Archives ofDisease in Childhood 1992; 67: 25-30

Delivery of therapeutic aerosols to intubated babies

Jonathan Grigg, Shmuel Arnon, Tracey Jones, Andrew Clarke, Michael Silverman

AbstractDelivery of drug aerosols to the lungs ofventilated neonates by metered dose inhalerand spacer (Aerochamber) and ultrasonicnebuliser (Pentasonic) was assessed usingsodium cromoglycate.The mean proportion of a known intra-

tracheal dose ofsodium cromoglycate excretedin the urine of four intubated infants was37-5%. After assuming that 38% of the sodiumcromoglycate aerosol reaching the neonatallung will be excreted in the urine, three puffs(15 mg) delivered by metered dose inhaler andspacer resulted in a pulmonary dose of 258 [ig(1-7%, n=7V. A dose of 20 mg (4 ml) sodiumcromoglycate ultrasonically nebulised overfive minutes into the inspiratory limb of astandard ventilator circuit produced a pul-monary dose of 257 [tg (1-3%, n=7).Of two in vitro lung models assessed, a

combination of filter and neonatal test lungwas superior to a multistage impactor inestimating the in vivo pulmonary sodiumcromoglycate dose delivered by metered doseinhaler and spacer (243 tg v 1740 ig).

Department ofPaediatrics andNeonatal Medicine,Royal PostgraduateMedical School,Hammersmith Hospital,London W12 ONNJonathan GriggShmuel ArnonMichael SilvermanFisons plc,Pharmaceutical Division,LoughbroughTracey JonesAndrew ClarkeCorrespondence to:Dr Silverman.Accepted 15 September 1991

Therapeutic aerosols are often used in intubatedneonates despite a paucity of information on thepulmonary dose or the most efficient deliverysystem. A number of devices are available forthe production of therapeutic aerosols.

Jet nebulisation is widely used and broncho-dilators administered by this method have beenshown to improve lung function in intubatedinfants with bronchopulmonary dysplasia.'There are, however, problems with jet nebulis-ation including gas cooling,2 reduction inhumidity,3 and a requirement for an auxiliaryhigh pressure gas supply. It is also very in-efficient, with 0-2% of the drug dose in thenebuliser reservoir reaching the neonatal lung.4

Table I Subject details

Subject Gestation Weight Diagnosts Sodium cromoglycateNo (weeks) (g) delivery method

1 35 2100 Myopathy IT+Pentasonic2 35 4000 Persistent fetal circulation IT+Pentasonic3 41 4200 Myopathy IT+Pentasonic4 31 1700 RDS IT+Pentasonic+Aerochamber5 24 800 RDS Pentasonic+Aerochamber6 30 1400 RDS Aerochamber7 38 3500 Gastroschisis Aerochamber8 26 1000 RDS Aerochamber9 25 1100 RDS Aerochamber10 27 500 RDS Aerochamber11 30 1400 Apnoea Pentasonic12 38 4700 RDS (diabetic mother) Pentasonic13 36 1400 Congenital abnormalities IT14 26 1000 RDS IT

RDS=respiratory distress syndrome; IT=intratracheal sodium cromoglycate dose.

Ultrasonic nebulisation and metered doseaerosol delivered by spacer are alternativedelivery methods which have little effect onventilator gas humidity or temperature. Neitherhas been assessed in intubated neonates.The Pentasonic ultrasonic nebuliser (De-

Vilbiss) nebulises drugs using 2-25 MHz pizo-electric crystal. It weights 160 g and is portable.The Aerochamber with 15 mm connection(Trudell Medical) is a modification of an infantspacer device accepting standard metered doseinhalers (MDI) and is designed to be insertedinto the inspiratory limb of an adult ventilatorcircuit. This 11 x4 1 cm spacer has an approxi-mate volume of 145 ml and allows aerosol to begenerated within the centre of the ventilator gasflow. Both the Pentasonic and Aerochamber canbe used in a neonatal ventilator circuit afterminimal adaptation.

This study aimed to assess the efficiency ofaerosol delivery to intubated infants lungs byusing sodium cromoglycate as a marker of drugdelivery. Sodium cromoglycate (Intal, Fisonsplc) is non-toxic and is excreted unchanged inthe bile and urine.5 We first estimated thefraction of a known intratracheal dose of sodiumcromoglycate excreted in the urine of ventilatedneonates over 24 hours. By combining thisinformation with 24 hour urinary sodiumcromoglycate excretion after an ultrasonic orMDI dose, the total dose deposited in the lungwas estimated. Pulmonary sodium cromoglycatedeposition by MDI in vivo was then comparedwith that estimated in vitro by either a test lungwith filter or a multistage impactor.

MethodsIN VIVO ASSESSMENTInfants studied were receiving intermittentpositive pressure ventilation via a pressurelimited, time cycled ventilator (Sechrist) for arange of conditions. These included respiratorydistress syndrome (n=8), myopathy (n=2),persistent fetal circulation (n= 1), surgery (n= 1),and multiple congenital abnormalities (n= 1)(table 1). All infants were intubated by ashouldered endotracheal tube (Portex) and hadblood urea and creatinine concentrations withinthe normal range.This study was approved by the ethics

committee of the Royal Postgraduate MedicalSchool. Infants were studied after writtenparental consent.

Intratracheal doseIsotonic sodium cromoglycate (1400 ,ug, 0-2 ml)

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Grigg, Arnon,3tones, Clarke, Silverman

was instilled through a size 5 French gaugesuction catheter wedged in the right mainbronchus of intubated neonates. Urine wascollected over a 24 hour period and assayed forsodium cromoglycate by radioimmunoassay.6 Ifleakage from the collecting bag occurred, the 24

Figure I Pentasonic nebuliser inserted into the inspiratory limb ofa ventilator circuit.

Figure 2 Ventilation through an Aerochamber spacer.

E

D

F

G

A B

JH

inspiratory line

hour collection was discarded. Sodium cromo-glycate removed from the lung by suction wasmeasured in the total pool of endotrachealaspirates collected over 24 hours after instillation.The actual intratracheal dose available to theinfant was the difference between the intra-tracheal dose delivered and the amount removedby endotracheal suction. The proportion of theintratracheal dose excreted in the urine over a24 hour period was then calculated.The urinary elimination half life of sodium

cromoglycate was calculated from a plot of themidtime point for each urine collection (min)against the log excretion rate ([ig/min).7

Assessment of nebuliser and MDIThe Pentasonic ultrasonic nebuliser was inserteddirectly into the inspiratory limb of the constantflow ventilator circuit, 10 cm from the rightangled endotracheal tube connector (fig 1).Before insertion the one way inspiratory valvewas removed from the nebuliser chamber.Humidified inspiratory gas entered the nebuliserthrough the upper part of the nebuliser andexited through a side port. The chamber wasloaded with 20 mg sodium cromoglycate dis-solved in 4 ml of normal saline and the nebuliserrun for five minutes. The 24 hour urinaryexcretion of sodium cromoglycate was measuredby radioimmunoassay on a single pooled sample.The Aerochamber was inserted directly onto

the endotracheal tube after disconnection fromthe ventilator circuit. Infants were then venti-lated by a thumb occluded 'Nottingham puffer'set at a flow of 8 I/min and an appropriate blowoff pressure and inserted into the end of thespacer (fig 2).Each infant received three puffs of 5 mg

sodium cromoglycate via MDI. The MDI wasactuated at end expiration and each dose wasseparated by five manual breaths. After remov-ing the spacer, infants were reconnected to theventilator circuit and 24 hour pooled urinarysodium cromoglycate excretion measured byradioimmunoassay.

IN VITRO MODELAerochamber assessmentThe neonatal lung was modelled by a test lung(Draeger) inserted onto a 3-5 mm shoulderedendotracheal tube. MDI aerosol passing throughthe endotracheal tube was collected by a 0 25[im filter (Aerosol Medical) inserted betweenthe tube tip and test lung (fig 3). The dose ofsodium cromoglycate and method of adminis-tration were similar to that used in vivo.Inspiratory pressure was set at 20 cm H20giving a tidal volume to the test lung of 15 ml.After three MDI doses (15 mg), sodium cromo-glycate was eluted from the filter with 20 mlwater and measured by radioimmunoassay.

Figure 3 In vitro models ofpulmonary sodium cromoglycate deposition by metered doseinhaler and spacer. A= test lung, B =filter, C=multistage impactor, D=3-5 mm endotrachealtube, E=Aerochamber, F=sodium cromoglycate metered dose inhaler, G=thumb occlusionvalve, H=pressure release valve.

Particle sizeThe mass median aerodynamic diameter(MMAD) ofparticles generated by the ultrasonicnebuliser was measured by laser diffraction.Ultrasonic aerosol was generated within a con-

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Delivery oftherapeutic aerosols to intubated babies

tinuous 8 I/min airflow which passed through 10cm of ventilator tubing and 3 5 mm Portexendotracheal tube. Particle size was measuredby a laser particle sizer (2600 Malvern Instru-ments) 2 cm from the endotracheal tube tip.The MMAD of particles generated by MDI

was measured by multistage impactor. Aerosolgenerated by MDI was carried through theAerochamber and endotracheal tube by a gasflow of 8 1/min. This was then sucked into amultistage impactor operating at 60 1/min andseparated into three size fractions (fig 3).Sodium cromoglycate deposited in each fractionafter 20 doses (100 mg) was assayed by aspectrophotometer that had been previouslycalibrated using sodium cromoglycate solutionsof known concentrations. The total dosedeposited within the multistage impactor and

100)

C1.°

0.- 0

co° .01c:

.001

0 0

0 0

.

0 200 400 600 800 100012001400Time (min)

Figure 4 Urinary excretion ofsodium cromoglycate fromsubjects 13 and 14.

Table 2 In vivo urinary excretion and estimated pulmonarydeposition after sodium cromoglycate delivered byAerochamber and metered dose inhaler

Subject 24 Hour urinary Estimated pulmonaryNo excretion of dose sodium

sodium aomoglycatetcromoglycate* (jig)(mg)

4 69 1815 68 1796 109 2877 118 3108 104 2739 143 37610 75 197

Mean (SEM) 98 (11) 258 (28)

*After 3x5 mg doses of sodium cromoglycate.tAssuming urinary excretion 38% of pulmonary dose.

MMAD of the aerosol was calculated from theamount eluted from each size fraction. At theend of the impactor experiment, sodium cromo-glycate deposited in the endotracheal tube andAerochamber was also eluted and assayed.

ResultsIN VIVOFour infants (subjects 1-4, table 1) had trachealaspirates saved after a 1400 tig intratrachealdose enabling an estimation of the actual intra-tracheal dose available for systemic absorption.Mean urinary excretion as a percentage of theestimated intratracheal dose was 37-5% (range22-3-5917%). In two infants (subjects 13 and14, table 1) several timed urine samples afterthe intratracheal dose were available, althoughtheir endotracheal aspirates were not saved.Their urinary excretion half lives were 100 and310 minutes (fig 4).

Seven infants received a dose of sodiumcromoglycate via the MDI and seven via theultrasonic nebuliser. Mean (SEM) 24 hoururinary sodium cromoglycate excretion after a15 mg dose via Aerochamber and MDI was 98(11) ,g (table 2). Mean 24 hour urinary sodiumcromoglycate excretion after five minutes ofultrasonic nebulisation with a nebuliser fill of 20mg was 98 (18) ,ug (table 3). Endotrachealsuction was not performed until at least fourhours after aerosolised sodium cromoglycate.However, endotracheal aspirates were not savedfor radioimmunoassay.

Assuming that 38% of an inhaled dose ofsodium cromoglycate is excreted in the urine,the Aerochamber and MDI delivered 258 (28),ug to the lung (1-7% of the 15 mg aerosoliseddose). The Pentasonic delivered 257 (47) ,tg(1-3% of the initial 20 mg nebuliser fill).

IN VITRO

Mean deposition of sodium cromoglycate onto afilter situated between the endotracheal tubeand test lung after 3 x 5 mg puffs delivered byMDI with Aerochamber was 243 pg (n=3).Total deposition within the multistage impactorafter 20 puffs into the Aerochamber was 11-6mg or 1740 pg per three MDI puffs (table 4). Ofthe total dose aerosolised by the MDI, 81-4%was deposited within the spacer and 7-8% in theendotracheal tube.

Table 3 In vivo urinary excretion and estimated pulmonary deposition after ultrasonic nebulisation ofa sodium cromoglycatesolution for 5 minutes

Subject Ventilator Ventilator Inspiratory 24 Hour EstimatedNo gas flow rate time urinary excretion pulmonary dose

(I/min) (per min) (sec) sodium cromoglycate* sodium cromoglycatet(mg) (mg)

1 8 30 0 5 104 2742 8 30 0-5 50 1323 8 30 0-5 170 4474 8 30 0 5 138 3635 12 75 0 4 47 123

11 8 20 0 3 63 15812 8 30 0 7 115 303

Mean (SEM) 98 (18) 257 (47)

*Nebuliser fill of 20 mg sodium cromoglycate in 4 ml.tAssuming urinary excretion 38% of pulmonary dose.

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Table 4 Comparison of in vitro and in vivo aerosol delivery of sodium cromoglycate

Initial nebuliser Mean pulmonary MMADfill or dose dose in vitro or (Psm)generated by in vivo (ig)MDI (mg) (% of initial dose)

Aerochamber+MDI in vitro;multistage impactor* 15 1740 (11-6) 90

Aerochamber+MDI in vitro;filter+test lung (n=3) 15 243 (1-62)

Aerochamber+MDI in vivo (n=7) 15 258t (1-72)Pentasonic in vivo (n=7) 20 257t (1-28) 3-4t*Calculated from 100 mg initial dose.tEstimated assuming urinary excretion 38% of pulmonary dose.1Measured in vitro using Malvern laser particle sizer.

The MMAD of particles generated by MDI,after passing through the Aerochamber andendotracheal tube, was 9 0 ,um. MMAD ofultrasonically nebulised sodium cromoglycateafter passing through an endotracheal tube was2-8 ttm (table 4).

DiscussionThe Pentasonic nebuliser and Aerochamberwith MDI delivered a detectable dose of sodiumcromoglycate to ventilated neonates. A signifi-cant proportion of the sodium cromoglycateaerosol generated by both delivery systems wasin droplets small enough to penetrate the distalairways. The pulmonary dose of sodium cromo-glycate aerosolised by MDI, estimated from theurinary excretion of a known intratracheal dose,was similar to that deposited on a filter modelusing a neonatal test lung. However, the dosedeposited in a multistage impactor significantlyoverestimated the in vivo dose.

Estimation of the pulmonary dose in vivodepends on the proportion excreted in theurine. Most published data is from adult sub-jects. Sodium cromoglycate is not metabolisedin the lung or liver and is excreted unchanged inthe bile and urine.5 Some 70-90% of a 1 mgdose of sodium cromoglycate instilled into theadult lung by fibreoptic bronchoscope will beabsorbed into the circulation and of this,3346% is excreted in the urine.8 9 The plasmahalf life of either a bronchoscopically instilled orinhaled dose is 64-165 minutes after an initialrapid half life of 1-9 minutes, with lungabsorption being the rate limiting step.8 Thepulmonary dose calculated from urinary excre-tion is similar to that obtained using plasmadata.'0 The wide variability in the fraction ofintratracheal sodium cromoglycate excreted inthe urine of ventilated neonates in this study isnot surprising. Pulmonary atelectasis, mucus,and epithelial damage may have significantlyaltered sodium cromoglycate bioavailabilitybetween infants. When combined with theclinical problems of collecting endotrachealaspirates and urine samples, the fractionalurinary excretion must be regarded as only arough approximation. However, if the urinaryexcretion half life is less than seven hours, acollection period of 24 hours should havecontained most of the dose excreted in theurine.

Combined in vitro and in vivo assessment ofaerosolised drug delivery in ventilated neonates

has previously been reported. Watterberg et al,using a multistage impinger model, detected19% of the sodium cromoglycate dose placed inthe reservoir of a jet nebuliser emerging from anendotracheal tube. However, when the samenebuliser and loading dose (20 mg) were used invivo, less than 0-1% (20 ,tg) was excreted in theurine of intubated infants.4 A similar over-estimate of the in vivo pulmonary dose wasobtained by the multistage impactor in ourstudy and may result from incomplete model-ling of aerosol behaviour. In a conventionalpressure limited, time cycled ventilator, inspir-ation is a result of the build up of pressurewithin the circuit from obstructing gas exitwhile fresh gas in-flow continues. The require-ment for a continuous gas flow during the restof the cycle, means that a significant proportionofa constantly nebulised drug will be unavailableto the infant. If all the flow through the circuitis directed into a multistage impactor, drugwasted in the expiratory phase in vivo will becollected. There is a similar reason for theoverestimation by multistage impactor of thedose delivered by Aerochamber with MDI.Here, the source of error is that the multistageimpactor cannot model inspiratory and expira-tory flow as aerosol needs to be continuouslydrawn through the impactor system. The com-bination of filter and neonatal test lung doesmodel inspiration and expiration and the agree-ment between the in vivo pulmonary dose (258,tg) and sodium cromoglycate deposited on thefilter (243 ,ug) after a 15 mg MDI dose reflectsthis improved modelling.The filter model also has the advantage that,

where aerosol is generated within the continuousgas flow, wastage of drug during expiration ismodelled. Filter/test lung models seem topredict accurately jet nebulised aerosol deliveryinto neonatal ventilator circuits in vivo. Usingaminophylline as a drug marker the Ultraventjet nebuliser delivers 0-22% of the reservoirdose to a test lung." A figure of 0 2% has beenreported after jet nebulisation in vivo.4 Despitethe errors in estimating the pulmonary dose ofsodium cromoglycate aerosol, urinary excretionof sodium cromoglycate by the infants in thisstudy reflects the absolute minimum amount ofdrug delivered to the lung. About 0-7% of theMDI dose and 0-5% of the ultrasonicallynebulised dose was excreted in the urine over 24hours. Although we did not measure it, thedeposition of aerosol into the lungs by ultrasonicnebuliser is likely to be dependent on thepattern of mechanical ventilation, as it is for ajet nebuliser inserted into a ventilator circuit. 12The Pentasonic has not previously been

assessed in vivo although the Aerochamber hasbeen used to deliver bronchodilators to intubatedadults receiving volume cycled ventilation. AnAerochamber and MDI inserted into theinspiratory limb of a ventilator circuit willdeliver 5 7% of the original dose to the adultlung.'3 In adult ventilator circuits, there is nocontinuous flow and most of the aerosoliseddrug is delivered to the patient's endotrachealtube. By placing the Aerochamber directlyonto the neonate's endotracheal tube the problemof continuous flow is overcome and delivery

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Delivery oftherapeutic aerosols to intubated babies 29

partially mimics that of the volume cycledventilator. It may also be possible to enhanceultrasonic drug deposition by placing thenebuliser directly onto the endotracheal tubeand ventilating through the chamber.The therapeutic effectiveness of an aerosol

depends not only on the quantity of drugreaching the lung but also on particle size, bestdescribed by the MMAD. MMAD is thediameter above and below which 50% of themass of the particles is found. Particles less than5 [tm are more likely to deposit in the distalairways whereas larger particles impact on thelarger diameterairways. 14Although theoptimumaerosol size for neonates is unknown, theoreticalmodels suggest a similar patterm of depositionto adults.'5 In the past, ultrasonic nebulisershave been bulky and have produced a highlyvariable output containing significant numbersof large droplets. 6 In this study the combinationof both the Pentasonic and Aerochamber withan endotracheal tube produced high qualityaerosol. The size distribution of aerosolgenerated by the Pentasonic was similar to thatproduced by jet nebulisation. "l The MMAD ofparticles generated within the Aerochamber waslarger (9 ,tm), as measured by the imperfectmultidose impactor model, but a significantproportion of the aerosol was below 5 [lm.The Pentasonic and the Aerochamber were

clinically easy to use. The Aerochamber fitteddirectly onto the standard Portex endotrachealtube connector without adaption and there wereno problems in ventilating infants through thespacer. The Pentasonic could be inserted intothe inspiratory line with minimal adaption.There was no change in ventilator pressuresduring ultrasonic nebulisation and no drop ingas temperature, as measured by a thermistersited in the endotracheal tube connector. It wasimportant to remove the one way valve from thePentasonic to allow any build up of pressure inthe circuit to be vented through the emergencyinspiratory blow off valve. The 145 ml Aero-chamber temporarily increased the ventilatordead space, and for this reason, we preferred toinsert the device briefly, and not to try tomaintain mechanical ventilation with the spacerin place. However, spacers are important whenusing a MDI in ventilator circuits. Particles areejected from the MDI canister with high velocityand mass.'7 18 As the propellants evaporateparticles decrease in size toward the respirablerange (

30 Grigg, Arnon,Jones, Clarke, Silverman

of DeVilbiss jet and ultrasonic nebulizers. Chest 1987;92:991-4.

17 Dhand R, Malik SK, Balakrishnan M, Verma SR. Highspeed photographic analysis of aerosols produced bymetered dose inhalers. J Pharn Pharmacol 1988;40:429-30.

18 Clarke SW, Newman SP. Differences between pressurizedaerosol and stable dust particles. Chest 1981;80:907-17.

19 Newman SP, Moren F, Pavia D, Little F, Clarke SW.

Depositon of pressurized suspension aerosols inhaledthrough extension devices. Am Rev Respir Dis 1981;124:317-20.

20 Silverman M. Aerosol therapy in the newborn. Arch Dis Child1990;65:906-8.

21 Salmon B, Wilson NM, Silverman M. How much aerosolreaches the lungs of wheezy infants and toddlers? Arch DisChild 1990;65:401-3.

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