizontal axis of the scope by one or two available tune constants.

52 39 l ì о.. о :. S β «. :! 5 5 β * : * 5 S 9 î \ Γ ΙΟ -г- 15 Fig. 11 Diagra of Jaeger and Otis (1964). Displaced gas volue fro Plethysograph due to change in teperature and water vapour saturation. (Reproduced with perission of the authors.) Because the respiratory quotient is norally less than 1, gas volue inside the Plethysograph decreases and gives rise to a drift of Д - in the opposite sense (Sidt and Muysers, 1968). The loss of gas volue is extreely sall with respect to the gas volue inside the Plethysograph, and it takes about 15 in before the loss of gas volue due to this factor becoes apparent.this is a relatively slew phenoenon (Bargeton, 1957). If easureents are perfored within 2 or 3 s it does not play any role in the easureent of W.

53 40 4. Tidal volue is wared up and saturated with water vapour during inspiration. During expiration the tenperature of expired gas decreases and the expired gas loses its water vapour. This eans that V is not the sane during expiration and inspiration. To avoid errors due to this phenoenon,v, which is easured at ATPS conditions inside the plethysnograph, ust be converted to V at BIPS conditions using a factor called K.. The different values of K. corresponding to conditions inside the Plethysograph are given in table II. Table II: Values of K. at different tenperatures inside the Plethysograph. Tenperature inside the Plethysograph. in С 0. К When calculating W_ in subjects, partial water vapour pressure at IV body tenperature has to be subtracted fro baroetric pressure because this partial pressure is only dependent on tenperature and is not influenced by conpression or decopression. In forule W (15) partial water vapour pressure (P ) has to be к H20 subtracted fro P ізаг Tidal volue and frequency are closely related in subjects in contrast to the conditions in odel I. In subjects only sall tidal volues

54 41 can be breathed at high, frequencies, otherwise hypocapnia ensues. 7. Pressure gradient Δ Рд can be easured directly in irodel I but only indirectly in subjects. B. Technique of the easureent of W R in subjects. The technique of the easureents of W parts: in subjects is divided into two 1. Measureent of V. о 2. Measureent of the loop surface {AJ) in the diagra (Δ V_ - V_). M 1. We siultanuously plot Δ V on the y-axis and Δ Ρ on the x-axis of an X - Y recorder. The shutter is closed and the subject is asked to ake respiratory oveents with open glottis against the closed shutter. Making this anoeuvreι a. straight line is obtained which akes an angle with the x-axis. Subtracting partial water vapour pressure at body tenperature fron the baroetric pressure, V can be calculated with forula (13) derived in chapter IV-C: V o = tga. К 2.Кз (Рв^-Р^) 1.36 (16) Ad 2. The diagra loop (Δ V n - V^) appears on the Χ- Y recorder if Δ ν η is plotted vertically and V horizontally when the subject is breathing through the breathing tube with open shutter. The surface of the loop (Ац) can be easured with a planieter. In this chapter (section A) we have discussed the drift of the zero line of Δ V. An identical phenoenon occurs in the zero line of V. The conditions of the gas inside the Plethysograph (tenperature, saturation with water vapour) are changing due to the presence of a subject inside

55 42 the Plethysograph. The change of conditions of the gas volue inside the Plethysograph to which V- and Δ V belong,therefore, influences the drift of V and Д equally, so the tie constant of Л ay be used to correct the stability of V as well. An iportant point in this technique is to take this diagra rapidly within 1 or 2 inutes, otherwise the tune oonstant has to be changed. Taking into account the differences between odel I and subjects discussed in this chapter sub A, forula W R (15) turns into: К W R = K "B'^Bar ^.g -P ^ Ο 7 ) ".10- ί " 1 (17) К V_"+V 2.V.K,-K. "o " tv o' v T, ' 4 r 14 4 С. Measureents. Measureents of W R have been perfored in the following groups of subjects: 1. Control group: This group has the following characteristics: Age: between and 40 years. Sex: 20 en breathing with tidal volues between 1000 and 1500 l. 23 лэтеп breathing with tidal volues between 750 and 1000 l. The liits of tidal volue are chosen arbitrarily due to the fact that ost individuals in the Plethysograph are breathing with these tidal volues due to the enlarged dead space of the breathing tube. All these subjects were: - Living and vrorkg the sae region as the group of patients which we exained later. - They did not soke and had no conplats of respiratory or cardiovascular disease 2. Miscellaneous group of "healthy" sokers and non - sokers; This group consisted of 43 subjects of between 20 and 35 years without coplaints of cardiovascular or lung disease. 3. Group of 13 sokers and 13 non - sokers: This group was aselectively chosen fro ale University personnel, aged between and 40 years.

56 43 They had no coplaints of cardiovascular or lung disease. During the easureent tidal volue was between 1100 and 1500 l. 4. Group of 116 patients: These patients were referred to the lung function laboratory for reasons of: - respiratory diseases: obstructive or restrictive - pre - operative screening In this group the following easureents were also perfored: - ЕЕ д^ in liters - FEVj/VC - FIV. in liters - F^/VC - peak flow in liters/seconds. D. Results. 1. Control group. The data of this group are listed in table III (en) and table IV (woen). 2. Miscellaneous group of healthy sokers and non-sokers. The data of this group are collected in figs. 12 (woen) and 13 (en). In these figures V is plotted horizontally and W vertically. These diagras suggest the following points: - W R sees to be an exponential function of V T. - Sokers (closed circles) see to have higher values of W^ than к non - sokers (open circles). 3. Group of 13 sokers and 13 non - sokers. Ihe data of this group are listed in table V.

57 Table III: Control group Men, with tidal volue between 1000 and 1500 l. V f Nae Age Weight V o T ^ K 4 K l K 2 P Bar W R year kg an an c/in n Joules R.S. T.A. J.H. M.G. F.T. P.D. F.P. G.R. F.W. J.С H.T. F.S. L. R.V. J.V

58 Table III: (œnt.) Nae Age Weight V V^, f 3 3,. year kg c c c/in ^ K 4 K l K 2 P Bar W R Joules A.A. A.V. W.B. I.B. W.J Я ean stand. dev

59 Table IV: Control Group Woen, with tidal volue between 750 and 1250 l. Nae Age Weight V V f Α,, Κ. Κ. K n? íil ^ ^ o T Ъ Bar R year kg c an c/in n ir Hg Joules E.O A.K I.D W.M P I.R F.T C.W I.S S.S R L.V W.W I.H

60 Table IV: (cont.) Nae Age Weight V V f 3 3,. year kg c c c/in h 2 rt K 4 K l K 2 P Bar it Hg W R Joules V.A. L.K. K.A. P.T. C.S. R.G. B.R. C.T. J.S ean stand. dev

61 48 WB (J) au,39 Ψ n ».22 o2i 34,2' 2i (.-7, a 24 1Θ т (cn-ä)-io 2 Fig. 12 Data of W nieasuranents in woen. H. V horizontally, W R vertically. Open circles: non - sokers. Closed circles: sokers. The figureß of the points refer to respiratory frequency during easureent of W D.

62 49 W R 'J)- 04 Ю -Р,7 19 2" т (ст3 )10 г Fig. 13 Data of W R easureinents in en V horizontally, W_ vertically. Open circles: non - sokers. Closed circles: sokers. The figures of the points refer to respiratory frequency during easureent of W. K.

63 Table V: Coparison between ale sokers and non - sokers. a. sokers, with tidal volue between 1100 and 1500 l. Nae Age Weight V o V T f % K 4 K i K 2 P Bar W R year kg.c c c/in inn Hg Joules M.B. F.P. W.V. J. B. F.M. S.G. W.W. B.L. W.K. M.S. T.A. H ean stand dev

64 Table V: Coparison between ale sokers and non - sokers. b. non - sokers, with tidal volue between 1100 and 1500 l. Nae Age Weight V o V T f Ag K 4 Kj K 2 Р ^ W R year kg c c c/in πτη Hg Joules F.T A.A M.G. H.S. J.II. T.B H.V. J.С L F.W. F.S J.W H.T ean dev

65 52 4. Group of 116 patients. The data of this group are listed in appendix II. E. Discussion. W к easured in control group. In the control group ean values and standard deviations are calculated for VL,, V, V rt frequency and age. A correlation is calculated between К О 1 ' W-, and the other variables (V. frequency and age). In the group of 23 woen a correlation is found between VL. and V (Pierson correlation к о coefficient 0.40 or 5.8 %).Other correlations could not be deonstrated. Based on the vrork of Rüke and Bezeer (1972) we ay expect that only 5% of the population have a value of W R above Joule in en and above Joule in vroen. Considering this value in vroen we have to be aware of low V and low frequency causing high values of W R. Probably the cross section of the airways is saller in woen. Based on the results of the control group we consider W R as deviating fro the control group if its value is higher than: Joule in ale subjects Joule in feale subjects. W easured in a group of patients. Introduction of a new paraeter (W R ) as an index of airway obstruction requires a coparison with other paraeters of airway obstruction: FEV,, FIV., peak flow. Ihe differences between W R and other paraeters are: a. FEV., FIV. and peak flow are easured at extreely high flow velocity, whereas W R is easured at relatively low flow velocity. b. During the easureent of W R the conditions in the airways differ fron those during the easureents of the conventional paraeters. When easuring FEV., FIV. and peak flow, airway copression occurs. This is probably absent when easuring W R.

66 53 Based on the differences between W R and the other paraeters of airway obstruction a coparison of W- with the others will, at least theoretically, result in three possible relationships: 1. The results of FEV,, FIV, and peak flow as well as those of W indicate an airway obstruction. 2. The results of FEV., FIV. and peak flow suggest an airway obstruction but the results of W R do not support this. 3. The results of FEV., FIV, and peak flow do not suggest an airway obstruction whereas the results of W_ do. We investigated whether these three relationships, vfaich were assued on theoretical grounds, existed in reality. FEV and FIV, easured in a group of 116 patients visiting our laboratory for reasons of respiratory or cardiovascular diseases, were copared with standard values given by Labadie (1968). W R easured in this group of 116 patients was related to the W R found in the control group. Only 38 of this group of patients have an age siilar to that of the control group. When coparing VL, and the other paraeters of airway obstruction tvro groups of patients can be distinguished according to the situations 2 and 3 entioned above: Group I : In 3 of the 38 patients situation 2 could be deonstrated t this eans :W 0 agrees with our control group but FEV. /VC is sall conpared with standard values. Data of this group are listed in table VI. If we take into consideration the whole group of 116 patients situation 2 oould be deonstrated in 22 patients though the age of these 22 patients differs fro that of the control group (x in appendix II). Group II : In 5 of the 38 patients situation 3 could be deonstrated. W has values above those of the control group, whereas FEV./VC agrees with standard values. Data of this group are listed in table VII. In the whole group of 116 patients this situation could be deonstrated in 11 patients (xx in appendix II).

67 Table VI: Data of group I with sall FEV. and FIV. but with W σοηtrol group. corresponding to Nae Sex Age Т.е. V.C. FEV 1 /VC% W,, V clin, diagnosis 1 К c an FIV /VC% Joules c H. f / asthatic bronchitis K. f / asthatic bronchitis 2 D / asthatic bronchitis

68 Table VII: Data of group II with noral FEV, and FIV, but increased W. Nane Sex Age T.C. V.C. FE^/VCI W R Vip clin, diagnosis c on FIV /VC%- Joules c B / lupus erythatodes E. f / scoliosis W / scoliosis H. s. f /96 94/ scoliosis scoliosis

69 56 W easured in sokers and non - sokers. i\ Clarke et al. (1970) and Zael (1970) denonstrated an increased airway resistance in sokers.it is interesting to knew whether a difference in W can be deonstrated between sokers and non-sokers. The sugges- K tion of W differences between sokers and non-sokers fro the results of W_ easureents in the iscellaneous group of 43 sokers and nonsokers is supported by a cortparison of W in a group of sokers and non-sokers. We chose aselectively 13 ale sokers and 13 non-sokers fro the personnel of the University of Nijegen, with ages between and 40 years, without coplaints of cardio-vascular or respiratory disease.fro the results of W in both groups ws ay conclude that a quite significant R difference exists in W between sokers and non-sokers. W in non- K к sokers is saller than in sokers (Wilcoxon Ρ < 1%). F. Suiiary. Before starting the presentation of W easureents in subjects,differences and siilarities between odel I and subjects are entioned. The ost inpressive differences are changes of teperature inside the Plethysograph and contraction or expansion of tidal volue during respiration. W is easured in a control group of 20 en and 23 vroen. Based on the к results of the control group we consider W as deviating fro the control group if its value is above Joule in ale subjects and above in feale subjects. Although results of W in a group of 116 patients frequently agree with к the results of the other paraeters of airway obstrution, discrepancies in results are found between both as already assued on theoretical grounds. A significant difference in W can be shown between sokers.k and nori-sokers.

70 57 VI.THE SIGNIFICANCE OF W 0 AS A CLINICAL LUNG FUNCTION TEST. A. Deterination of obstructive lung disease. Obstruction to gas flow in huan airways ay be deterined by the following lung function tests: 1. Forced expiratory gas volue during the first second of expiration (FEV 1 ). After a axiu inspiration a forced expiration is perfored. Displaced gas volue during the first second of expiration is easured. This figure can be given as an absolute value or as a relative value with respect to vital capacity (FEV 1 /VC % ). The agnitude of this figure is deterined by: - work perfored by respiratory uscles,which ay be decreased in uscle disease, - deforation resistance of thorax wall and lungs. This factor is sall and can be neglected in ost cases, - restrictive lung disease, - airway obstruction, - cooperation of the subject. Standard values are given by Ericsson and Iell (1969) and Berglund et al.(1963). 2. Forced inspiratory gas volue during the first second of inspiration (FIV 1 ). After a axiu expiration a forced inspiration is perfored. Displaced gas volue during the first second of inspiration is easured. This figure can be given as an absolute value or as a relative value with respect to the vital capacity (FIV-j/VC % ) (Labadie, 1968). The agnitude of this figure is deterined by: - work perfored by respiratory uscles, - deforation resistance of thorax wall and lungs, - restriction of total lung capacity, - airway resistance.

71 58 - cooperation of the subject. Standard values are given by Labadie (1968). 3. Peak flow. This is the axiu volue flow during forced expiration (V ). The agnitude of peak flow is deterined by: - work of respiratory uscles. - deforation resistance of thorax wall and lungs. - airway obstruction. - cooperation of the subject. The proble of flow liitation (peak flow) was first studied by Fry and Hyatt (1960). 4. Closing volue. The closing volue is that lung volue at which airways in the dependent zones of the lung begin to close during expiration (Leblanc et al. 1970). If this volue is larger than noral, airway obstruction ay be expected. 5. Pulrronary copliance at different breathing frequencies. Although this technique is thought to reflect changes in sall airways (Mackle, 1972) it is not generally used yet as a clinical lung function test due to serious probles for subjects and investigators. 6. Airway resistance. Airway resistance ay be easured at different volune flows. We have already discussed the proble of the easureent of airway resistance by the panting ethod of DuBois et al. (1956) in which high volue flows are used (chapter I). Therefore Bargeton et al. (1957) introduced the easureent of airway resistance during quiet breathing. For details we refer to chapters I-C and II-A. B. W R as a paraeter of airway obstruction. W R can be considered as a paraeter of airway obstruction during the whole period of the respiratory cycle. Coparing the results of WR with those of other paraeters of airway obstruction (FEV,, FIV, and peak flow) discrepancies assuned before on theoretical grounds can be deonstrated. The possible origins of these

72 59 discrepancies are discussed in chapter V-E. Apparently W phenoenon. and the other paraeters do not describe exactly the sae First, aerodynaic conditions in the airways during quiet breathing are not equal to those during forced expiration, due to increased turbulence in the latter case. Secondly,airway copression occurs at high volue flow, but is nearly absent during quiet breathing. Finally, it ay be noticed that the relationship 2 (FEV.,FTJ, flow suggest an airway obstruction but the results of W this,chapter V-Ε) between W к and peak do not support and the other paraeters is ore frequently found if patients aged over 50 years are included in this coparison. The increased frequency of this discrepancy nay be due to loss of stability in the walls of sall airways which causes airway copression only at high flow velocity but not at low flow velocity (quiet breathing).relationship 2 (chapter V-Ε) ay be found in the transition phase between beginning and alost oonplete loss of wall stability, when the patient gets older. Relationship 3 (FEV,,FIV and peak flow do not suggest an airway obstruction whereas the results of W do,chapter V-Ε) occuring in group II can к be derronstrated in 5 of 38 patients and 4 of these are suffering fron scoliosis. The following explanations can be given for the discrepancies between W and the other paraeters of these patients: к - deforation of ajor airways causing turbulence in gas flow. W R is extreely sensitive to turbulence. - restriction of VC causing relatively large values of FEV,/VC %. Fro the figures of table VI we ay conclude that this is not the ost iportant factor. - atelectasis of sall areas without loss of stability of the walls in saller airways. Although restriction of VC in our group cannot be deonstrated clearly, it ay be that V in these patients is relatively sall due to atelectasis during quiet breathing. Because V appears in the denoinator

73 60 of the forula of VL, W D ay be relatively high.instability of the walls к к of the saller airways probably plays a inor role in the explanation of the high W_ because this instability cannot be expected in this group к of young people. It is ipossible to give a definite answer to this question here, but further research of airway obstruction in patients suffering fro scoliosis ay provide irore inforation. In our opinion, the introduction of W provides an opportunity to easure airway obstruction during quiet breathing. However,localisation of the obstruction (in saller or larger airways) is not possible. Good cooperation of the subject is desirable but not required. The only proble is claustrophobia of the patient. С W forula of Matthys and Overrath (1971). Although Jaeger and Otis (1964) introduced a forula for W, they were rainly interested in airway resistance (R). They derived the following forila for W R : W R = V (P Bar~ ^o' V + h V ο τ () А^ = loop area in Д - V diagra, P n = baroetric pressure car Р = partial water vapour pressure The denoinator (V + % V_) is called the ean thorax volue during respiration. This rrean thorax volue is the intrathoracic gas volue deterined in the Plethysograph at the end of expiration, plus half the tidal volue. Matthys and Overrath (1971) found that this forula () cannot be used in easureents of W in non-hoogeneously ventilated lungs. In their opinion only that part of the gas volue in the lungs which has an open connection with ajor airways, should be considered in forula ().

74 61 They,therefore, easured the functional residual capacity with the heliu dilution ethod (FRC^ ) before starting W R easureents with the body Plethysograph and introduced FRC^ into the deroninator of forula () to replace V. The trapped air in the lungs is supposed not to participate in deterining the value of W R because it does not œntribute to build up a pressure gradient during inspiration and expiration. For better understanding of their ideas we refer to figure 14. Fig. 14 Model of Matthys and Overrath(1971).

75 62 A cylinder is placed in the Plethysograph. The lateral wall of the cylinder can be copressed in one direction only. The wall inside the cylinder can also be oonpressed in one direction.part of the gas volue inside the cylinder is trapped. During copression of the cylinder fre ЕЕ to EI tidal volue V- leaves the cylinder, but the trapped gas volue inside the cylinder is copressed. A pressure equilibriu between both parts of the cylinder during copression and decopression does not occur, because the inner wall can be oonpressed in one direction only. If Δ V and V T are recorded on an x-y diagra part of the loop area of the Δ Vn - V diagra between line EI - ЕЕ, the vertical axis and curve 13 1 segent,does not belong to factorag of forula () but is a easure of the vrork due to copression of trapped gas volue. Matthys and Overrath divided the loop area of (Δ V B - V T ) diagra into three parts: Area Ag (expiration) is situated on the left of line EI - ЕЕ. Area A 1 (inspiration) is situated on the right of the vertical axis. There reains a part of the loop area between vertical axis, line EI- ЕЕ and a curve segent. This part of the loop area should be included for the calculation of W R. Matthys and Overrath used the following forula derived fro forula (19) of Jaeger and Otis, replacing Aj, by (Ap + AJ and the denoinator by (FHC^ + 1/2 V T ). (A E + V (P Bar - ^ W = = (19) FRC^ + 1/2 V T Matthys and Overrath neasured W with this forula 30 healthy subjects. They found values of W R which are higher than our values of W R in healthy subjects;0.646 Joule at a tidal volue of 1250 l, whereas we have found about Joule. This ay be evident when considering the denoinator in our forula and in their forula (19). The denoinator of the latter is saller than that of the forer.

76 63 Considering the denoinator in forula (19) of Matthys and Overrath, this forula is, in our opinion, not quite correct for the following reasons : 1. FRCL is easured before the subject enters the body Plethysograph. Most of the tie the subject does not breathe at exactly the sae level of lung inflation inside and outside the Plethysograph. 2. Trapped gas volue inside the lungs ay contribute to build up the pressure gradient in the airways (chapter V-Α). These trapped gas volues are not easured with the heliu dilution ethod FFCL. Gielen (1971) also deonstrated that FRQ, is not equal to the endexpiratory intrathoracic gas volue. D. Suary. To describe airway obstruction several paraeters ay be used in clinical lung function exaination. Scene of these are easured at high volune flow when aerodynaic conditions in the airways ay be different frc those occurring in quiet breathing. Airway resistance is a questionable paraeter because different values ay exist at equal alveolar pressure or volue flow. Introduction of W provides an opportunity to describe airway obstruction during the whole period of a quiet inspiration and expiration. Expected discrepancies between the results of W R and those of the other paraeters are found and discussed. In our opinion, the forula of Matthys and Overrath (1971) is not correct as a critical evaluation shows.

77 64 SUMMARY Obstructive lung disease is very οοπτηοη in the huid, air-polluted cliate of North-Vfeste Europe. Research workers have been looking for paraeters to describe the degree of airway obstruction. One of these paraeters is airway resistance (R). However, difficulties are inherent to the use of airway resistance as a easure of airway obstruction during quiet breathing: 1. At equal pressure gradients or volue flow different values of airway resistance ay be found depending on the type of flow. 2. Changing pressure gradient and volue flow during respiration cause a changing value of the quotient of both figures. 3. Diaeter and geoetric configuration of the airways are changing during the respiratory cycle. Factors in 2 and 3 induce instability of the flow pattern in the airways which gives rise to continuously changing resistance in the airways. A paraeter with such a variability can hardly be used as a easure of airway obstruction. Lost vrork due to obstruction (W R ) is, in our opinion, a reliable paraeter of airway obstruction during quiet breathing. The purpose of this investigation is to introduce this paraeter (W R ) as a clinical lung function test. The advantages of W R are: a. Type of gas flow does not atter in calculations of W R. b. Level of lung inflation, which deterines the diaeter of the airways, is included in the forila of W R by factor V. c. W R involves the whole respiratory cycle with its changing pressure gradient and volue flow. d. W R is a ore convenient factor in the study of total work of breathing with respect to the total aount of energy yielded by the body. e. W p is easily easured in 2 to 3 in without stress to the patient.

78 65 The disadvantages are: 1. An expensive body Plethysograph is necessary for easuring W R. 2. Standard values of various groups of subjects are not available at this oent. Much ore research is needed to secure the different standard values of several groups of patients. 3. Breathing frequency is not directly represented in the forula of W R and has to be deterined separately. Jaeger and Otis (1964) have developed a forula for W_,. We introduced a odification in the denoinator of this forula.the new forula was tested in a odel and appeared to be reliable for W R values up to 1.1 Joule. VL. is easured in a group of 116 patients with various diseases and copared with the forced expiratory volue after 1 second (FEV,) found in these patients because for the latter standard values are known fro the work of any authors. In soe patients discrepancies are found between these two paraeters with respect to airway obstruction. Group I has abnoral FEV. values whereas the W values agree with those of the control group. Group II has noral FEV. values whereas high W R values are easured copared with the control group. Most patients of this group suffer fron scoliosis. Divergence between FEV. and W R with respect to airway obstruction is due to differences in the nature of the respective paraeters: a. FEV. is easured at very high volue flow. W R is easured at volue flows occurring during quiet breathing. A large difference exists between the flow pattern during forced expiration (FEV.) ooitpared with that during quiet breathing (W R ). b. Airway copression occurring during forced expiration (FEV.) ay be absent during quiet breathing. c. Factors affecting FEV. and W R ay be different: - forced expiration ay be inpaired by uscle disease, - forced expiration nay be inpaired by high deforation resistance of thorax wall and lung tissue,

79 66 - Cooperation of the subject is ore iportant during easureent of FEV. Pain during deep expiration, e.g., is a liiting factor in deterining FEV,.

80 67 SAMENVATTING. Obstructieve longziekten koen zeer veel voor in het vochtige en door luchtvervuiling aangetaste kliaat van Noord-West Europa. Reeds gedurende een halve eeuw heeft en ernaar gestreefd paraeters te vinden,welke de graad van luchtweg-obstructie zouden kunnen aangeven. Men eent in de luchtweg-weerstand (R) een betrouwbare paraeter gevonden te hebben c een luchtweg-obstructie tijdens rustig adeen te kunnen vaststellen. Er blijken zich echter oeilijkheden voor te doen bij het gebruik van deze paraeter: 1. Bij gelijkblijvende drukgradient of volue verplaatsing per tijdseenheid kunnen verschillende waarden voor luchtwegweerstand geeten worden. 2. Veranderende drukgradient en veranderende volue verplaatsing per tijdseenheid tijdens de adehaling veroorzaken een veranderend quotient van beide grootheden. 3. De doorsnede en stereoetrische configuratie van de luchtwegen veranderen tijdens de adehaling. De onder 2 en 3 genoede factoren veroorzaken een voortdurend wijzigen van het stroo-patroon in de luchtwegen. Dit voortdurend wijzigen van het stroo-patroon geeft op zich zelf weer een telkens wisselende waarde van de luchtwegweerstand.het gebruik van een paraater wet een dergelijke variabiliteit o de nate van de luchtweg-obstructie te beschrijven, is aanvechtbaar. Het doel van het onderzoek is het aangeven van een betrouwbare paraeter o de ate van luchtweg-obstructie tijdens rustig adeen te beschrijven. De hoeveelheid arbeid,die nodig is o de luchtweg-obstructie te overwinnen tijdens rustig adeen (W ) is naar onze opvatting een eer betrouwbare paraeter.de voordelen van W zijn de volgende: R a. Het stroo-patroon behoeft geen gegeven te zijn bij berekenen van de waarde van VL.

81 b. Het niveau, waarop de proefpersoon of patient adet, en dat de doorsnede van de luchtwegen bepaalt, is in de forule voor W R vertegenwoordigd door factor V. c. W R betreft, in tegenstelling tot de luchtweg-weerstand (R), de gehele cyclus van in- en uitadeing, reet zijn veranderende drukgradient en veranderende volue verplaatsing per tijdseenheid. d. W is ogelijk een beter hanteerbare grootheid bij de bepaling van de totale hoeveelheid arbeid tijdens adeen en bij de bestudering van de energie-huishouding binnen het lichaa. e. W R is eenvoudig te bepalen en te eten in 2 tot 3 inuten zonder noeenswaardige belasting voor de patient. De nadelen zijn: 1. Het is noodzakelijk een relatief dure lichaas-plethysograaf aan te schaffen. 2. Standaard-waarden voor diverse groepen personen zijn nog niet voorhanden. Een uitgebreid onderzoek is nodig o de diverse standaardwaarden te achterhalen. 3. De adefrequentie is als zodanig niet in de forula opgencen en dient daaro als toegevoegd gegeven vereld te worden. Jaeger en Otis hebben een forule voor W R ontworpen. Wij gebruiken deze forule, aar in de noeer vrordt een verandering aangebracht. De nieuw gevorde forule wordt getest aan de hand van proefneingen bij een odel. Het blijkt, dat de nieuw gevorde forule betrouwbaar is bij de bepaling van W R aan het odel tot waarden van 1.1 Joules. W R vrordt geeten bij een serie gezonde jonge proefpersonen tussen en 40 jaar. Deze groep vrordt de controle-groep genoed. Het blijkt, dat W R geeten bij rokers van deze groep een hoger gelegen geiddelde waarde heeft dan die, geeten bij niet-rokers van de groep. W R vrordt tevens geeten bij een groep van ongeveer 116 patiënten, lijdend aan diverse ziekten en de W R vrordt vergeleken et de bij deze patienten geeten axiaal uitgeadede lucht in 1 seconde (FEV,). Juist de FEV., wordt hiervoor gekozen, odat van deze paraeter verschillende

82 69 standaardwaarden bekend zijn uit diverse onderzoekingen. Ofschoon er een overeenkost bestaat tussen afwijkende waarden voor FEV, en afwijkende (t.o.v. controle-groep) waarden voor W R, worden bij een groep patiënten verschillende waarden tussen beide paraeters gevonden. Groep I heeft afwijkende waarden voor FEV., terwijl de waarden voor W R overeenkcnen net die van de controle-groep. Groep II heeft norale waarden voor FEV., terwijl de waarden voor W hoog uitvallen ten opzichte van de controle-groep. Bij navraag is gebleken, dat eer dan de helft van de patiënten in deze groep lijdt aan scoliose. De verschillen tussen FEV en W ten aanzien van luchtweg-obstructie X к kunnen naar onze irening verklaard worden uit de volgende factoren: a. FEV. wordt gerieten bij extree hoge stroosnelheden, terwijl W R geeten wordt bij stroosnelheden voorkoend bij rustig adeen. Het stroc-patroon bij hoge stroosnelheden verschilt sterk van dat tijdens rustig adeen. b. Copressie van de luchtwegen, welke optreedt tijdens snel uitadeen, с behoeft niet noodzakelijk voor te koen tijdens rustig adeen. Bepaalde factoren, welke belangrijk zijn tijdens het bepalen van FEV,, behoeven niet van invloed te zijn op de grootte van W R : - spierziekten kunnen de waarde van FEV beïnvloeden - hoge vervoringsweerstand van thoraxwand en longweefsel kunnen bij geforceerde uitadeing een belenerende rol spelen - coöperatie van de patient is noodzakelijk bij het bepalen van FEV. Pijn bij diep geforceerde expiratie is een beperkende factor voor FEVj^

83 70 REFERENCES. AGOSTONI, E. and FENN, W.O. (1960). Velocity of uscle shortening as a liiting factor in respiratory air flow. J. Appi. Physiol., 15: ATiTfN, G.W. and SABIN, S. (1971). Coparison of direct and indirect aasureent of airway resistance. A. Rev. Resp. Dis., 104: ALPERS, J.H. and GYATT, A.R. (1967). Significance of a looped appearance of the flow: alveolar pressure relationship of the lung as exained by the whole body Plethysograph. Clin. Sci., 33: BARGETON, D., BARRèS, G., LEFEBRE, R. and GAUGE, P. (1957). Mesure de la résistance des voies aériennes de l'hoie dans la respiration norale. J. Physiol. (Paris), 49: BARGETON, D., BARRèS, G., LEFEBVRE, R. and GAUGE, P. (1957). Résistance des voies aériennes de l'horie au cours du cycle respiratoire. Société de Biologie, Séance du 9 Mars: BARTER, CE. and CAMPBELL, A.H. (1973). Coparison of airway resistance easureents during panting and quiet breathing. Respiration, 30: BARTLEIT, R.G., BRUBACH, H.P., TRIMPLE, R.C. and SPECHT, H. (1959). Airway resistance easureent during any breathing pattern in an. J. Appi. Physiol., 14:

84 71 BEDELL, G.N.,MARSHALL,R.,DuBOIS,A.В. and CQMROE, Jr.,J.H. (1956). Plethysographie deterinations of the volue of gas trapped lungs. J. Clin. Invest., 35: BEDELL, G.N., MARSHALL, R., DuBOIS, A.B. and HARRIS, J.H. (1956). Measureent of the volue of gas in the gastrointestinal tract. Values in noral subjects and abulatory patients. J. Clin. Invest., 35: BERGLUND, E., BIRATH, G., BJURE, J., GRIMBY, G., KIELLMER, I., SANDQVIST, L. and ЗООЕШОШ, В. (1963). Spiroetrie studies in noral subjects. Acta Med. Scand., 173: BLIDE, W.R., KERR, H.D. and SPICER,Jr., W.S. (1964). Measureent of upper and lower airway resistance and conductance in an. J. Appi. Physiol., 19: BLUM, B. and SCHERRER, M. (1970). Ströungsabhängigkeit des Bronchialwiderstandes bei Astha und Ertphyse. Schweiz. Med. Wschr., 100: BOSMAN, A.R., HONOUR, A.J., LEE, G., MARSHALL, R. and STOIT, F.D. (1964). A ethod for easuring instantaneous pulonary capillary bloodflow and right ventricular stroke volune in an. Clin. Sci., 26: BOUHUYS, A. and JONSON, B. (1966). Adeinweerstand. Ned. T. v. Geneesk., 110: BOUHUYS, A. and JONSON, B. (1967). Alveolar pressure, airflow and lung inflation in an. J. Appi. Physiol., 22:

85 72 BOYLE, R. (1662). New Experients. Life and Wbrks of the Honourable Robert Boyle. L.T. More, New York (1944). BRISCOE, W.A. and DvßOIS, A.B. (1958). The relationship between airway resistance, airway oonductance and lung volue in subjects of different age and body size. J. Clin. Invest., 37: BUCKINGHAM, E. (1915). Model experients and the fors of epirical equations. Trans. A.S.M.E., 37. CLARKE, B.C., GYATT, A.R., ALPERS, J.H., FLETCHER, CM. and HILL, I.D. (1970). Changes in airway conductance on soking a cigarette. Thorax, 25: COTES, L.E., ROSSITER, C.E., НІССШЗ, I.T.T. and GILSON, J.C. (1966). Average noral values for the forced expiratory volue in white Caucasian ales. Brit. Med. J., 1: DufeOIS, A.B., BOTELHO, S.Y. and CQMROE,Jr., J.H. (1956). A new ethod for easuring airway resistance in an using a body Plethysograph: values in noral subjects and in patients with respiratory disease. J. Clin. Invest., 35: DUBOIS, A.B., EBODY, A.W., LEWIS, D.H. and BURGESS, B.F. (1956). Oscillation echanics of lungs and chest in an. J. Appi. Physiol., 8:

86 73 ERICSSON, E.A. and IRNELL, L. (1969). Spiroetrie studies of ventilatory capacity in elderly people. Acta Med. Scand., 5: FERRIS, B.C., MEAD, J. and OPIE, L.H. (1964). Partitioning of respiratory flow resistance in an. J. Appi. Physiol., 19: FISHER, A.B., DuBOIS, A.B. and HYDE, R.W. (1968). Evaluation of the forced oscillation technique for the deterination of resistance to breathing. J. Clin. Invest., 47: FLENLEY, D.C., GYATT, A.R., SIDDORN, J.A. and BRASH, H. (1971). Frequency dependence of conpliance. Proc. Roy. Soc. Med., 64: FREOUR, P., NACEF, T., CHIUDER, H., BERNADOU, M., CHOMY, P. and MALLET, J.R. (1971). Mesure des résistances dynaiques ventilatoires par la éthode de l'interruption brève-valeurs norales. Respiration, 28: FRY, D.L. (1958). Theoretical considerations of bronchial pressure-flow-volue relationship with particular reference to the axiu expiratory flow volue curves. Phys. Med. Biol., 3: FRY, D.L. and HYATT, R.E. (1960). Pulonary echanics. A. J. Med., 29:

87 74 GIELEN, M.J.M. (1971). Body plethysography. A conparative study of volue easureents in a constant-volue and a constant-pressure body Plethysograph. Thesis,University of Nijegen,1971: GIMENO, F., BERG, W.CH., SLUITER, H.J. and TAMMELING, G.J. (1972). Spiroetry-induced bronchial obstruction. A. Rev. Resp. Dis., 105: GRIMAUD, CH., GAYARD, P. and CHARPIN, J. (1969). Mesure de la résistance dynaique des voies aériennes par la Plethysographie corporelle. J. Fr. Msd. Chir. Thorac., 23: GYATT, A.R. and ALPERS, J.H. (1968). Factors affecting airways conductance. A study of 752 working en. J. Appi. Physiol., 24: GYATT, A.R., AIDERS, J.H. and DAVIES, E.E. (1967). Design of body Plethysograph for use in field studies. J. Appi. Physiol., 22: GYATT, A.R., ALPERS, J.H., HILL, I.D. and BRAMLEY, A.C. (1967). Variability of Plethysographie easureents of airways resistance in an. J. Appi. Physiol., 22: HAGEN, G. (39). Über die Bewegung der Wassers in ovgen zylindrischen Röhren. Pogg. Annal.d.Phys.u.Cheie, 16: ΗΥΑΊΤ, R.E. (1961). The interrelationship of pressure flow and volue during various respiratory anoeuvres in noral and ephyseatous subjects. A. Rev. Resp. Dis., 83:

88 75 HYATT, R.E. and WILCOX, R.E. (1963). The pressure-flow relationship of the intrathoracic airway in an. J. Clin. Invest., 42: INGRAM, R.H. and SCHIIDER, D.P. (1966). Effect of gas copression on pulonary pressure, flow and volue relationship. J. Appi. Physiol., 21: JAEGER, M.J. and MATTHYS, H. (1968/1969). The pattern of flow in the upper huan airways. Respir. Physiol., 6: JAEGER, M.J. and MATTHYS, H. (1970). The pressure flow characteristics of the huan airways. Airway Dynaics,edited by A.Bouhuys Ch.C.Thoas, Springfield, 1970, JAEŒR, M.J. and OTIS, A.B. (1964). Effects of copressibility of alveolar gas on dynaics and work of breathing, J. Appi. Physiol., 19: JAEGER, M.J. and OTIS, A.B. (1964). Measureents of airway resistance with a volue displaceent bodyplethysograph. J. Appi. Physiol., 19: JONSON, B. and BOUHUYS, A. (1966). Measureent of alveolar pressure. J. Appi. Physiol., 22:

89 76 LABADIE, H. (1968). In- and expiratory Tiffeneau in subjects with different ages. Asterda. Unpublished research. LEBLANC, P., RUFF, F. and MILIC-EMILI, J. (1970) Effects of age and body position on airway closure in an. J. Appi. Physiol., 28: MACKLEM, P.T. (1972). Obstruction in sall airways - a challenge to edicine. A. J. Med., 52: MATTHYS, H. and OVERRATH, G. (1971). Dynaics of gas and work of breathing in obstructive lung disease. Bull. Physio-Path. Resp., 7: McFADDEN, E.A. and LYONS, H.A. (1969). Serial studies of factors influencing airway dynaics during recovery fre acute astha attacks. J. Appi. Physiol., 27: MEAD, J. (1960). Volue displaceent body Plethysograph for respiratory easureents in huan subjects. J. Appi. Physiol., 15: MEAD, J. and MILIC-EMILI, J. (1964). Theory and ethodology in respiratory echanics with glossary of sybols. Handbook of Physiology, Section 3: Respiration, vol. 1, edited by W.O. Fenn and H. Rahn. Aerican Physiological Society, Washington D.C., 1964,

90 77 MEAD,J., TURNER,J.M., Μη,ΟΚΠΕΜ,Ρ.Τ. and LITTLE, J.B. (1967). Significance of the relationship between lung recoil and axiu expiratory flow. J.Appi.Physiol., 22: MEAD,J. and WIHTTENBERGER, J.L. (1954). Evaluation of airway interruption technique as a ethod for easuring airflow resistance. J.Appi.Physiol., 6 : MEERTEN, R.J. van (1966). Concentration curves of expired gas. Thesis,University of Nijegen,1966. NADEL, J. and COMROE Jr.,J.H. (1961). Acute effects of inhalation cigarette stroke on airway conductance. J.Appi.Physiol.,16: NEERGAARD,K. von, and Wirz,K. (1927). über eine Methode zur Messung der Lungenelastizität a lebenden Menschen,insbesondere bei Ephyse. Z.Klin.Med., 105: NOLTE,D. (1970). Das Verhalten von Ateirweg-Resistance und intrathoracale Gasvoluen nach Inhalation eines Hydroxyphenyl-Derivates des Ociprenaline. Respiration,27: NOLTE,D.,REIF,E. and ULMER,W.Τ. (1968). Die Ganzkörperplethysrtographie. Respiration, 25:

91 78 OTIS, A.B. (1964). The work of breathing. Handbook of Physiology, section 3: Respiration, vol. 1, edited by W.O. Fenn and H. Rahn. Aerican Physiological Society, Washington D.С, 1964, OTIS, A.B. (1954). The work of breathing. Physiol. Rev., 34: OTIS, A.B., FENN, W.O. and RAHN, H. (1950). Mechanics of breathing. J. Appi. Physiol., 2: OTIS, A.B., MdKERROW, C.B., BARTLETT, R.A., MEAD, J., McILROY, M.B., SELVERTONE, N.J. and PADTORD, E.P. (1956). Mechanical factors in distribution of pulonary ventilation. J. Appi. Physiol., 8: OTIS, A.B. and PROCTOR, D.F. (1948). Measureent of alveolar pressure in hurran subjects. A. J. Physiol., 152: PESET, R., QUANJER, Ph.H. and TAMMELING, G.J. (1969). Bronchodilatation estiated by body plethysography (coparison between the panting and spontaneous breathing ethods). Progr. Pespir. Res., 4: PRIDE, N.B., PERMUTI, S., RILEY, R.L. and BRQMBERGER-BARNEA, B. (1967). Deterinants of axial expiratory flow fro the lungs. J. Appi. Physiol., 23: POISEUILLE, J.L.M. (41). Recherches expérientales sur le ouveent des liquides dans les tubes de très petits diaètres. Ann. d. Chi. et Physiol., (3) 21:

92 79 POISSON, S.D. (35). Theorie athéatique de la chaleur, Paris. Leerboek der Natuurkunde, R. Kronig, Asterda (1966), 816. REYNOIDS, O. (83). An experiental investigation of the circustances which deterine whether the notion of water shall be direct or sinuous, and of the laws of resistance in parallel channels. Phil. Trans. Roy, Soc., 174. Papers, 2: ROHRER, F. (1915). Der Strcungswiderstand in den enschlichen Atewegen und der Einfluss der unregelässigen Verzweigung des Bronchialsystes auf den Atungsverlauf in verschiedenen Lungenbezirken. Arch.ges.Physiol.,162: RÜMKE, CHR.L. and BEZEMER, P.D. (1972). Methoden voor bepaling van norrraalwaarden. Ned. T. Geneesk., (116) 35: SMIDT, U. and MUYSERS, K. (1968). Kritische Betrachtungen zu den ethodischen Grundlagen der Ganzkörperplethysographie. Respiration, 25: SOBOL, B.J. (1970). A siple, rapid technique for assessing airway resistance during quiet breathing. A. Rev. Resp. Dis., 102: STAMESCU, D.C., ΡΑΊΤΥΝ, J., CLEMENT, J. and WOESTYNE, K.P. van de (1972). Glottis opening and airway resistance. J. Appi. Physiol., 32:

93 80 TORRICELLI, E. (1644). De irotu graviu naturaiiter descendentiu et projectoru,libri duo, Opera geoetrica,florence. Opere di Evangelista Torricelli,G.Loria and G.Vassura, Faensa, ( ). ULMER, W.T. and REIF, E. (1965). Die obstruktiven Erkrankungen der Atertwege. Dtsch. Med. Wschr.,41: VARêNE,P.,TIMBAL,J. and JACQUEMIN,CH. (1966). Effect of different abient pressures on airway resistance. J.Appi.Physiol.,22: VISSER,B.F. (1973). Quantities and units in respiratory physiology. Bull. Physio-path. Resp.,9: VOOREN,P.H. (1976). Meting van de adereerstand net de interruptieethode. Thesis,Leiden VUILLEUMIER,P. (1944). Ueber eine Methode zur Messung des intraalveolären Druckes und des Strönungswiderstandes in den Aterwegen des Menschen. Ztschr. f.klin. Med.,143: WASSERMAN,К.,BOTLER,J.,KESSEL,A.van, and VERMEIRE,?. (1966). Factors effecting the pulonary capillary blood flow in an. J.Appl.Physiol.,21:

94 81 WOESTIJNE,K.P. van de,and VERMEIRE, P. (1967). La Plethysographie corporelle. L' Eploration Fonctionnelle Pulonaire, edited by Denolin,H.,Sadoul,P. and Orie,N.G.M. Flanarion,Paris,1964, 514a - 5l4z. WDITOWITZ, H.J.,BUCffflEIM, F.W. and ТОГГОШТг,К. (1967). Zur Theorie und Praxis der Ganzkörperplethysiragraphie in der Lungenfunktionsanalyse. Praxis der Pneuologie,21: ZAMEL,N. (1970). Airway resistance and peak expiratory flow-rate in sokers and nonsokers. Lancet,!: ZEDDA,S. and SARroRELLI,E. (1971). Variability of Plethysographie easureents of airway resistance during the day in noral subjects and in patients with bronchial astha and chronic bronchitis. Respiration, 28:

95 82 APPENDIX I. ΔΡ Α = "Bar.V (10) In this forula the quotient P Bar /^ i s changing during respiration because V varies between V and (V + V ).Therefore, we have to look for a ean value of this quotient. If the teperature is constant the relationship between pressure and volue of an enclosed gas volue is ruled by Boyle's law: P.V = С If we have two gas volues V and (V + V ) this relationship ay be visualized in a P-V diagra by two curves P.V = С (V ) and P.V = C- (V o + V T ): Figure 15. Fig, 15.Two curves : P.V = C. and P.V = C 2. Because the end-inspiratory pressure is equal to the end-expiratory pressure (= baroetric pressure) a horizontal line is drawn fro the

96 83 vertical axis in the diagra. This line crosses one curve in point E (P = P_ ), the other in point F (Ρ = Ρ ).Fro E and F perpen- E Bar F Bar dicular lines are drawn to the horizontal axis. The distance fron the projection of E on the horizontal axis to the origin is equal to V ( = V ),that fro the projection of F to the origin is equal to v o+ v T (=v F ). A line is drawn fron point F to the origin of the diagra, which crosses the other curve in point F'. In point E slope t to the curve is: dp P Bar Tu dv V о C l ^Е = ' 4 c i In point F slope t to the curve is: dp P Bar T- dv V + v V In point F' slope t to the curve is: С Ρ 2 dp ~L _ V V dv 2 " α η i V The ean value of the slope ( t) between E and F' is:

97 84 So we ay write the nean value of Ρ /V as: Ρ Ρ Bar = Bar V (aan) ν^ξττ^")

98 APPENDIX II: Results of W easurenents in patients. Nae Sex Age Multergan FEV 1 /VC% FEV. peak fi. V- f. W years c. 1/sec. c c/in Joules X X c. R /92 57/ / / X 62.5/ / R. L. f / / / / / / V. S. f /93 35/ / / / / / / / S. s / / / /

99 χ χ χ χ Nae Κ. G. G. Ρ. Ν. V. S. L. W. Τ. J. R. Sex f f f f Age years Multergan Ь, Е 1 / С% 38/68,5 61.5/94 54/79 55/ / / / / /91 75/89 24/61 34/68 54/83 50/79 62,5/99 65/91 66/89 45/90 ьъ 1 3 an 1131/ / / / / / / / / / / / / / / / / /3375 peak fi. l/sec т 3 c f. c/ir \ ι Joules

100 Nane Sex Age Multergan FEV 1 /VC% peak fi. years 3 c 1/sec. c c/in Joules + 57/88 X S. f / /79.5 S / /60 Η. 60 X Β. 61 D. f 49 к χ χ S. D. S. V. R. D. S. f f f /72 60/87 57/ / /97 75/90 56/87 64/ / /82 41/ / / / / / / / / / / / / / / / / / / / / ,.298 0,.113 0,.104 0:.821 0, , о , ,

101 Nae Sex Age Multergan years FEV 1 /VC% FEV, c peak fl. 1/sec. V,,. W, R c c/in Joules R / / / / / / /90 75/ W / / s. f 40 26/74 73/86 900/ / K / / / / / / / / к. в. f 29 85/96 30/ / / /94 925/ D / / XX Ζ. f 17 93/ / XX Zy. f 17 93/ /

102 Nae Sex Age Multergan FEV,/VC% FEV, peak fl. V f. W J- J- X \ 3 3 years c 1/sec. c c/in Joules K / / E. M. V. T. G. V. R. K. M. s. J. f f f f f f / / / / / / /64 72/99 81/ / / / /97 69/ / / / / / / / / / / / / / / / / /

103 Nae Sex Age Multergan FEV 1 /VC% years РЕ 1 peak fi. V T f. W R 3 3 c l/sec. απ c/in Joules D. f 31 80/ / A /70 800/ / / V / / K. 89/ / J / / G / / N. 6 69/80 775/ R. T. f /90 63/ / / B. f 26 73/ / / / K / / / / M. w. s /93 94/ / / / /

104 Nae Sex Age Multergan FEV /VC% years FE^ peak fi. V T f. W R 3 3 c 1/sec. c c/in Joules + 55/79 00/ В. V. s. M. f f /96 82/91 38/75 43/ / / / / L. H. J. f /74 71/94 80/90 83/ / / / / / / / / /68 00/ S. B /98 63/ / / L. W. P /96 71/94 59/ / / /

105 Nae Sex Age Mulffirgan І;, Ь 1 / С% ь, ь 1 peak fi. V T f. W R years c l/sec. απ 3 c/in Joules W / / D. f 49 63/ / J /91 50/ /94 950/ H / / X L / / / / X T / / / / X W. f 60 62/ / С / / / / К / / В. f 42 42/ / w. T /87 70/88 34/ / / /

106 Nae Sex Age Multergan FEV 1 /VC% years FEVj^ peak fi. V T f. W R 3 3 c 1/sec. an c/in joules H. f /79 68/ / / H. M. T. K. H. P. D. V. L. f f f f /90 66/91 69/97 49/81 57/ /84 42/94 47/ /93 61/97 59/ /88 41/80 63/90 67/ / / / / / / / / / / / / / / /

107 Nae Sex Age Multergan FEV^/VCl years FEV 1 3 c peak fi. l/sec. v T f. W R c c/itiin Joules 37 61/ /91 XX К /96 V. T. H. f f /87 82/96 63/ /90 M. f 25 56/ /90.5 L /94 XX В /92 M /98 XX W. f 28 80/90 K. 64.5/ / / / / / / / / / / / / / / / / o , ,.390 0, ,143

108 95 Curriculu vitae. De schrijver van dit proefschrift is op 11 noveber 1939 geboren te Rotterda.In juni 1959 behaalde hij het diploa gynasiu-b aan het Stanislascollege te Delft.Hij studeerde edicijnen aan de Rijksuniversiteit te Leiden alwaar hij op 23 juni 1967 het artsexaen et goed gevolg kon atleçgen. Na het vervullen van de ilitaire dienst ging hij in opleiding bij Prof.dr.J.F.Crul te Nijegen voor het specialise anaesthesiologie. In 1972 kreeg hij de gelegenheid te gaan werken bij dr. H.H.Beneken Koler,lector in de anaesthesiologie in het bizonder de pathofysiologie van de adehaling aan de Katholieke Universiteit te Nijegen en hoofd van het longfunctielaboratoriu van het St.Radboudziekenhuis aldaar.hij vestigde zich in 1975 als anaesthesist te Alelo.Sinds februari 1976 is hij tevens als wetenschappelijk hoofdedewerker verbonden aan het Centru voor Medische Techniek van de Technische Hogeschool te Delft.

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112 STELLINGEM. 1. Odat drukverval en strocsnellieid in de luchtwegen van de ens et-proportioneel veranderen en et op hetzelfde tijdstip eetbaar zijn,dient het begrip luchtwegweerstand bij de beschrijving van een obstructie in de luchtwegen achterwege te blijven. (Hoofdstuk II-A.) 2. Tussen rokers en niet-rokers blijkt een verschil aantoonbaar te zijn in arbeid,welke nodig is c de luchtwegobstructie te overwinnen. (Hoofdstuk V-E.) 3. Er zou een onderzoek ingesteld oeten worden naar de aard en de ate van luchtwegobstructie bij jonge scoliose-patiënten»waarbij norale waarden voor FEV.,Ρΐν η en peak flow geeten worden,doch waarbij de arbeid o de luchtwegobstructie te overwinnen hogere waarden heeft dan die uit de contrôle-groep. (Hoofdstuk VI-B.) 4. Het verbod tegen het oprichten van een beadeings-afdeling,opgelegd door de overheid aan het grotere streekziekenhuis et eer dan 500 bedden, zal de vaak gewenste postoperatieve beadeing in de praktijk onogelijk aken. Daardoor wordt aan de patiënt uit de regio van een dergelijk streekziekenhuis een onvolledig en veelal onvolwaardig pakket geneeskundige zorg aangeboden. (Rondschrijven van het Ministerie van Volksgezondheid en Milieuhygiene, nr DG Vgz/VKG.) 5. Het verdient de voorkeur aan kinderen,waarbij een adenotonsilectoie volgens Sluder wordt uitgevoerd, een inhalatie-anaesthesie toe te dienen zonder intubatie bij zittende houding van het kind. Als voordelen gelden een snel te sturen anaesthesie,iniale stuwing in het halsgebied en het achterwege blijven voor het kind van het gevreesde tweede prikje. (Syposiu van de Afdeling Anaesthesiologie van het Acadeisch Ziekenhuis bij de Universiteit van Asterda, 27 april 1978.)

113 6. Voor een nauwkeurige begeleiding van de patient in het ziekenhuis behoort het tijdig vastleggen van zijn ziektegeschiedenis en behandelingswijzen in een status, welke eigendo is van het ziekenhuis en beheerd wordt door het hoofd van de verpleeg- c.q. polikliniekafdeling, afdwingbaar te zijn. (Intercollegiale toetsing in algeene ziekenhuizen. Rapport van een geeenschappelijke cortissie ingesteld door de Geneeskundige Vereniging t.b.v.h. Ziekenhuiswezen en de L.S.V.,Conclusie VIII-3 en IX.) 7. De edicus ist door zijn gebrekkige opleiding in de exacte vakken vaak een hechte basis voor het verrichten van edisch wetenschappelijk onderzoek. ( De basisvakken en de Geneeskunde. Prof.dr.H.Galjaard, N.T.v.G., jrg.l21,nr.43, 1977.) 8. De "bioedisch technoloog" zal bij zijn opleiding kennis van (edische) ethiek bijgebracht dienen te worden,zodat een eigen verantwoordelijkheidsgevoel zich bij he kan ontwikkelen voor patiënten en proefdieren waarop hij zijn vaardigheden toepast. 9. Kippen in een legbatterij zouden één vreugde in hun bestaan kunnen vinden,naelijk dat hun producten worden opgedrongen aan ensen in een consuptiebatterij. (Een dier kan duizendaal sterven, Ds.H.Boua.)

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