`JOURNAL or Arpunn PHYSIOLOGY
`Vol. 36, No. 6, June 1974.
`Printed in U.S.A.
`
`Contribution of airway collapse
`
`to supramaximal expiratory flows
`
`RONALD J. KNUDSON, JERE MEAD, AND DWYN E. KNUDSON
`Department of Physiology, Harvard School of Public Health, Boston, Massachusetts 02115; and
`Section of Pulmonary Diseases, University of Arizona College of Medicine, Tucson, Arizona 85724
`
`KNUDSON, RONALD J., JERE MEAD, AND DWYN E. KNUDSON.
`Contribution of airway collapse to supramaximalflows. J. Appl. Physiol.
`36(6): 653—667.
`1974.~«A flowmeter which enclosed the head
`and had a lOO—Hz frequency response was used to measure rapid
`expiratory flow events. During these events, peak flow exceeded
`maximum expiratory flow (me). Voluntary coughs and rapid
`expiration had similar time courses with maximum volume ac—
`celeration of about 300 1/52, while triggered flow transients were
`of greater amplitude and shorter duration. Because flows greater
`than Vmu presumably represent a displacement of gas from intra-
`thoracic airways undergoing dynamic compression, integration of
`supramaximal flows yielded estimates of the volume displaced
`from these airways (AVaw). In normal subjects, AVaw ranged
`from 50 to 150 ml, increasing with pleural triggering pressure and
`after administration of aerosol bronchodilator. From plots of
`instantaneous supramaximal flow against
`its integral, we esti-
`mated time constants for the displacement of 3—8 ms in normal
`subjects. These values are similar to ones based on the compliance
`of major intrathoracic airways and resistance mouthward from
`them. Patients with chronic obstructive lung disease had time
`constants for airway compression ranging from 20 to 60 ms.
`
`forced expirations; cough; airway
`expiratory flow transients;
`compliance; frequency dependence of compliance; time constants;
`dynamic compression of airways; flow limitation; airway dynamics
`
`THE MAXIMUM EXPIRATORY flow-volume (MEFV) curve (9,
`10, 15) describes the relationship between volume and the
`maximum flow (me) which cannot be exceeded at that
`volume. Hyatt
`(14) demonstrated that emphysematous
`subjects exhibiting marked decrease in maximum expira-
`tory flows may be generating their maximum flows even
`during quiet breathing, expiring along their MEFV curves.
`This was confirmed by Takishima and coworkers (37). The
`latter, however, found that many patients with obstructive
`disease, unlike normal subjects, were able to generate ex-
`piratory flow transients during the maximum voluntary
`ventilation (MVV) maneuver which ‘ 'ere substantially in
`excess of Vmu . Often the flows were greater than the peak
`flow achieved during the forced vital capacity (FVC)
`maneuver. They concluded that, during the MVV, a space
`with a very short time constant was participating in the
`ventilation and that
`the conducting airways themselves
`might constitute such a space.
`these airways function
`In terms of their distensibility,
`mechanically in parallel with lung parenchyma, sharing in
`
`the volume excursions of the respiratory system. It has been
`pointed out
`(25)
`that
`the mechanical
`time constant for
`volume change of the airways should be quite small com—
`pared to that for
`the parenchyma. This suggests
`that
`properties of conducting airways could be revealed by de-
`tailed examination of very rapid flow events.
`We have studied flows at the onset of the rapid forced ex-
`pirations occurring during cough, forced expiration, or arti—
`ficially triggered flow transients. We believe we have been
`able to time these initial flow events accurately and, by com-
`pressing in time the events which result in dynamic com-
`pression of airways, to measure the volume displaced from
`the airways by this dynamic compression.
`
`METHODS
`
`All studies involving human subjects were performed in a
`volume displacement body plethysmograph (J. H. Emerson
`Co.) of the type described by Mead (24-), with the air-con-
`ditioning and pressure compensation modifications de-
`scribed by Grimby and coworkers (12).
`To produce very rapid flow events, a modification of the
`method described by Pride and associates (33) was em-
`ployed. The subject, with noseclip in place and breathing
`on a mouthpiece, was instructed to generate an expiratory
`effort against a closed shutter obstructing the apparatus air—
`way. When pleural pressure, monitored with a helium-filled
`esophagel balloon catheter, reached a predetermined value,
`the shutter was released and details of the resulting flow
`transient were examined. This method of generating flow
`transients and the brief duration of the events to be mea-
`
`sured presented unusual demands on the response charac-
`teristics of the instrumentation involved.
`
`Dome flowmeter. Under the conditions described above,
`the flow which results when the shutter is opened,
`if mea-
`sured in the usual way with a pneumotachograph at the
`mouth (Fig. 1A), would have three components for the
`duration of the transient. In that brief interval one would
`
`measure 1) the volume displaced from lung parenchyma, 2)
`volume displaced from intrathoracic airways by dynamic
`compression, and 3) volume displaced by dynamic collapse
`of distended extrathoracic upper airways,
`specifically
`cheeks and oropharynx. Because We were concerned only
`with the first two components, it was necessary to exclude the
`third from our measurements. This was accomplished by
`isolating the head, and, therefore, upper extrathoracic air—
`653
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00001
`
`

`

`'I‘JL’DSCX‘, MEAL), ANU EXHIBSON
`
`dental dam, with an urtretrrtclwd neck hole, circumfcrcncc of
`‘21 3 cm scum-(l
`tin:-
`
`1 against
`lmlm Fwtwccn thr dmnt‘
`that
`and plctlzysmogmpll chmhlst. W12 lwlicvc,
`lllt‘I‘tz‘lter,
`potential crmrs due to “radical 0ch mm uncut or {mks can
`lift clii‘nimtcd tn"m ("angidmrmmt
`It
`”5...“...1“ ”AHMVMAM‘
`612......
`utuuig
`1““)qu L‘,\Il,\,l<1U.u uuu
`,
`l1” (i‘fiLHVlllK I“. Hi "i Oillc
`without ahc triqgvrcd slmttcr the Subject rutlld brmthc un~
`
`cncnmi‘wrcd l).l'l.{)1l1l’lpl{‘(‘~‘.’. 2m tdxamatxc \«i mt rcmrding
`A IlCL‘ZEilK‘C hm: flow ml" 0.5
`firms Lt‘l'fl‘imttd (.‘lmim: cuttglt
`nt' mom air
`the
`'
`l
`‘
`'m’d :1 fit)“
`through
`
`
`
`:tddcd {lf‘éld space was that of thc moutl’lpiccc and slanttrr
`assttmbly.
`rifliAE Li...” ...,ulwfl...
`\1
`1 il(
`IIL)VG“I‘ 315EI\( l U." 111C I
`
`«a rzf ,
`
`’
`
` S
`
`Yi
`of which was; rmumémd m 1hr imcnw m tm (lulu: 3:}
`
`t‘niz-k-wztllvd 3~mm 1). mafipi‘ri‘m tublmz 323 cm 1E“) knelt}.
`A milibrmlnn cttm'c was" (“Onstri irwd using nréttt'c In: «Ira N
`
`
`iFlt" l' ulnlmunl M'2% Slli’; lily HUI?
`[U :3“ F S.
`1!? flow": Ltj)
`Emma and fimv lllt‘;l;~sll§‘{"i]1if‘l§lfi
`‘nt‘l‘t‘, mmugut‘mly {Ol'i't‘t’tt‘d
`according to that curw Tht“ orificc motors held boon l'al’n‘i‘
`
`mtvd in t’ltt‘
`lnf'mrzttrow shop fitciiitivs {H.lrx'ardl zmd pro-
`
`
`
`tin“
`(ti
`rmj'mmf. Tlxc dynamic Chart-lflt‘rtslit"s
`Z‘mzmre‘zrr
`cqtdpmcnt wart: studied by txgwlpiyizw the: sinc warm ml"
`v, 11nd t’
`
`whining amplitude zmd gullzlsc R“
`
`
`! lap 9“!"
`("I Hz
`1 1n,dummt.
`l
`
`
`,
`trc and How was qcncmtc.1 by a loudfilcakm‘
`(Acoustic Rcscarcll Ali—l} drivcn by 2m amplifier 11mm“
`«111th of,” a sitw—waw ltmctiuu qrrtm~zttrzr. first,
`tllt" clam»
`actm’istics of thc prcswl‘c tmmdtmrr mcd to n’wdfittrc flmv
`
`mcrc cmmincd by comparifiun again.“
`.1 mndt-nscr mint?)—
`phonc the cF'tatrzlctcristics of which wcrc F\Il(')\‘v’ll. The me-
`rlmniml
`tmlg‘mt
`(If 1.119
`loudspcalwr was conncctcd m A
`closed clmmbcr which containcd tl‘lc I'nicmphomt and m
`
`
`
`rm. 2. Dome flmvmmt‘r with dummy hcad. MW holes cmcx‘cd with
`Mitt-mesh dawn umstimtc the flow rcgistim n-lcnmm. Bias Haw tubing
`is srm distal tn thc shutter assembly.
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00002
`
`(if/Ar“
`@114
`
`f3:.pneumolcuzl’t
`
`
`
`.4:
`1714; F.
`
`standard mmhud at” mcmuring flow with pmmnmmcho-
`the,
`{:I.
`azimuth. B: $011222}: display-Li from cullap'eiztg chuck; and
`E.;gtph
`
`
`upwl airwz
`
`
`r,L
`'M.
`
`
`intx ill)“ I nurn.Lg Irmtl illiiIlIUDIfii‘ii SF‘fih’” uii
`F 1“ Fix nu 0.3L wilds, 3t;
`tilt Ct Li putt ml [in 1‘. uwmctcr \ him; How It. duccs (find span; in that of
`tht mouthpiece assmnbiy 211mm.
`
` FE). A rubber
`in a scpareltc (:mnpartmcnt
`(i
`ways,
`fitted around the
`llllcd with fine plastic bcads, w
`collar,
`
`
`“013211“, it
`
`1111 is amp
`51113399173 ”0mg H. new 1.: LI,;{
`.rdttzwllid. 29)
`
`
`lmmlng :1 seal and sopamazing thc l')l')€l}'
`clutrrabcr
`
`rtogmph chamber below from the head
`plethy
`1I
`wad chambcr ll”?
`u but
`
`
`‘Jlastit 'domc l(instituting, t}(t
`h, md 10 ‘x‘t‘f‘l m‘
`gagn11 \.\. g9 wm:
`.
`
`
`
`/ [PMl‘rpouttcd Sum tht (3mm? wall was. 'I. pnr‘vn’ny
`[LtthOLIjI‘EEPlI dwailx‘d htlow The substzmtial
`tolumt- dirt»
`
`plated lmm tltt militpac 43f d-h’d‘fldi‘é‘i. <admit a: ‘
`Elli,
`tF'ii'fiRS 6Otild Fit; ulciifi‘cfi‘i‘u 2133"
`9‘:
`
`,
`tltc mum into tl'w (3mm? gmd mam“
`
`surcd at the mouth. This subtraction could be achicvcd va
`cl‘lm’tically by routing the total flew back £11m the dome,
`'ld
`r,.... .t,mv
`(Fig. EC}. Bf»; this
`I“ ‘
`I‘
`'57,"
`Sidc the flowmctcr and Huw meadwcd with the dome pneu—
`z'nmachograp‘tt, tltct‘t‘it)rt:, includcd only flow which entered
`the domc from lmmthommc structures.
`Bccattsc wc wcrc m be cunccmcd 'witilh mcasuring only the,
`considcrd
`x‘zllnmf‘ of.it"reutcting 1r lcmmII this domf’. wt“
`and attcmmvdare mIinimizc nmr ntial artifacts resulting from
`Vertical mmcmcm at the neck. With thc dome rcmmcd and
`
`El lincar distal accl'nmtt, transdumr (chl {rd—Packard Linmh
`mm 5851 H3250) mounted m the tap (if the head, wc mea-
`szut'cd vertical hmd mmrcmcm in two sttbjccts as they”CI‘lC'
`mtcd triggered flow transients.
`it" the}
`1(:2ld movUncut ac
`{“xii‘éi
`(’
`,,
`rx nun ant.
`,
`v m,
`.r.~..«.nnt..wan\ v11" m{
`I
`F All”
`5
`v
`.
`.
`
`nu [mutt lllt in VA Tu’ (’n ululi‘nfi‘:(}n5, d1} ("1 '
`
`unto displacement due. 10 vcrtical motion of about 7 ml in
`mac subject and 5 ml in the other. However, thc ltcad dis-
`placcmcm in thc two subjccts was;
`in opposite directions
`and indccd may rcprcscnt only h Ind bobbing and mat 11cc};
`mm'cmcm~ Actual vertical neck movcmcm is very likely
`much Smaller and, under
`the cxpcrimcmal conditiona,
`probably small enough to be ignored. T0 rceu‘l) tllc dome
`mmtlitpiccc a Qubjcm was required to sit with Shouldcrs
`gnt‘(*<sc.rl fitmlx against the mp of the. nicthvsmocrdbh and
`m“.Kr.umtwhat am fiMtt’d.3 cma, “139}; hula 0:” the bflfid I aim:
`had .1
`flaccid circumflermce of 29.5 cm and had to be
`stretchcd to fit around the neck bcforc it was hardcncd. An
`additional attached tight—fitting: secondary cctllar of mbbcr
`
`

`

`SUPR AMAXIMAL FLOWS AND AIRWAY COLLAPSE
`
`655
`
`which the transducer was connected in the same manner as
`
`it was to be used. When the microphone and transducer
`were exposed to the 5: me sinusoidal oscillation of pressure, the
`transducer was found to have a frequency response ade-
`quate up to and beyond 150 Hz. This transducer in turn
`was compared to two others of the same model and their
`response characteristics were found to be identical. The
`three transducers were to be used to measure dome flow,
`input flow for tuning (described below), and pleural (esoph-
`ageal) pressure, respectively.
`With a subject’s head in the dome, the response charac—
`teristics of the dome flowmeter itself were than examined
`in the manner depicted in Fig. 3A. The loudspeaker was
`used to generate a sinusoidal input flow. This flow was
`measured as the resistive pressure drop across a 400-mesh
`21.6—cm2
`screen pneumotachograph substituted for
`the
`mouthpiece assembly. While this pneumotachograph had
`been calibrated with steady-state flows,
`the pressure—flow
`relationships would be
`the
`same
`for periodic flows
`through 100 Hz if inertial pressures were negligible. For
`periodic flow through a tube, the ratio of inertial to vis-
`cous forces is expressed by a.
`(1':
`
`(IVE/“v
`
`where a = the hydraulic radius of the tube, to = the angular
`frequency (21rf), and u = the kinematic viscosity of the gas.
`For the 37—pm holes of a 400-mesh screen at a frequency of
`100 Hz, a is approximately 0.13. For an infinitely long tube,
`
`
`output
`
`V
`'
`(filtered)
`
`@
`
`loudspeaker
`
`
`
`oscillator
`
`
`
`-
`
`_______ unfiltered i,”
`
`output
`
`I
`
`x”
`
`01
`to
`
`I
`30
`
`n
`50
`
`frequency
`I
`.
`7o
`90
`
`I
`no
`
`|
`130
`
`I
`150 Hz
`
`© 470.0.
`o—dew——¢vvvv~
`2509.
`
`lHY
`
`l8 K9.
`
`-
`
`4
`FIG. 3. A: apparatus for tuning the frequency amplitude response of
`the dome flowmeter as described in text. B: frequency amplitude re-
`sponse of dome flowmeter before and after electrical filtering. C: cir-
`cuit diagram of filter used to tune dome flowmeter.
`
`2.25"!de OJ "1de l
`
`the inertial contribution would be negligible at this fre»
`quency, and for screen pores 25 um long, may be ignored.
`Thus, the screen pneumotachograph calibrated with static
`flows accurately measures changing flows through a fre-
`quency of 100 Hz.
`The input flow signal and output dome flow signal were
`displayed on a dual trace time-base cathode—ray oscilloscope
`and the observed amplitudes made equal at a frequency of
`10 Hz. The ratio of output/input flow amplitudes was then
`examined through frequencies up to 150 Hz after having
`been set at unity at 10 Hz. This ratio was found to increase
`with frequency as illustrated by the upper curve in Fig.
`3B. The shape of this curve and magnitude of amplifica—
`tion, however, varied with the subject and seemed to be a
`function of the size or physical properties of the head within
`the dome. An electrical filter was constructed which com-
`
`this phenomenon (Fig. 3C). The variable
`pensated for
`resistance in the filter circuit permitted individual tuning
`for each subject. In this manner, it was possible to obtain a
`filtered frequency-amplitude response which was flat through
`100 Hz for each subject tested (lower curve in Fig. 38).
`Phase lag of the system was proportional to frequency and
`was equivalent to a fixed time delay of 3 ms.
`Because one of the objects of the study was to measure
`small volumes by integration of the flow signal,
`the ac-
`curacy with which such measurements could be made was
`evaluated. A cylindrical piston-bellophragm device which,
`when completely emptied, expelled a measured volume of
`41 ml of air was used as a volume source. When the piston
`was struck, the flow from this device was introduced into
`the sealed dome and the dome flow signal displayed on a
`time-base storage oscilloscope. This maneuver produced
`transients of flow up to 5 1/5 in amplitude and lO~15 ms in
`duration. Measurement of the area under these flow-time
`
`curves yielded volume values which were within :l:5 % of
`the actual volume displaced from the device.
`The expiratory flow transients were generated upon
`opening the valve obstructing the apparatus airway. The
`resistance to flow presented by the partially opened valve
`shutter could itself be a factor in limiting flow at any in-
`stant during the opening.
`It was necessary,
`therefore,
`that the valve could be opened very rapidly and that its
`position be monitored during opening. Because inertia
`must be overcome at
`the beginning of valve opening,
`solenoid-operated valves are relatively slow to move in the
`initial phase of activation. However, by striking the trigger
`arm, rapid opening could be achieved using a manually
`operated shutter. For later studies,
`the same valve was
`modified so that it could be solenoid operated but with the
`inertial problem eliminated.
`The shutter consisted of a double-leaf circular gate valve
`(17) which, when closed, completely obstructed the 2.5-cm
`diameter tube constituting the apparatus airway. When it
`was manually operated, a linear potentiometer physically
`coupled to the pivot shaft produced a signal by which the
`shutter position was monitored and the opening electrically
`timed (Fig. 4A). During the experiments to be described,
`the full shutter opening time was approximately 10 ms.
`When the manually operated shutter was used, only one
`triggered transient could be produced during a single
`expiratory vital capacity maneuver. To obtain a series of
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00003
`
`

`

`C33U1m
`
`KNUBSON, MEAD, AND KNUDSON
`
`H a solenoid
`
`no. 4. A: manually operated shutter assem-
`bly with potentiometer
`to monitor shutter
`position. B: shutter modified for solenoid op
`eration. When activated, solenoid plunger ac-
`celerates before striking trigger arm, opening
`shutter. When deactivated,
`falling plunger
`again strikes trigger arm closing shutter. Po-
`tentiometer to monitor shutter position is not
`shown here.
`
` 1
`
`-i®
`Q1'.
`
`G s
`
`'1
`\
`1%
`-
`5 "1\
`l
`l
`1
`\
`ii
`\\
`E
`!
`Shutter+Dcme
`5,
`
`i
`\\
`g
`: shutter
`k 0|
`o
`i0
`TIME
`
`.1
`V
`Ni (51
`
`3'01.
`!
`l
`I: 5i
`hr
`i
`1
`
`0
`
`mSIc
`
`/
`/
`I
`I
`.I/
`'I
`
`5
`
`10
`
`
`
`5
`
`
`. X . ith this .11odifica
`nne1at1o'1. full shutter opening could he acnieve
`1-1c11rd:1.
`.-1-:3a 13.C11-10 __1
`:5:‘~<
`than it; ms as measured electrica
`'
`tiometer signal.
`The triggered flow transients we shall describe weremof
`brief d1
`"""""""""
`subjects. BecauseIuil shutter opening could be accomplished
`within it} ms, it was necessary to determine the extent to
`4.L_ 1],“..— “.2 m
`_nJ L_,1 fi..,1 is nnnnn full" Afinn
`which the shutter itself contributed to the resistance limiting
`.i. \ii uuo
`uu: iiUW’o WC uiCa
`
`EU US UK:
`ii, Wei?) iuny UPC“.
`
`I
`
`F153. 5. Contribution of shutter to apparatus resistance during 10
`ms of shutter opening. A: resistance of shutter (solid line) and entire
`dome flowmeter assembly including shutter
`(dashed line), during
`shutter opening. B: flow in first 10 ms of the triggered transient during
`shun»? nnpning Fvnia—xnhnn1n mag:
`
`“‘c‘ -_.-_r...__ _.-__ ___ ”a
`
`analysis, we examined in detail the factors which might
`limit flow during one of the transients generated at 50% of
`the vital capacity and a pleural pressure of 100 CIDHgO in
`one of the normal subjects. This transient flow reached its
`peak in 10 ms during which time the shutter opened smoothly
`to its fully open position With the shutter held in different
`positions, we 111easured flow through t11e shutter and the
`pressure drop across it. Therefore, knowing the instan-
`taneous shutter position during the ‘10 ms of openingaand
`assuming steady-state flow resistance to be the same as
`instantaneous resistance, we were able to calculate the
`resistance contributed by the shutter at each instant in
`time during opening. With the shutter in the fully opened
`position, we measured the relationships 01”flow to resisti"e
`pressure drop across
`the entire dome flowmeter
`from
`mouthpiece to room. We used these data to apply
`empirical equation of Rohrer (344-). P = Kiv -i- K; V? and
`obtained calculated values, K1: 0.188 and K2—— 0. 013.
`From this we were able to estimate the resistance contributed
`by the apparatus during the transient. in Fig. 5 is de—
`picted flow and shutter resistance plotted in time during
`the 10 ms of shutter opening. In 5 ms, shutter resistance
`has fallen to 0.31 cmHgo/l per 5, contributing 53 % of the
`total resistance of 0.58 cmHgo/l per s of the entire flow-
`meter assembly including mouthpiece,
`shutter,
`tubing,
`and dome. By introducing sinusoidal flows at the mouth-
`
`piece and relating volume acceleration at if tants of zero
`flow to associated changes in pressure difi"erences across
`the system, we found the inertial impedance of the flow—
`meter assembly to be 0.0009 cmH2O/l per 32. Since sig
`nificant changes in mechanical
`impedance occur within
`
`the first 4 ms of shutter opening while our flowmeter is
`capable of responding only to frequencies through 100 Hz,
`such impedance changes would have an undetectable
`influence on the flow patterns observed during the trig—
`gered flow transient.
`Pressure 115nm!
`IeJflOnE. Esophageal pressure, as an in-
`direct determination of pleural pressure, was measured in
`the manner described by Milic-Emili and coworkers (30)
`with a lO-cm—long thin-walled latex balloon fastened to the
`end of a PIE-200 catheter
`ilO cm long. The dynamic
`response of the balloon—catheter-manometer system was
`subject to the same examination as other parts of the system
`in flu:- fnllnuying “ray
`the mechanical
`-reviousiy described,
`Ou+nsit ré' 11111.: lnnria eakerV733 COBDCCEEd .n aChambpr can-
`
`tairiing the esophageal balloon. Pressure changes within
`the chamber were senseed by a differential pressure trans-
`ucer connected directl" to it. The balloon catheter was
`connected to a second ytransducer. The dynamic charaCQ
`teristics of both transducers (Sanborn 2683) had been
`previously examined and found to be satisfactory and
`identical. When sinusoidal oscillations of pressure were
`generated by the loudspeaker, the pressure signals sensed
`by the two transducers were made equal in amplitude at a
`frequency of 5 Hz and amplitude and phase lag compared
`as frequency was increased. When filled with 0.2 ml of air,
`the esophageal balloon system recorded pressure amplitudes
`greater than actual pressure at frequencies above 20 Hz.
`While the frequency response could be improved by shorten<
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00004
`
`

`

`SUPRAMAXIMAL FLOWS AND AIRWAY COLLAPSE
`
`657
`
`ing the catheter or by using a catheter of larger caliber,
`such solutions were impractical.
`As Fry and his associates (7, 11) have pointed out, the
`properties of the fluid (gas) filling the pressure recording
`device will affect its response characteristics. We found that
`when the system was filled with helium (0.4—0.6 ml) the
`frequency—amplitude response of the esophageal balloon
`system was flat through 90 Hz. The time delay of such a
`system depends on the length of the catheter as well as its
`caliber and the fluid which fills it. By examining the time
`delay of different lengths of helium-filled PE—200 catheter,
`it was determined that such a catheter 110 cm in length
`introduces a time delay of 3 ms which was constant at
`frequencies through 90 Hz. This time delay is less than half
`that of an air-filled system. The llO-cm catheter length was
`chosen so that the time delay of the pressure measuring
`system would be equal to that of the electrically filtered
`flow signal allowing temporal correspondence of pressure
`and flow as measured.
`
`Transient triggering. Two series of experiments were carried
`out involving, in addition to other expiratory maneuvers,
`triggered flow transients. In the first series, the shutter was
`manually operated and triggered by the investigator. Flow
`and volume were displayed on an X-Y cathode-ray storage
`oscilloscope (Tektronix 564). Each transient was produced
`with the volume history of having first inspired to total lung
`capacity (TLC). In every instance but those done at TLC,
`the subject expired slowly to the preselected lung volume
`at which point the shutter was closed. An expiratory effort
`was then generated until the desired pleural pressure had
`been reached,
`the pleural pressure being displayed on a
`separate oscilloscope within sight of the subject and operator.
`The shutter was then opened by striking the trigger arm, the
`flow transient produced, and the subject then continued
`the forced expiration until residual volume (RV) had been
`reached.
`
`the shutter was
`In the second series of experiments,
`solenoid operated and the triggering automated. The
`pleural pressure at which the transients were to be generated
`was preselected. When this target pressure was achieved,
`the signal from a zero crossing detector started the free
`running gated pulse generator of a Digitimer (Devices)
`beginning the timing cycle. The solenoid was activated
`within 1 ms. After 70 ms, the solenoid was deactivated and
`the shutter permitted to close as the solenoid plunger fell
`by its own weight. Shutter closing took approximately 30
`ms and was fast enough for the experiment. The cycle was
`not permitted to start again until an additional 90 ms had
`elapsed. If pleural pressure was then above the target value,
`the shutter would reopen and the cycle repeat. If pleural
`pressure was below target value, the cycle would not repeat
`until that pressure had again been achieved. All efforts
`were started from full inspiration and, while specific lung
`volumes were not preselected, each effort produced a series
`of transients as the subject expired to RV and these could
`later be related to lung volume. Furthermore,
`the static
`measurements of volume and transpulmonary pressure ob—
`tained during the intervals of valve closure could be used to
`construct static deflation pressure—volume curves.
`Data collection. During the experiments,
`simultaneous
`recordings were made of volume, flow (unfiltered and elec—
`
`trically filtered), shutter position, pleural (esophageal) pres—
`sure, and with another differential pressure transducer
`measuring the differences between esophageal and mouth
`pressure, transpulmonary pressure. Data were recorded on a
`multichannel oscillograph (Sanborn), on magnetic tape
`using a seven—channel FM instrumentation tape recorder
`(Precision Instruments, Inc.), and flow and volume moni-
`tored on a storage oscilloscope (Tektronix 564). Subse-
`quently, the tape-recorded information was examined from
`oscilloscopic displays of flow vs. volume and flow, pleural
`pressure, and shutter position in time.
`
`RESULTS AND DISCUSSION
`
`In addition to generating the triggered flow transients,
`the subjects performed other respiratory maneuvers; several
`forced vital capacity maneuvers, a series of short forced
`expirations initiated with glottis open beginning at TLC
`and progressing sequentially down the vital capacity with-
`out intervening inspirations, a series of voluntary coughs
`beginning at TLC and continuing down the vital capacity
`in the same manner, and several maximal voluntary ven-
`tilation (MVV) maneuvers.
`,
`Comparison of rapid flow events. It has been anticipated that
`the coughs and triggered flow transients would appear as
`similar phenomena. In both instances the expiratory effort
`was generated before flow was permitted to begin; in one
`instance flow was initiated upon opening the glottis and in
`the other upon opening the shutter. In generating a forced
`expiration with glottis open, on the other hand, one would
`expect flow to reach peak more slowly inasmuch as the
`effort-dependent phase during which expiratory muscular
`effort is generated has a finite duration.
`These three respiratory maneuvers are depicted in Fig.
`6A. They were performed at the same lung volume with
`the same volume history, displayed as flow in time. These
`results, typical of those seen in all subjects studied, show
`that peak flow during the forced expiration can be attained
`in 3540 ms in a trained subject. The time required to reach
`peak flow upon initiating a cough is of the same order, no
`less than 30—35 ms in most instances, whereas flow reaches
`its peak in lO~15 ms during the triggered transient. Maxi-
`mum volume accelerations were about 300 1/52 during
`cough and forced expirations and at least 1,200 1/52 for
`triggered transients. Thus the volume acceleration of cough
`and of forced expiration are similar in magnitude but about
`one—fourth that seen in the triggered event. From this it is
`apparent that laryngeal opening at the onset of cough is not
`analogous to the triggered opening of a shutter but is an
`event of longer duration. Published evidence suggests that
`cough is initiated by rapid abduction of the arytenoid
`cartilages, an active phenomenon (38)
`involving muscle
`contraction. Using high-speed photographic techniques
`(31), von Leden and Isshiki
`(38) were able to measure
`laryngeal dimensions during cough. From their data,
`it
`appears that laryngeal opening time is about 25~30 ms,
`of sufficient magnitude to account for the time observed to
`reach peak flow in the cough. The early upward concavity
`of the flow—time curve during cough is suggestive of diminish-
`ing flow resistance oHered by the widening glottis during
`this initial phase. Both forced expiration and cough are
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00005
`
`

`

`658
`
`KNUDSON, MEAD, AND KNUDSON
`
`
`
`®
`
`1
`‘g
`e
`,1
`3 113i
`‘
`I / \
`g
`51 / \ K951 .
`=
`’
`\ v
`'
`'
`'
`
`GL’
`'0 l
`[.1 2
`15
`l .l \l\ 3
`3.
`1
`T“If“ Tmnmm
`i I M?“ 5
`3
`‘95
`u 10
`5 1'
`Ill
`i
`i]; ”(Ba :3
`,I
`l.
`MM
`
`
`
`4°
`
`20
`TIME
`
`30
`
`500
`
`5°
`mSec
`
`\\ \.\ \
`FIG. 5. A: flow-time representations
`of forced expiration, cough, and trig-
`7\\ \~;\\.‘
`% gered transient performed at the same
`lung volume in a normal subject. B: on
`left is the flow-volume representation of
`a series of voluntary coughs beginning
`at TLC and progressmg sequentially
`down the vital capacity superimposed
`on the subject’s MEFV curve. On
`tue nu.tubersd conghs are rcpt“:-
`right,
`'5 ‘l
`
`se..ted as flow in tits. 1
`i
`'
`briefArapid expiratory efforts are de—
`//2T\\
`to 5
`picted nthe same manner as the coughs.
`/3\ \
`1
`4 \ \ All data in this figure are derived from
`1
`5 A}Q\\\\— the same normal subject.
`
` C
`presnon '15 represented by the region of
`
`to airway com
`supramaximal
`1.c
`
`p \JIJLLIJA y
`
`if: airway Ufluluuuuu,
`in the instance of the coughs and brief
`describe below.
`forced expirations, supramaximal
`flow is of sufficiently
`lav-tar d11rgt1nn 1;th +kprn 1g
`51 mnggnrghlp prrpqcp no hint?
`b.2115 uuianvh that.
`iiiviL ‘11 u iiiLuJua quay uceaeuue 111.
`iuazb
`volume, and hence Pst(L), and concomitant fall in Vmax
`during this interval. However, during the triggered transient
`(Fig. 6A), initial volume acceleration is much greater than
`during cough or forced expiration, and supramaximal flow
`is of such a short duration that fall in lung volume and
`Vmax is negligible. Thus, by resorting to this device we have
`been able to compress in time the sequence of events which
`result in dynamically compressed airways.
`tttttttt By d‘
`,‘
`Tagging flaw
`{ite flow-volume
`representation of a series of flow transients generated at
`different lung volumes but at the same pleural triggering
`pressure and comparing these to the MEFV curve, it can
`be observed that the transient flows reach a peak quickly
`and almost as quickly fall back to Le MEFV we The
`transient peak flows can be quite high, particula-ly at high
`1
`pleural pressures, even at very low lung volumes. In the
`normal subject illustratedin Fig. 7, transients were generated
`at a Ppl of 80 cmH20 and, even at volumes as low as 3 %
`of VC, reached a flow of 7 l/s. If the end of the transient
`is defined as the instant flow falls to me , it can be seen
`that the change in lung volume is extremely small during
`the transient. We made the assumption, therefore, that the
`static recoil pressure (Pst(L)) of the lung was virtually un-
`changed for the duration of the transient, or that the change
`would at least be negligible. Based on the analysis of Mead
`and associates (27), the assumption of a fixed Pst(L) per—
`mitted the additional assumption that, in the brief period
`of the transient interval, the equal pressure points (EPP)
`became anatomically fixed, the length of the compressible
`
`Monaghan Medical v. Smiths Medical, IPR2018-01466
`
`Monaghan Medical Exhibit 1009-00006
`
`
`
`, and fore
`dependent on muscle activitV
`ships, involving expiratory 111'wles '
`laryngeal musclesin the second Th
`I}
`in am
`of expiratory muscles during the rising
`l
`1
`U1
`Cd CAUIJ auufi is
`csumain y s111a' '
`that required of the laryngeal muscles during opening of
`the glottis. Thus it is not surprising that the duration of t‘re
`volume acceleration phase is of similar magnitude in both
`Ldét’o
`
`sortening
`nAm-«nv‘
`hase of flow during
`n lain q-n
`nun, LU
`Lulllpal
`
`CC and
`
`Voluntary coughs vs. forced expiratz'ons. Figure 6, B and C,
`
`of voluntary coughs (6B) and a series of brief rapid expira—
`tions (60) beginning at TLC and generated sequentially
`down the vital capacity. It can be seen from the time plots
`that the initial volume acceleration is nearly identical for
`both types of maneuver and is independent of the volume
`at which the maneuver is initiated. Itis also apparent that,
`in comparison with the MEFV curve, the c ughs and brief
`g“:
`maximally rapid expirations produce peaKflows which
`are substantiallyin excess of the maximum flows produced
`during an uninterrupted maximal forced expiration,
`the
`result of the dynamic airway compression which occurs
`11111.11“.
`in1f1 al
`\uu, uu,
`mm a: 40). Thengh the
`during these 111aneu'ers
`the individual curves are
`risein flowiis identical for all,
`n‘vnv‘lnhv‘: 1“"-
`page '11-
`4.1““-
`366’] LG uCUalL fiom 1.116513 CUmLuGfi \UVLJIappi“51' Cu: Vb.) an
`.
`DI‘Ogressively shorter inte1vals from the onset of flow as
`lung volume decreases. These deviations precede any dif—
`ferences in driving pressure and presumably reflect the onset
`of airway compression. Dynamic compression begins sooner
`at low than at high volumes and as a result peak flows are
`attained sooner at low than at high volumes. We have ex-
`plained these brief intervals of supramaximal
`flows by
`considering flow as coming from two sources, the air spaces
`within the pulmonary parenchyma and the airways sub-
`nay-HI
`1.1