Thorax 1988;43:360-365 Imaging of the airways by bronchoscintigraphy for the study of mucociliary clearance STEFFEN GROTH, JANN MORTENSEN, PETER LANGE, ERIK P MUNCH, PETER GRUNDTVIG S0RENSEN, NIELS ROSSING From the Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, and Rigshospitalet Medical Department P, Bispebjerg Hospital, Copenhagen, Denmark ABSTRACT A method for functional imaging of the large airways (bronchoscintigraphy) has been developed. It is based on the administration of aerosolised albumin labelled with technetium-99m using a special inhalation technique to produce central airway deposition. The method was evaluated as a measure of mucociliary clearance by recording the movement of radioactivity in the airways of 11 healthy, non-smoking subjects on two separate days. A series of bronchoscintigrams was acquired at five minute intervals for two hours after termination of the inhalation. After the first broncho- scintigram 1 25 mg terbutaline or placebo was administered from a metered dose inhaler (five puffs) according to a randomised, double blind, crossover design. The scintigrams were evaluated blind. After terbutaline the segmental bronchi were no longer visible after a median time of 10 minutes, the lobar bronchi after 20 minutes and the main bronchi after 30 minutes. In six cases the trachea was cleared after two hours. After placebo the segmental bronchi disappeared after a median of 15 minutes, but at two hours half the lobar bronchi remained visible. In only two cases was it no longer possible to see the main bronchi or the trachea. It is concluded that bronchoscintigraphy can be used to examine regional mucociliary clearance in healthy subjects and that terbutaline significantly increases the clearance of the deposited radioactive aerosol. Mucociliary clearance, one of the most important defence mechanisms of the airways, is usually measured by non-invasive external detection of the clearance rate of an inhaled radioaerosol.' For this measurement it is often recommended that the individual inhales the radioaerosol by tidal volume breathing so that lung deposition is diffuse rather than selectively reaching the large airways. Hence mucociliary clearance is usually calculated for the whole lung or for arbitrarily determined lung regions. As mucociliary clearance occurs in bronchi and bron- chioles the possibility of making such measurements in selected morphologically defined airways is desirable. The aim of this study was to determine whether a special inhalation technique consisting of slow inspira- tions and forced expirations, performed as close to Address for reprint requests: Dr Steffen Groth, Department of Clinical Physiology and Nuclear Medicine, Finsen Institute, 49 Strandboulevarden, DK-2100 Copenhagen 0. Accepted 1 February 1988 residual volume as possible, might cause a selective deposition of a radioaerosol on the airways, thus providing a morphological scintigraphic image and measurement of mucociliary clearance. Evaluation of the validity of this inhalation technique was combined with a study to determine whether terbutaline has an acute effect on mucociliary clearance in healthy non- smoking subjects. The change in radioactivity with time was taken as a measure of mucociliary clearance and was monitored by repeated scintigraphic acquisi- tions over two hours. Methods SUBJECTS Eleven healthy subjects who had never smoked par- ticipated in the study, which was approved by the local ethical committee. Their median age was 21 (range 18- 42) years. All subjects had a normal forced expiratory volume in one second (FEV,) and forced vital capacity (FVC), the median FEV, being 94% (range 82-108%) predicted and the median FVC 101% (range 87- 128%) predicted.2 360
Transcript
Thorax 1988;43:360-365
Imaging of the airways by bronchoscintigraphy for thestudy of mucociliary clearanceSTEFFEN GROTH, JANN MORTENSEN, PETER LANGE, ERIK P MUNCH,PETER GRUNDTVIG S0RENSEN, NIELS ROSSING
From the Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, and RigshospitaletMedical Department P, Bispebjerg Hospital, Copenhagen, Denmark
ABSTRACT A method for functional imaging of the large airways (bronchoscintigraphy) has beendeveloped. It is based on the administration of aerosolised albumin labelled with technetium-99musing a special inhalation technique to produce central airway deposition. The method was evaluatedas a measure ofmucociliary clearance by recording the movement ofradioactivity in the airways of 11
healthy, non-smoking subjects on two separate days. A series of bronchoscintigrams was acquired atfive minute intervals for two hours after termination of the inhalation. After the first broncho-scintigram 1 25 mg terbutaline or placebo was administered from a metered dose inhaler (five puffs)according to a randomised, double blind, crossover design. The scintigrams were evaluated blind.After terbutaline the segmental bronchi were no longer visible after a median time of 10 minutes, thelobar bronchi after 20 minutes and the main bronchi after 30 minutes. In six cases the trachea was
cleared after two hours. After placebo the segmental bronchi disappeared after a median of 15minutes, but at two hours half the lobar bronchi remained visible. In only two cases was it no longerpossible to see the main bronchi or the trachea. It is concluded that bronchoscintigraphy can be usedto examine regional mucociliary clearance in healthy subjects and that terbutaline significantlyincreases the clearance of the deposited radioactive aerosol.
Mucociliary clearance, one of the most importantdefence mechanisms of the airways, is usuallymeasured by non-invasive external detection of theclearance rate of an inhaled radioaerosol.' For thismeasurement it is often recommended that theindividual inhales the radioaerosol by tidal volumebreathing so that lung deposition is diffuse rather thanselectively reaching the large airways. Hencemucociliary clearance is usually calculated for thewhole lung or for arbitrarily determined lung regions.As mucociliary clearance occurs in bronchi and bron-chioles the possibility ofmaking such measurements inselected morphologically defined airways is desirable.The aim of this study was to determine whether a
special inhalation technique consisting ofslow inspira-tions and forced expirations, performed as close to
Address for reprint requests: Dr Steffen Groth, Department ofClinical Physiology and Nuclear Medicine, Finsen Institute, 49Strandboulevarden, DK-2100 Copenhagen 0.
Accepted 1 February 1988
residual volume as possible, might cause a selectivedeposition of a radioaerosol on the airways, thusproviding a morphological scintigraphic image andmeasurement of mucociliary clearance. Evaluation ofthe validity of this inhalation technique was combinedwith a study to determine whether terbutaline has anacute effect on mucociliary clearance in healthy non-smoking subjects. The change in radioactivity withtime was taken as a measure of mucociliary clearanceand was monitored by repeated scintigraphic acquisi-tions over two hours.
Methods
SUBJECTSEleven healthy subjects who had never smoked par-ticipated in the study, which was approved by the localethical committee. Their median age was 21 (range 18-42) years. All subjects had a normal forced expiratoryvolume in one second (FEV,) and forced vital capacity(FVC), the median FEV, being 94% (range 82-108%)predicted and the median FVC 101% (range 87-128%) predicted.2
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Imaging of the airways by bronchoscintigraphy for the study ofmucociliary clearance
BRONCHOSCINTIGRAPHY AND MUCOCILIARYCLEARANCERadionuclide Sodium pertechnetate (9'TcO4) waseluted in isotonic saline from a 9Mo/9Tc generator.The pertechnetate was tagged to human albumin(Venticoll, Solco) by injecting 350-700 MBq of thepertechnetate into a phial containing albumin.Isotonic saline was added to make the volume up to5 ml.Aerosol generation, administration, and inhalation tech-nique The aerosol was generated in an ultrasonicnebuliser (DeVilbiss 35B) containing the 5 ml 9'Tcalbumin. The aerosol was inhaled directly from thenebuliser via a tube 10 cm long with a T valve at themouth. The T valve ensured that expired aerosol wastrapped. The median mass particle diameter was 5(range 1-7) pm. The subject inhaled while sitting andwearing a nose clip, with the nebuliser in series with aspirometer to allow inspiratory volume and flow rateto be monitored. Subjects were instructed to inspireslowly (inspiratory flow rate < 30 1/min) from residualvolume until 600 ml had been inspired and to followthis with a maximal forced expiration to residualvolume. Subjects made a total of 10-20 inhalationsusing this pattern of ventilation. This usually resultedin a count rate of around 2000 counts/second on thegamma camera.Data acquisition Immediately after inhaling theaerosol subjects were placed in the supine posture withtheir backs against a gamma camera (Maxi Camera,General Electric) with a large field of view size crystaland a parallel hole 140 KeV collimator. Initialscintigrams were made from the static acquisition of a200 000 count image. The acquisition was repeatedevery five minutes until 120 minutes after the inhala-tion to follow mucociliary clearance of the 9'Tcalbumin. Each image was made at the same intensityas the initial one and, apart from being corrected forthe physical decay of 9'Tc, the acquisition time alsoremained unchanged,. The acquired number ofcountswas disregarded. In this way it was intended thatchange in scintigrams contained biological informa-tion only. The background radioactivity of the room(5-16 counts/s) was negligible by comparison with thesubject's radioactivity.
EFFECT OF TERBUTALINE ON MUCOCILIARYCLEARANCEOn two separate days at least one week apart five puffsof terbutaline (1 25 mg) or placebo were administeredby inhalation from a conventional metered doseinhaler. The drugs were administered immediatelyafter the first gamma camera acquisition, five minutesafter the end of the inhalation of the 9'Tc albumin.Inhalation of terbutaline and placebo was performed
Fig 1 An example of the morphological information thatmay be obtained by bronchoscintigraphic imaging.
as recommended by Newman,3 according to a doubleblind crossover design.
DATA ANALYSISThe number of bronchi that could be identified on thebronchoscintigrams was counted and the time afterinhalation when they could no longer be seen wasnoted. The effect of terbutaline and placebo onmucociliary clearance was compared by the sign test.The scintigrams were evaluated independently by twospecialists who were unaware of whether placebo orterbutaline had been given.
Results
An example of the morphological informationobtained by the bronchoscintigraphic imaging tech-nique is shown in figure 1. Individual bronchi areeasily identified; peripheral to the segmental bronchithe structures merge with the background. In mostcases a substantial part of the radioactivity wasdeposited in the mouth. Most of the radioactivity inthe stomach comes from the aerosol originally
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Table 1 Last time (min, < 120 min) at which it was possible to identify the anatomical structures on the bronchoscintigrams aft,administration ofplacebo (P) or terbutaline (T)
Main bronchi Lobar bronchi
Trachea Left Right Left superiorSubjectNo P T P T P T P T
*Number of identified segmental bronchi.tNot visible.
deposited in the mouth. The oesophagus is seenfaintly.As a result of mucociliary clearance there was a
gradual decrease in radioactivity to background levels,and the morphological structures became increasinglyindistinct. This effect spread from the smallest visibleairways (segmental bronchi) to the larger airways(lobar and main bronchi), as table 1 shows. This doesnot necessarily imply a greater mucociliary clearancein peripheral airways, because when central airwaysare considered separately there is a fairly constantdecrease in radioactivity, despite the continuousadmixture of radioactivity from the periphery.The stimulatory effect of terbutaline on mucociliary
clearance was evident for all visible airways and in all11 cases the day with the faster clearance as identifiedby the readers, was the day when terbutaline had beengiven (p < 0 01). After terbutaline almost all the mainand lobar -bronchi were cleared to scintigraphic in-visibility at a rate three times greater than on theplacebo day (p < 0-01). Table 1 presents averagevalues for the last points (< 120 min) given by the tworeaders at which it was still possible to identify theanatomical structures on the bronchoscintigrams afterplacebo and after terbutaline.A typical example of the series of bronchoscin-
tigrams is shown in figure 2. The uppermost scin-tigrams on both panels show the initial distribiition ofradioactivity in the lung immediately after inhalation.The images were similar on the two days, the majorpart of the retained activity being deposited in thelarge airways. Mucociliary clearance was considerablygreater after terbutaline than after placebo.None of the subjects coughed during the examina-
tions, so no correction for coughing as an independentclearance mechanism was required.
Fig 2 An example of the effect ofplacebo (left) andterbutaline (right) on mucociliary clearance as seen,fromseries ofbronchoscintigrams.
The results of this study show that inhalation of aradioaerosol by a slow small inspiration followed by aforced expiration made as close as possible to residualvolume provides selective deposition of the aerosol inthe airways, allowing scintigraphic imaging andmeasurement of mucociliary clearance.The choice of pattern of inhalation is based on the
behaviour of aerosol particles in tubing systems.45 If asubject inspires an aerosol at a low flow rate, asubstantial part of it should be carried by thepredominant laminar airflow into the lungs withoutpremature deposition in the mouth or pharynx. If atthe same time expiration is forced, the aerosol wouldtend to be retained in the airways by impaction due to
the effect of turbulence. If the inhalation is as close toresidual volume as possible alveolar deposition shouldbe reduced, as a consequence of the relative increase indeadspace ventilation. In addition, the deposition ofaerosol in the airways should be enhanced, since theprobability that the aerosol particles will strike thesmall airways should increase, when the small airwaysclose.
Since 19556 several methods have been introducedfor the measurement of mucociliary clearance. Noneof the methods, however, has been widely accepted forroutine clinical use. The radioactivity retained in thenon-ciliated airways behaves as background noise andmay interfere with the measurements of mucociliaryclearance. A few studies have tried to solve thisproblem, usually by obtaining a selective deposition of
Table 2 Results ofprevious studies on the effect of fl2 agonists on mucociliary clearance (MC) in healthy individuals
EffectNo of Study on
Authors Year individuals f2 agonist Dose and route design clearance
Konietzko et al" 1975 1 1 Terbutaline Oral 5 mg DB o + LMCCamner et al'2 1976 8 Terbutaline Sc 0 25 mg DB o + LMCFoster et al's 1976 10 Isoprenaline lnh 0-005 M p + LMC
364the radioactivity in the airways with guided ven-tilation.'7 Normally monodisperse particles of 5 gm ormore are used. Because oftheir uniform size they oftenensure a reproducible deposition. The resulting scin-tigrams do not, however, allow identification of eventhe large bronchi. No matter how large the particles,when tidal volume breathing is used much of theradioactivity will be deposited in airways withdiameters smaller than the resolution power of thegamma camera. This results in a blurring of details ofthe image. Conventional techniques are not normallyrequired to identify larger bronchi, and when precisemeasurements of background activity are achievedalveolar deposition may be useful as an index of theinitial topographic distribution of radioactivity in thelungs. It may reflect patency of the airways when themode of inhalation has been kept constant. Whenparticles are under 5 gm tidal volume breathing causesan initial background count rate that may constituteas much as 40-60% of the total initial count rate.348With particles of 5 gm or more the background countrate may be reduced.9"'The main purpose of our study was to determine
whether the pattern of ventilation we chose couldprovide scintigraphic visualisation of the bronchialtree. The reason why the trachea was not always seenon the initial picture is probably that the forcedexpirations were initiated at lung volumes as little as500-600 ml above residual volume (fig 2). Ifexpirationhad been initiated at TLC, the maximal flow wouldhave been far greater than at low lung volumes, when itwas presumably too low to cause effective impactionof the aerosol in the trachea. A deeper inspirationmight have reduced bronchial deposition owing to adecrease in the relative deadspace ventilation. As themucociliary beating gradually moved the radioactivitytowards the mouth, radioactivity accumulated in thetrachea (fig 2). It was not our aim, however, todetermine the importance of the individual compo-nents of our ventilation technique for aerosol deposi-tion. Perhaps the information obtained from thescintigrams could be increased by identifying andsubsequently enhancing the effect of the most impor-tant components of the ventilation manoeuvre.' 4
In this study data were analysed by a blindedsemiquantitative approach. If this method of analysisis applied in clinical trials with paired data, it will besufficiently sensitive to identify significant changes inmucociliary clearance when the signals are as strongas those produced by terbutaline on mucociliaryclearance in this study. The information will bestrengthened if the quality of the imaging can beimproved and if a kinetic model of absolute andregional mucociliary clearance is created.
In normal subjects some previous studies havefound an effect of subcutaneous or oral terbutaline on
Groth, Mortensen, Lange, Munch, Sorensen, Rossingmucociliary clearance and others have found noeffect7 ""' (table 2). Six previous trials, all using anopen design, have looked at the effect of inhaled 2agonists on mucociliary clearance in normal sub-jects.7 '3 '0-'" Yeates et ar found an increase in trachealmucociliary clearance in eight subjects after inhalationof fenoterol. Foster et al'3 141618 found an increase inmucociliary clearance after inhalation of a single doseof various f2 agonists in 30 subjects and Lafortuna etal7 found similar changes after salbutamol when threesubjects were compared with three others who did notreceive salbutamol. Our study is the first controlledstudy to show unambiguously a stimulatory effect ofan inhaled f2 agonist on mucociliary clearance innormal subjects.
In view of the striking effect of terbutaline onmucociliary clearance in healthy non-smokers it issurprising that the results of previous trials on theeffect of terbutaline on mucociliary clearance inchronic obstructive lung disease are so conflicting. Inpatients with chronic bronchitis some authors havefound an increase in mucociliary clearance after f2agonists," 17 2022 but others have not.2325 In asthmaticpatients8 2130 an increase in mucociliary clearance hasbeen found in three of six trials.20-' There is thereforeno well established consensus that fl2 agonists increasemucociliary clearance in pulmonary disease.
In most normal individuals and patients maximal ornear maximal bronchodilatation can be achieved with0 5 mg terbutaline from a metered dose inhaler. In thisstudy we used a higher dose ofterbutaline (1-25 mg); soit remains to be established whether similar effects onmucociliary clearance would be produced by doses ofterbutaline used in clinical practice.
Because of the conflicting and often negative resultsofprevious investigations on the effect off2 agonists inpatients with chronic bronchitis and asthma, it wouldbe too early to extrapolate our results to such patients.Further investigations must determine whether ourmethod for semimorphological imaging of bronchiwill provide similar convincing information aboutregional mucociliary clearance in patients withobstructive lung disease.
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