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JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 30, Number 0, 2017 ª Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/jamp.2017.1392
Methacholine Challenge: Comparison of Airway Responsiveness Produced by a Vibrating Mesh Nebulizer Versus a Jet Nebulizer Christianne M. Blais, BSc,1 Donald W. Cockcroft, MD, FRCPC,1,2 Justine Veilleux,3 Marie-E`ve Boulay, MSc, CCRP,3 Louis-Philippe Boulet, MD, FRCPC, FCCP,3 Gail M. Gauvreau, PhD,4 Tara X. Scime, BSc, CCRC,4 Richard M. Watson, HBSc(Kin), RCPT(c),4 Paul M. O’Byrne, MB, FRCPC, FRSC,4 and Beth E. Davis, PhD1,2
Abstract
Background: The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer. Methods: Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the methacholine PD20 were calculated following each methacholine challenge. Results: The geometric mean methacholine PC20 values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD20 results are comparable by clinical standards [81.7 lg (Solo) vs. 64.7 lg (Wright)], although the slight difference in dose was statistically significant ( p ¼ 0.018). Conclusions: The comparability of PD20 values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT. Keywords: dose,
methacholine challenge testing, nebulizer, standardization
muscarinic receptor agonist that mimics the airway constricting effects of acetylcholine.(1) MCT is traditionally performed in patients whose spirometry results are inconclusive but where asthma is suspected. In research, MCT has several uses, including the assessment of effects of pharmaceutical agents in asthma patients.
Introduction
M
ethacholine challenge testing (MCT) is a bronchoprovocation testing method commonly used to assess airway hyperresponsiveness induced by the direct bronchoconstricting agent methacholine.(1) Methacholine is a
Departments of 1Physiology and 2Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 3 Institut Universitaire de Cardiologie et de Pneumologie de Que´bec, Universite´ Laval, Quebec City, Quebec, Canada. 4 Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
1
Downloaded by Linkoping University Library from online.liebertpub.com at 09/04/17. For personal use only.
2
The American Thoracic Society (ATS) drafted guidelines in 1999 to standardize MCT.(1) These guidelines outline the 2minute tidal breathing protocol and the calibration procedure for the English Wright (Wright) jet nebulizer. This methodology and device have become routine for MCT in pulmonary function laboratories. However, standardization remains difficult to achieve for several reasons, most importantly are the diversity of nebulizers and the reporting of the response as a PC20 [provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (FEV1)]. The European Respiratory Society (ERS) has since published updated guidelines for MCT that address these factors(2); among the new recommendations are the characterization of nebulizers before their use in MCT, the incorporation of a minimum 1-minute inhalation period in new testing protocols, and the reporting of data as the PD20 (provocative dose of methacholine causing a 20% fall in FEV1) instead of the PC20. The PD20 accounts for the use of different protocols and devices, thereby improving the comparability of findings within patients and between testing sites.(2–6) However, PD20 values can only be calculated if the nebulizer used has been well characterized, particularly with regard to its output (i.e., dose delivery). In recent years, the Wright has become increasingly difficult to commercially obtain. In addition, this nebulizer requires a specially fitted and expensive Hans Rudolph valve, the nebulizer is not disposable (i.e. infection control concerns), and like other jet nebulizers, the dose of methacholine delivered is largely overestimated due to evaporative loss.(7,8) It is imperative that new reliable nebulizers be identified to ensure continued diagnostic and research application of bronchoprovocation testing with direct-acting stimuli. The objective of this study was to determine if the Aerogen Solo (Solo) vibrating mesh nebulizer produced similar methacholine PC20 and/or PD20 values compared to the Wright jet nebulizer. Materials and Methods Participants
Eligible participants were at least 18 years old with mildto-moderate asthma, a methacholine PC20 £ 16 mg/mL (i.e., asthmatic), and baseline lung function (% predicted FEV1) greater than or equal to 65%. Participants were required to abstain from long-acting beta-2 agonists and long-acting muscarinic antagonists for the withdrawal periods provided in the ATS guidelines.(1) Additional exclusion criteria included pregnant and lactating women, those suffering from cardiovascular problems, and those affected by an upper respiratory tract infection or allergy-induced asthma exacerbation within 4 weeks of the study. Smokers were eligible to participate provided their smoking history did not surpass 10 pack-years and they did not smoke for at least 1 hour before testing. Inhaled corticosteroids were allowed if taken regularly at a stable dose for a minimum of 30 days before study enrolment. Rescue medication (i.e., salbutamol) was avoided for at least 6 hours before a laboratory visit. Each laboratory obtained site-specific Research Ethics Board approval before starting the study. The study was registered with clinicaltrials.gov (NCT 02822859). Written informed consent was obtained from each participant before beginning testing.
BLAIS ET AL. Study design
This was a randomized crossover study performed at three respiratory research laboratories (University of Saskatchewan, Universite´ Laval, and McMaster University). A screening visit was first performed using the 2-minute tidal breathing protocol to identify a positive methacholine challenge and adequate lung function. The screening visit was omitted if a participant had a documented PC20 £ 16 mg/mL with the 2-minute tidal breathing protocol in the 6 months preceding the study. Following screening, participants who met the study criteria underwent two methacholine challenges in random order, one with the Wright jet nebulizer (Roxon Medi-Tech, Etobicoke, Ontario, Canada)and one with the Solo vibrating mesh nebulizer (Aerogen Ltd., Dangan, Galway, Ireland). These study visits were performed at least 24 hours apart at roughly the same time of the day within a 2-week time frame. Methacholine challenge testing
Before the study, Wright nebulizers were calibrated to an output of 0.13 g/min based on the procedure outlined in the ATS guidelines.(1) The Wright devices were loaded with a volume of 1, 1.5, or 3 mL for each inhalation (site-specific and dependent on the vial capacity and the volume used during the calibration procedure). We determined the output of the Solo nebulizers for each concentration administered by weighing the loaded devices pre- and postnebulization. The Solo nebulizers were loaded with a volume of 1 mL for each inhalation period to ensure that the devices would not run dry. The Wright nebulizers were operated with pressurized air, while the Solo nebulizers were operated using the Aerogen Pro-X Controller (Aerogen Ltd., Dangan, Galway, Ireland) run on continuous mode. The 2-minute tidal breathing protocol was performed as outlined in the ATS guidelines for the methacholine challenges performed with the Wright nebulizers.(1) The same protocol was used with the Solo except for the modification of the inhalation time to 1 minute. Each study visit began with baseline spirometry to record three reproducible FEV1 maneuvers. Following spirometry, participants wore nose clips and were instructed to calmly inhale nebulized aerosol through a mouthpiece for a timed period of 2 minutes with the Wright or 1 minute with the Solo. FEV1 measurements were then taken at 30 and 90 seconds postinhalation. If the FEV1 measurement at 90 seconds was over 5% lower than that measured at 30 seconds, a third FEV1 measurement was performed at 150 seconds postinhalation. The next inhalation cycle was initiated at 5 minutes after the start of the previous inhalation period. The first inhalation of each methacholine challenge consisted of nebulized saline (0.9%). Subsequent inhalations involved doubling concentrations of methacholine [Provocholine (Methapharm, Inc. Brantford, ON, Canada)], and the same starting concentration was used for both nebulizers for each participant. This procedure was continued until a minimum 20% fall from the lowest FEV1 value post-saline was reached. Following each methacholine challenge, participants were given 200 lg of salbutamol to reverse the effects of methacholine. The Wright nebulizers were then cleaned for reuse, while a new Solo nebulizer was used for each participant.
METHACHOLINE CHALLENGE—NEBULIZER COMPARISON Statistical analysis
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The methacholine PC20 (mg/mL) data for both nebulizers were calculated with Formula 1.(9) The doses (lg) of methacholine delivered to the mouth by the Solo devices were then calculated according to Formula 2(10) with an estimated inspiratory duty cycle of 1/3. The weight loss of the nebulizer was measured in grams, and 1 g was assumed to be equivalent to 1 mL. These doses were then used to calculate the methacholine PD20 values for the Solo nebulizers with Formula 3(4): Formula 1 : PC20 ¼ antilog[(
20 R1 ) · log 2 þ log C1]; R2 R1
Formula 2 : Dose ¼ concentration of methacholine ðlg=mLÞ · weight lossðmLÞ · duty cycle; Formula 3 : PD20 ¼ antilog[ðlogD2 logD1Þ 20 R1 ) þ logD1]; · ( R2 R1 where R1 signifies the % fall in FEV1 after the next-to-last concentration of methacholine (C1), while R2 denotes the % fall in FEV1 following the last concentration of methacholine. D1 and D2 are the next-to-last and the last dose of methacholine administered. Based on a recent publication by Coates et al.,(11) the Wright nebulizer, after 2 minutes of inhalation, has a dose delivery to the mouth of *0.025 mg of methacholine (or 25 lg) per 1 mg/mL concentration (taking into account any evaporative loss). Wright PD20 data were therefore calculated by multiplying Wright PC20 values by 25. Log transformed PC20 and PD20 data were then compared using a paired t-test. Significance was two sided and set at 0.05. Geometric mean results are reported with 95% confidence intervals unless otherwise stated. With a sample size of 60, the study had 100% power to detect a one-half concentration change in methacholine responsiveness. Results Participants
Seventy participants enrolled in the study (Table 1). Only 60 (n = 20 per study site) met all eligibility criteria and
Table 1. Participant Demographics (n = 60) Category
Value
Mean age, years (SD) 31 (12) Mean height, cm (SD) 169 (9) Male sex 20 (33%) Smoking status (
JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 30, Number 0, 2017 ª Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/jamp.2017.1392
Methacholine Challenge: Comparison of Airway Responsiveness Produced by a Vibrating Mesh Nebulizer Versus a Jet Nebulizer Christianne M. Blais, BSc,1 Donald W. Cockcroft, MD, FRCPC,1,2 Justine Veilleux,3 Marie-E`ve Boulay, MSc, CCRP,3 Louis-Philippe Boulet, MD, FRCPC, FCCP,3 Gail M. Gauvreau, PhD,4 Tara X. Scime, BSc, CCRC,4 Richard M. Watson, HBSc(Kin), RCPT(c),4 Paul M. O’Byrne, MB, FRCPC, FRSC,4 and Beth E. Davis, PhD1,2
Abstract
Background: The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer. Methods: Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the methacholine PD20 were calculated following each methacholine challenge. Results: The geometric mean methacholine PC20 values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD20 results are comparable by clinical standards [81.7 lg (Solo) vs. 64.7 lg (Wright)], although the slight difference in dose was statistically significant ( p ¼ 0.018). Conclusions: The comparability of PD20 values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT. Keywords: dose,
methacholine challenge testing, nebulizer, standardization
muscarinic receptor agonist that mimics the airway constricting effects of acetylcholine.(1) MCT is traditionally performed in patients whose spirometry results are inconclusive but where asthma is suspected. In research, MCT has several uses, including the assessment of effects of pharmaceutical agents in asthma patients.
Introduction
M
ethacholine challenge testing (MCT) is a bronchoprovocation testing method commonly used to assess airway hyperresponsiveness induced by the direct bronchoconstricting agent methacholine.(1) Methacholine is a
Departments of 1Physiology and 2Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 3 Institut Universitaire de Cardiologie et de Pneumologie de Que´bec, Universite´ Laval, Quebec City, Quebec, Canada. 4 Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
1
Downloaded by Linkoping University Library from online.liebertpub.com at 09/04/17. For personal use only.
2
The American Thoracic Society (ATS) drafted guidelines in 1999 to standardize MCT.(1) These guidelines outline the 2minute tidal breathing protocol and the calibration procedure for the English Wright (Wright) jet nebulizer. This methodology and device have become routine for MCT in pulmonary function laboratories. However, standardization remains difficult to achieve for several reasons, most importantly are the diversity of nebulizers and the reporting of the response as a PC20 [provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (FEV1)]. The European Respiratory Society (ERS) has since published updated guidelines for MCT that address these factors(2); among the new recommendations are the characterization of nebulizers before their use in MCT, the incorporation of a minimum 1-minute inhalation period in new testing protocols, and the reporting of data as the PD20 (provocative dose of methacholine causing a 20% fall in FEV1) instead of the PC20. The PD20 accounts for the use of different protocols and devices, thereby improving the comparability of findings within patients and between testing sites.(2–6) However, PD20 values can only be calculated if the nebulizer used has been well characterized, particularly with regard to its output (i.e., dose delivery). In recent years, the Wright has become increasingly difficult to commercially obtain. In addition, this nebulizer requires a specially fitted and expensive Hans Rudolph valve, the nebulizer is not disposable (i.e. infection control concerns), and like other jet nebulizers, the dose of methacholine delivered is largely overestimated due to evaporative loss.(7,8) It is imperative that new reliable nebulizers be identified to ensure continued diagnostic and research application of bronchoprovocation testing with direct-acting stimuli. The objective of this study was to determine if the Aerogen Solo (Solo) vibrating mesh nebulizer produced similar methacholine PC20 and/or PD20 values compared to the Wright jet nebulizer. Materials and Methods Participants
Eligible participants were at least 18 years old with mildto-moderate asthma, a methacholine PC20 £ 16 mg/mL (i.e., asthmatic), and baseline lung function (% predicted FEV1) greater than or equal to 65%. Participants were required to abstain from long-acting beta-2 agonists and long-acting muscarinic antagonists for the withdrawal periods provided in the ATS guidelines.(1) Additional exclusion criteria included pregnant and lactating women, those suffering from cardiovascular problems, and those affected by an upper respiratory tract infection or allergy-induced asthma exacerbation within 4 weeks of the study. Smokers were eligible to participate provided their smoking history did not surpass 10 pack-years and they did not smoke for at least 1 hour before testing. Inhaled corticosteroids were allowed if taken regularly at a stable dose for a minimum of 30 days before study enrolment. Rescue medication (i.e., salbutamol) was avoided for at least 6 hours before a laboratory visit. Each laboratory obtained site-specific Research Ethics Board approval before starting the study. The study was registered with clinicaltrials.gov (NCT 02822859). Written informed consent was obtained from each participant before beginning testing.
BLAIS ET AL. Study design
This was a randomized crossover study performed at three respiratory research laboratories (University of Saskatchewan, Universite´ Laval, and McMaster University). A screening visit was first performed using the 2-minute tidal breathing protocol to identify a positive methacholine challenge and adequate lung function. The screening visit was omitted if a participant had a documented PC20 £ 16 mg/mL with the 2-minute tidal breathing protocol in the 6 months preceding the study. Following screening, participants who met the study criteria underwent two methacholine challenges in random order, one with the Wright jet nebulizer (Roxon Medi-Tech, Etobicoke, Ontario, Canada)and one with the Solo vibrating mesh nebulizer (Aerogen Ltd., Dangan, Galway, Ireland). These study visits were performed at least 24 hours apart at roughly the same time of the day within a 2-week time frame. Methacholine challenge testing
Before the study, Wright nebulizers were calibrated to an output of 0.13 g/min based on the procedure outlined in the ATS guidelines.(1) The Wright devices were loaded with a volume of 1, 1.5, or 3 mL for each inhalation (site-specific and dependent on the vial capacity and the volume used during the calibration procedure). We determined the output of the Solo nebulizers for each concentration administered by weighing the loaded devices pre- and postnebulization. The Solo nebulizers were loaded with a volume of 1 mL for each inhalation period to ensure that the devices would not run dry. The Wright nebulizers were operated with pressurized air, while the Solo nebulizers were operated using the Aerogen Pro-X Controller (Aerogen Ltd., Dangan, Galway, Ireland) run on continuous mode. The 2-minute tidal breathing protocol was performed as outlined in the ATS guidelines for the methacholine challenges performed with the Wright nebulizers.(1) The same protocol was used with the Solo except for the modification of the inhalation time to 1 minute. Each study visit began with baseline spirometry to record three reproducible FEV1 maneuvers. Following spirometry, participants wore nose clips and were instructed to calmly inhale nebulized aerosol through a mouthpiece for a timed period of 2 minutes with the Wright or 1 minute with the Solo. FEV1 measurements were then taken at 30 and 90 seconds postinhalation. If the FEV1 measurement at 90 seconds was over 5% lower than that measured at 30 seconds, a third FEV1 measurement was performed at 150 seconds postinhalation. The next inhalation cycle was initiated at 5 minutes after the start of the previous inhalation period. The first inhalation of each methacholine challenge consisted of nebulized saline (0.9%). Subsequent inhalations involved doubling concentrations of methacholine [Provocholine (Methapharm, Inc. Brantford, ON, Canada)], and the same starting concentration was used for both nebulizers for each participant. This procedure was continued until a minimum 20% fall from the lowest FEV1 value post-saline was reached. Following each methacholine challenge, participants were given 200 lg of salbutamol to reverse the effects of methacholine. The Wright nebulizers were then cleaned for reuse, while a new Solo nebulizer was used for each participant.
METHACHOLINE CHALLENGE—NEBULIZER COMPARISON Statistical analysis
Downloaded by Linkoping University Library from online.liebertpub.com at 09/04/17. For personal use only.
The methacholine PC20 (mg/mL) data for both nebulizers were calculated with Formula 1.(9) The doses (lg) of methacholine delivered to the mouth by the Solo devices were then calculated according to Formula 2(10) with an estimated inspiratory duty cycle of 1/3. The weight loss of the nebulizer was measured in grams, and 1 g was assumed to be equivalent to 1 mL. These doses were then used to calculate the methacholine PD20 values for the Solo nebulizers with Formula 3(4): Formula 1 : PC20 ¼ antilog[(
20 R1 ) · log 2 þ log C1]; R2 R1
Formula 2 : Dose ¼ concentration of methacholine ðlg=mLÞ · weight lossðmLÞ · duty cycle; Formula 3 : PD20 ¼ antilog[ðlogD2 logD1Þ 20 R1 ) þ logD1]; · ( R2 R1 where R1 signifies the % fall in FEV1 after the next-to-last concentration of methacholine (C1), while R2 denotes the % fall in FEV1 following the last concentration of methacholine. D1 and D2 are the next-to-last and the last dose of methacholine administered. Based on a recent publication by Coates et al.,(11) the Wright nebulizer, after 2 minutes of inhalation, has a dose delivery to the mouth of *0.025 mg of methacholine (or 25 lg) per 1 mg/mL concentration (taking into account any evaporative loss). Wright PD20 data were therefore calculated by multiplying Wright PC20 values by 25. Log transformed PC20 and PD20 data were then compared using a paired t-test. Significance was two sided and set at 0.05. Geometric mean results are reported with 95% confidence intervals unless otherwise stated. With a sample size of 60, the study had 100% power to detect a one-half concentration change in methacholine responsiveness. Results Participants
Seventy participants enrolled in the study (Table 1). Only 60 (n = 20 per study site) met all eligibility criteria and
Table 1. Participant Demographics (n = 60) Category
Value
Mean age, years (SD) 31 (12) Mean height, cm (SD) 169 (9) Male sex 20 (33%) Smoking status (
