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`715
`
`ORIGINAL ARTICLE
`Comparison of lung deposition of colomycin using the
`HaloLite and the Pari LC Plus nebulisers in patients with
`cystic fibrosis
`N M Byrne, P M Keavey, J D Perry, F K Gould, D A Spencer
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`ArchDisChild 2003;88:715–718
`
`See end of article for
`authors’ affiliations
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Correspondence to:
`Mrs N Byrne,
`Rehabilitation Department,
`Royal Victoria Infirmary,
`Queen Victoria Road,
`Newcastle upon Tyne
`NE1 4LP, UK;
`nuala.byrne@
`nuth.northy.nhs.uk
`
`Accepted
`4 November 2002
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Aim: To examine the effectiveness of delivery of nebulised colistin by the HaloLite nebuliser compared
`to the Pari LC Plus in patients with cystic fibrosis.
`Methods: Randomised crossover trial of 15 patients aged >6 years. Inhalation of one mega unit of
`colistin in 3 ml diluent, labelled with technetium-99m DTPA, was used to assess lung deposition. The
`Pari was nebulised to dryness and one button press of the HaloLite was completed. Following a seven
`day washout period, patients inhaled colistin twice daily for seven days through the first device. Spu-
`tum specimens were analysed for colistin levels and pseudomonas load. This procedure was repeated
`with the alternative device.
`Results: Lung uptake of radiolabelled colistin was significantly higher with the Pari. However, lung
`uptake calculated as a percentage of the amount of drug used was significantly higher for the HaloLite.
`Time to nebulise was significantly shorter with the HaloLite. Sputum levels of colistin were higher follow-
`ing use of the Pari; this was close to significance.
`Conclusion: The manufacturer’s recommended dosages for nebulising antibiotics with a HaloLite result
`in a lower delivery than patients receive when using a Pari nebuliser. The concept of adaptive aerosol
`delivery has several theoretical advantages but the recommended doses for the HaloLite need to be
`modified in order to improve effectiveness.
`
`Progressive lung disease in patients with cystic fibrosis
`
`(CF) is characterised by colonisation with Pseudomonas
`aeruginosa.1 Studies have shown that twice daily inhala-
`tion of antibiotics improves respiratory function, decreases
`hospital admissions, and reduces the frequency of positive
`pseudomonas cultures in recently colonised patients.2–4 The
`use of inhaled antibiotics is one of the few treatments shown
`by systematic review to slow down the decline in lung
`function and therefore increase longevity in patients with
`CF.5 6
`Currently, administration of nebulised antibiotics is usually
`by use of breath enhanced nebuliser systems such as the Pari
`LC Plus (Pari Medical Ltd, Surrey, UK). There are multiple dif-
`ficulties with this method, including unpredictability and
`variability of drug dosage, loss of drug substance to the envi-
`ronment especially during expiration,
`lengthy treatment
`times, no adaptation to the respiratory cycle of the patient,
`and variable adherence to treatment.7 8
`The HaloLite nebuliser (Medic Aid Ltd, Bognor Regis, UK) is
`an adaptive aerosol delivery system which aims to overcome
`these problems. It analyses the pressure changes relating to
`airflow during the first three breaths, establishing the shape of
`the respiratory cycle and thereby ascertaining the correct
`starting point for aerosol delivery. It then delivers a pulse of
`aerosol during the first 50% of each inspiration and only
`pulses aerosol when the patient is inspiring through the
`mouthpiece. It is programmed to release a preset dose and
`signals audibly when the dose is complete. Proposed
`advantages of the system include more efficient delivery to the
`lungs and reduced loss of aerosol into the atmosphere. As
`completion of drug delivery is signalled by a bleep and time
`taken to nebulise could be less, adherence may be improved.
`There are currently no published data examining the effec-
`tiveness of the HaloLite. Initial abstracts have indicated some
`improvement
`in adherence to treatment
`in asthmatic
`patients.9 10 In terms of drug delivery, it has been shown that in
`
`vitro, 80% of the particles were less than 5 mm in diameter and
`there was a linear output to pulse time.11 The nebuliser has
`been tested in vivo in ten asthmatic and nine healthy subjects
`by assessing inhalation of saline and Tc-DTPA, showing that
`the HaloLite can accurately deliver a preset dose to the patient
`with less than 3% exhaled to the environment.11
`None of this preliminary work included comparisons with
`existing nebuliser systems or investigation of antibiotic deliv-
`ery in patients with CF. We have compared drug deposition
`achieved by the HaloLite and Pari LC Plus in children and
`young adults with CF.
`
`METHODOLOGY
`Fifteen subjects were recruited from the CF clinic at the Royal
`Victoria Infirmary, Newcastle upon Tyne. This number was
`based on a power calculation expecting a 15% reduction in the
`drug volume required by the HaloLite to achieve the same level
`of deposition in the lungs as the Pari. The power was 90% and
`the significance level was set at 0.05. The regional ethics com-
`mittee granted ethical approval. Inclusion criteria were a
`diagnosis of CF confirmed by two positive sweat tests and/or
`positive genotype, colonisation with Pseudomonas aeruginosa
`requiring daily inhalation of colistin (Colomycin, Forest Labo-
`ratories Europe), ability to expectorate sputum, aged >6 years,
`and stable disease state. Patients who were colonised with
`Burkholderia cepacia, or had haemoptysis or pneumothorax
`were excluded from the study. Eligible patients were enrolled
`and randomly allocated as to which nebuliser they used first.
`Following recruitment, each subject was provided with a
`HaloLite nebuliser system and taught how to use it correctly.
`Their technique with the Pari LC Plus and Pariboy compressor
`was also reviewed. Baseline measurements (age, height,
`weight, FVC, FEV1, and oxygen saturations) were recorded.
`The study was divided into two sections. Lung deposition
`was measured firstly by inhalation of radiolabelled colistin
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`716
`
`Byrne, Keavey, Perry, et al
`
`Table 1 Baseline characteristics for all subjects participating in the study
`
`Age (y)
`
`Height (cm) Weight (kg)
`
`FVC (% pred.)
`
`FEV1 (% pred.)
`
`SaO2 (%)
`
`Mean
`SD
`
`14.1
`4.6
`
`154
`15.8
`
`45.2
`11.7
`
`66.9
`19.5
`
`56.5
`18.9
`
`97
`1.7
`
`Table 2 Dosage used and lung uptake following inhalation of a dose of radiolabelled colistin using the HaloLite and
`Pari nebulisers
`
`Mean (SD)
`p value
`95% CI
`
`Dosage used (ml)
`
`Lung uptake (MBq)
`
`Lung uptake (as % dose used)
`
`HaloLite
`
`0.55 (0.24)
`
`Pari
`
`HaloLite
`
`Pari
`
`HaloLite
`
`Pari
`
`2.29 (0.34)
`<0.0001
`- 2 to - 1.47
`
`9.0 (3.17)
`2.96 (1.08)
`<0.0001
`- 8.1 to - 3.98
`
`30.79 (17.98)
`
`19.75 (6.56)
`<0.04
`- 0.46 to 21.63
`
`solution and secondly by microbiological analysis of colistin
`levels and semiquantitative culture of pseudomonas load in
`sputum. Each subject participated in both arms of the study in
`random order. Subjects attended the medical physics depart-
`ment on two occasions, at least one week apart. Lung function
`was measured pre- and post-inhalation using a Vitalograph
`micro (Vitalograph) and subjects then inhaled their pre-
`scribed dose of b agonist. In order to assess lung deposition,
`the nebuliser was primed with 60 MBq Tc99m-DTPA and 1
`mega unit of colistin in a volume of 3 ml (2 ml of 0.9% saline,
`1 ml of water). The nebulisers were weighed before the prim-
`ing dose was added and on completion of the nebuliser dose in
`order that residual drug volume could be calculated. The sub-
`jects were seated with their back resting against a Camstar
`XR/T (GE Medical Systems) gamma camera. The shielded
`nebuliser was placed on a table in front of the subject. During
`inhalation a dynamic acquisition of the posterior lungs was
`performed with a frame duration of 10 seconds and continu-
`ing for approximately one minute following the end of nebuli-
`sation. The end point for the Pari was dryness. The HaloLite
`stopped automatically when the preset dose had been
`delivered. One button press was completed for the HaloLite as
`recommended by the manufacturer. Immediately after inhala-
`tion, a posterior static view of the lungs was acquired with a
`total of 100 000 counts. On completion, the subjects were
`asked to drink a glass of water to help remove any radioactive
`material from the oropharynx. At the next visit, the procedure
`was repeated using the second nebuliser.
`For the microbiology section of the study, there was an ini-
`tial washout period of seven days prior to usage of each neb-
`uliser system. Following this, the subjects inhaled nebulised
`
`colistin twice daily from the first device for seven days.
`Sputum specimens were collected at one and four hours after
`the final dose. Following a further washout period of seven
`days, the procedure was repeated with the alternative device.
`
`Analysis of data
`Radionuclide data
`The fraction of the priming dose used was calculated to give
`the nebulised activity in megabecquerels (MBq). Regions of
`interest were drawn around both lungs on the static images
`and the total lung counts per second were calculated after
`correcting for background activity using a C-shaped region of
`interest lateral to each lung. A conversion factor obtained from
`data on 18 patients undergoing standard lung perfusion scans
`was used to convert the lung counts to activity in MBq. Small
`differences in the priming dose added to the nebuliser were
`accounted for by normalising the data to a standard priming
`dose of 20 MBq/ml. Lung activity was also expressed as a per-
`centage of the dose which was actually nebulised.
`Time-activity curves were produced from the dynamic
`acquisition after applying background correction and nor-
`malisation as described above. The time from the start of the
`acquisition to the beginning of a “plateau” region defined the
`duration of inhalation. A straight line was fitted to the inhala-
`tion phase and used to calculate the rate of uptake into the
`lungs.
`For each patient, a common lung outline was produced
`from the HaloLite and Pari static images (the larger of the
`two) for each lung. This was used to define central and
`peripheral regions as described previously.12 The central region
`was a rectangle over the middle third of the medial border of
`
`Figure 1 Lung deposition of
`radiolabelled colistin for each subject
`following use of the HaloLite and Pari
`LC Plus nebulisers.
`
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`Lung deposition of colomycin
`
`717
`
`Table 3 Mean differences for rate of aerosol uptake
`and levels of peripheral deposition using the HaloLite
`and Pari LC Plus nebulisers
`
`Rate of aerosol uptake
`(counts/second)
`
`Peripheral deposition
`(%)
`
`Mean
`difference
`Standard error 1.9
`
`9.62
`
`1.34
`
`1.14
`
`the lung and extending halfway across the lung. The
`peripheral region was the remainder of the lung. A single
`C-shaped region of interest for each lung was used to estimate
`background activity for both the peripheral and central
`regions. An indication of the pattern of aerosol deposition was
`given by the uptake in the peripheral region expressed as a
`percentage of the total counts in the lung.
`
`Microbiology data
`Ideally, all sputum specimens were analysed on the day of col-
`lection. If this was not possible, specimens were refrigerated at
`a temperature of 0–4°C and tested within a maximum of 24
`hours. Colistin levels were calculated by bioassay based on the
`procedure described by Grove and Randall (1955) and
`modified by the antibiotic reference laboratory at Southmead
`Hospital, Bristol, UK. A measured amount of sterile sputolysin
`sufficient for digestion was added to the sputum samples and
`left for 20–30 minutes. The quantity of liquid sputum was
`measured and the dilution factor calculated. This solution was
`then placed in wells made in agar plates and left to incubate
`overnight at 37°. All zone sizes produced were read the follow-
`ing day and concentrations in the samples were read from a
`standard curve and multiplied by the dilution factor.
`Paired t tests were used to analyse both the radionuclide
`data and the log normal distributed microbiology data.
`
`RESULTS
`Fifteen subjects aged 7–23 years participated in the study; 14
`completed the radionuclide section and 13 the microbiology
`section. One subject became too ill and the second did not
`wish to complete the study. Table 1 presents baseline values for
`the whole sample.
`There was no significant difference between the volume of
`the priming doses for each of the two nebuliser systems: mean
`(SD) 2.97 (0.2) ml for the HaloLite and 3.02 (0.2) ml for the
`Pari (p = 0.4). The HaloLite used significantly less drug
`volume than the Pari during each study (see table 2).
`Lung uptake was significantly higher following use of the
`Pari nebuliser than the HaloLite. However, analysis of lung
`uptake as a percentage of the dose used showed that a greater
`percentage of the solution from the HaloLite than from the
`Pari was deposited in the lungs (see table 2 and fig 1).
`Time to nebulise was less with the HaloLite (298 (50.14)
`seconds)
`than with the Pari
`(382.5 (68.3)
`seconds)
`(p < 0.001, 95% CI -133.5 to -41.49). Rate of aerosol uptake
`was linear for both nebuliser systems but was significantly
`higher with the Pari (p < 0.0006). There was no significant
`difference in percentage peripheral deposition of colistin
`between the two nebulisers (p = 0.17). Table 3 shows mean
`differences (SE) for aerosol uptake and peripheral deposition.
`Lung function results pre- and post-use of each nebuliser
`showed no significant change in FEV1 following use of either
`of the nebulisers (Pari, p = 0.2; HaloLite, p = 0.6).
`In terms of microbiology results, drug delivery was log nor-
`mally distributed as were levels of pseudomonas load. Colistin
`levels in sputum were higher following use of the Pari. These
`results were near to significance at one hour and not
`significant at four hours. Figure 2 illustrates values at one
`hour.
`P aeruginosa was not recovered from five specimens from the
`HaloLite group and six specimens from the Pari group. Table 4
`presents results of sputum analysis.
`
`Figure 2 Colistin levels in sputum at
`one hour after use of the HaloLite and
`Pari LC Plus nebulisers.
`
`Table 4 Geometric mean values, significance levels, and confidence intervals for colistin levels and pseudomonas load
`following use of the HaloLite and Pari nebulisers
`
`HaloLite
`Pari
`p value
`95% CI
`
`Colistin levels (mg/l)
`
`Pseudomonas load (pseud/ml)
`
`1 hour
`
`64.2
`183.6
`0.06
`- 2.09 to 0.03
`
`4 hours
`
`51.8
`22.6
`0.6
`- 1.05 to 1.7
`
`1 hour
`1.2·10 6
`2.4·10 6
`0.9
`- 3.18 to 3.53
`
`4 hours
`3.7· 106
`1.6· 106
`0.5
`- 1.75 to 3.37
`
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` on November 17, 2021 by guest. Protected by copyright.
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`718
`
`Byrne, Keavey, Perry, et al
`
`DISCUSSION
`The results of this study show that there is greater lung depo-
`sition of radiolabelled colistin solution using the Pari LC Plus
`system than with the HaloLite when using the manufacturer’s
`recommended doses. However, percentage deposition of emit-
`ted drug solution was greater with the HaloLite, illustrating
`improved efficiency. Devadason and colleagues13 illustrated
`that there is a linear relation between one and two actuations
`of the HaloLite. Therefore, using the current preset doses,
`patients would need to carry out three button presses with the
`HaloLite to achieve the same level of deposition as with the
`Pari. Although time to nebulise was significantly less with the
`HaloLite in this study, this will be negated in clinical practice
`by the increased time needed for extra button presses.
`These results are comparable with the results of a study by
`Devadason et al in children with CF.13 Delivery of rhDNase was
`measured using the HaloLite and the Pari LC Plus. Results
`showed that the Pari LC Plus was more effective and that at
`least two button presses of the HaloLite were needed to
`achieve an equivalent level of deposition. They also found a
`significantly higher level of peripheral deposition of radiola-
`belled DNase using the HaloLite in children with CF. In this
`study, a small difference was shown, with the HaloLite show-
`ing slightly greater peripheral deposition. However, this did
`not reach significance. The mass median diameter of particles
`emitted from the HaloLite (3 mm) is smaller than those from
`the Pari (3.8 mm). Theoretically, the HaloLite should therefore
`improve peripheral deposition. It may be that the method used
`here was not sufficiently sensitive to detect the difference.
`Separate studies using xenon or krypton gas would give a
`more accurate lung outline and allow better definition of the
`peripheral region. There have been reports that colistin can
`cause bronchoconstriction in patients with CF.14 Lung function
`results illustrated that no bronchoconstriction occurred
`following inhalation of colistin with either nebuliser.
`A recognised difficulty with any nebuliser study carried out
`in a laboratory setting is that the subjects’ adherence is likely
`to be far better than in “real life”. Adherence is known to be
`generally poor in this group of patients. The HaloLite has been
`purported to improve adherence to treatment, but there is as
`yet no published data to substantiate this claim.
`The microbiology data for pseudomonas load illustrated no
`significant difference between the two nebuliser systems.
`However, as five to six specimens from each group did not
`grow pseudomonas, it is likely that this represents a type two
`error. Colistin levels in sputum were higher when using the
`Pari compared to the HaloLite, and the difference was nearing
`significance. The difference between the two nebulisers in the
`microbiological assay was not as great as that found in the
`radionuclide section. There was a larger variability in
`individual data as can be seen in fig 2, indicating that this was
`probably a less reliable method of measurement than the
`radionuclide data.
`Commercially, a HaloLite nebuliser is five times more
`expensive than a Pariboy compressor and Pari LC Plus
`nebuliser. The HaloLite does use less colistin which is advan-
`tageous financially, but because of the extra button presses
`required, this may not be of economic advantage.
`The concept of adaptive aerosol delivery is innovative in
`terms of improved patient technique and a reduction in the
`amount of colistin used. It may also have an effect on improv-
`ing adherence to treatment. The current problem with the
`HaloLite is that the preset doses were originally based on
`inhaled budesonide and these do not correspond with the
`
`required dose of colistin. To achieve equivalent levels of colis-
`tin, patients would need to complete three button presses with
`the HaloLite. A possible alternative could be to increase the
`concentration of the colistin solution. This would require fur-
`ther work to ascertain the correct concentration. Very careful
`monitoring would be necessary as colistin is known to
`increase bronchospasm in some CF patients,15 16 and this effect
`may be exacerbated by increasing the concentration.
`Currently, nebuliser devices are not licenced, allowing new
`systems to be marketed with little or no data to prove their
`efficacy. The results of this study emphasise the need to move
`towards licensing of devices via the Medicines and Healthcare
`Products Regulatory Agency (formerly Medical Devices
`Agency). It also emphasises the need for objective assessment
`of individual devices with specific drugs used in patients with
`CF prior to their use in clinical practise.
`
`ACKNOWLEDGEMENTS
`We would like to thank Terry Hawkins for his intellectual contribution
`to the research. Technical support was given by Victoria Snowdon, for
`which we are very grateful. We would also like to thank the patients
`and their families for their participation. This research received
`support from Medic Aid Ltd who supplied the HaloLite nebuliser
`units.
`
`. . . . . . . . . . . . . . . . . . . . .
`Authors’ affiliations
`N M Byrne, D A Spencer, Regional Paediatric Cystic Fibrosis Unit,
`Newcastle upon Tyne Hospitals NHS Trust, UK
`P M Keavey, Regional Medical Physics Department, Newcastle upon
`Tyne Hospitals NHS Trust
`J D Perry, F K Gould, Microbiology Department, Newcastle upon Tyne
`Hospitals NHS Trust
`
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