Improved Laboratory Test Methods for Orally Inhaled Products

• European Directorate for Quality in Medicines and HealthCare (EDQM). Monograph 2.9.18: European Pharmacopeia, Preparations for inhalation: aerodynamic assessment of fine particles, Council of Europe, 67075 Strasbourg, France, Ph.Eur.7.5 (USB 7th Edition). 7.52012 (2012).
   Google Scholar
• United States Pharmacopeial Convention. Chapter 601: Aerosols, Nasal Sprays, Metered-Dose Inhalers and Dry Powder Inhalers. Rockville, MD, USA, USP 35-NF 30 (2012).
   Google Scholar
• Canadian Standards Association. Spacers and holding chambers for use with metered-dose inhalers. Mississauga, Ontario, Canada, CAN/CSA/Z264.1–02:2002 rev. (2008).
   Google Scholar
• European Medicines Agency. Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products. London, UK. EMEA/CHMP/QWP/49313/2005 Corr. 2006. (2006).
   Google Scholar
• US FDA. Reviewer guidance for nebulizers, metered dose inhalers, spacers and actuators. Center for Devices and Radiological Health. Rockville, MD, USA (1993).
   Google Scholar
• US FDA. Draft guidance: metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products chemistry, manufacturing and controls documentation. Center for Drug Evaluation and Research. Docket 98D-0997. Rockville, MD, USA (1998).
   Google Scholar
• Mitchell JP , NewmanS, Chan H-K. In vitro and in vivo aspects of CI tests and inhaler performance: a review. AAPS PharmSciTech8(4), 237–248 (2004).
   Google Scholar
• Mitchell J , DolovichMB. Clinically relevant test methods to establish in vitro equivalence for spacers and valved holding chambers used with pressurized metered dose inhalers (pMDIs). J. Aerosol Med. Pulmon. Deliv.25(4), 217–242 (2012).
   PubMed Web of Science ®Google Scholar
• Dolovich MB , MitchellJP. Canadian Standards Association standard CAN/CSA/Z264.1–02:2002: a new voluntary standard for spacers and holding chambers used with pressurized metered-dose inhalers. Can. Respir. J.11, 489–495 (2004).
   PubMedGoogle Scholar
• US FDA. Draft guidance: applying human factors and usability engineering to optimize medical device design. Center for Drug Evaluation and Research. Rockville, MD, USA (2011).
   Google Scholar
• European Medicines Agency. Requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. London, UK. CPMP/EWP/4151/00 Rev. 1 (2009).
   Google Scholar
• Boe J , DennisJH, O‘DriscollBR. European Respiratory Society guidelines on the use of nebulizers. Eur. Respir. J.18(1), 228–242 (2001).
   PubMed Web of Science ®Google Scholar
• Chavan V , DalbyR. Novel system to investigate the effects of inhaled volume and rates of rise in simulated inspiratory air flow on fine particle output from a dry powder inhaler. AAPS PharmSci4(2), 7–12 (2002).
   Google Scholar
• Tiddens HAWM , GellerDE, ChallonerPEet al. Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older. J. Aerosol Med. 19(4), 456–465 (2006).
   PubMedGoogle Scholar
• Barry PW , O‘CallaghanC. Drug output from nebulizers is dependent on the method of measurement. Eur. Respir J.12(12), 463–466 (1998).
   PubMedGoogle Scholar
• Bonam M , ChristopherD, CipollaDet al. Minimizing variability of cascade impaction measurements in inhalers and nebulizers. AAPS PharmSciTech 9(2), 404–413 (2008).
   PubMed Web of Science ®Google Scholar
• Mitchell JP , NagelMW. Cascade impactors for the size characterization of aerosols from medical inhalers. Their uses and limitations. J. Aerosol Med.16(4), 341–377 (2003).
   PubMedGoogle Scholar
• Mitchell J , BauerR, LyapustinaSet al. Non-impactor-based methods for sizing of aerosols emitted from orally inhaled and nasal drug products (OINDPs). AAPS PharmSciTech 12(3), 965–988 (2011).
   PubMed Web of Science ®Google Scholar
• Dunbar C , MitchellJP. Analysis of CI mass distributions. J. Aerosol Med.18(4), 439–451 (2005).
   PubMedGoogle Scholar
• Copley M , MitchellJP, SvenssonMet al. Chapter 10. In: Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products. Tougas TP, Mitchell JP, Lyapustina SA (Eds). Springer, NY, USA, 283–357 (2013).
   Google Scholar
• Prime D , HamiltonM. Development of the hydraulic lung. Presented at: Drug Delivery to the Lungs 23, The Aerosol Society. Edinburgh, UK, 5–7 December (2012).
   Google Scholar
• Mitchell J . Opportunities for clinically relevant methods in the laboratory evaluation of spacers and valved holding chambers (VHCs). Presented at: Drug Delivery to the Lungs 23, The Aerosol Society. Edinburgh, UK, 5–7 December (2012).
   Google Scholar
• Ehtezazi T , SouthernKW, AllansonDet al. Suitability of the upper airway models obtained from MRI studies in simulating drug lung deposition from inhalers. Pharm. Res. 22(1), 166–170 (2005).
   PubMed Web of Science ®Google Scholar
• Zhang Y , GilbertsonK, FinlayWH. In vivo–in vitro comparison of deposition in three mouth-throat models with Qvar and Turbuhaler inhalers. J. Aerosol Med.20(3), 227–235 (2007).
   PubMedGoogle Scholar
• Kim CS , TrujilloD, SacknerMA. Size aspects of metered dose inhaler aerosols. Am. Rev. Respir. Dis.132(1), 137–142 (1985).
   PubMed Web of Science ®Google Scholar
• Shemirani FM , HoeS, LewisDet al. In vitro investigation of the effect of ambient humidity on regional delivered dose with solution and suspension MDIs. J. Aerosol Med. Pulmon. Deliv. (2013) (Epub ahead of print).
   PubMedGoogle Scholar
• Mitchell JP . Appropriate face models for evaluating drug delivery in the laboratory: the current situation and prospects for future advances. J. Aerosol Med.21(1), 1–15 (2008).
   Google Scholar
• Golshahi L , NogaML, FinlayWH. Deposition of inhaled micrometer-sized particles in oropharyngeal airway replicas of children at constant flow rates. J. Aerosol Sci.49(1), 21–31 (2012).
   Google Scholar
• Esposito-Festen JE , AtesB, Van Vliet FLM et al. Effect of a facemask leak on aerosol delivery from a pMDI-spacer system. J. Aerosol Med.17(1), 1–6 (2004).
   PubMedGoogle Scholar
• Mitchell JP , NagelMW, FinlayJB. Advances in models for laboratory testing of inhalers: there‘s more to it than meets the nose or mouth – the ADAM face models. In: Respiratory Drug Delivery Europe 2011. Dalby RN, Byron PR, Peart J, Suman JD, Young PM (Eds). Davis Healthcare International Publishing, LLC, River Grove, IL, USA, 457–462 (2011).
   Google Scholar
• Shah SA , BerlinskiA, RubinBK. Force-dependent static dead space of face masks used with holding chambers. Respir. Care51(2), 140–144 (2006).
   PubMed Web of Science ®Google Scholar
• Amirav I , NewhouseMT. Dead space variability of face masks for valved holding chambers. Isr. Med. Assoc. J.10(3), 224–226 (2008).
   PubMed Web of Science ®Google Scholar
• Fink JB , DhandR, GrychowskiJet al. Reconciling in vitro and in vivo measurements of aerosol delivery from a metered-dose inhaler during mechanical ventilation and defining efficiency-enhancing factors. Am. J. Respir. Crit. Care Med. 159(1), 63–68 (1999).
   PubMed Web of Science ®Google Scholar
• Dhand R . Aerosol delivery during mechanical ventilation: from basic techniques to new devices. J. Aerosol Med. Pulmon. Deliv.21(1), 45–60 (2008).
   PubMed Web of Science ®Google Scholar
• Ari A , HarwoodAJ, SheardMMet al. An in vitro evaluation of aerosol delivery through tracheostomy and endotracheal tubes using different interfaces. Respir. Care. 57(7), 1066–1070 (2012).
   PubMed Web of Science ®Google Scholar
• Nikander K , DenyerJ. Breathing patterns. Eur. Respir. Rev.10(76), 576–579 (2000).
   Google Scholar
• Berg EB , PicardRJ. In vitro delivery of budesonide from 30 jet nebulizer/compressor combinations using infant and child breathing patterns. Respir. Care54(12), 1671–1678 (2009).
   PubMed Web of Science ®Google Scholar
• Leach CL , ColiceGL. A pilot study to assess lung deposition of HFA-beclomethasone and CFC-beclomethasone from a pressurized metered dose inhaler with and without add-on spacers and using varying breathhold times. J. Aerosol Med. Pulmon. Deliv.23(6), 355–361 (2010).
   PubMed Web of Science ®Google Scholar
• Mitchell JP , NagelM, AvvakoumovaVet al. Extending the performance of an existing breath-actuated nebulizer for domiciliary use: initial data. In: Respiratory Drug Delivery 2012. Dalby RN, Byron PR, Peart J, Suman JD, Young PM (Eds). Davis Healthcare International Publishing LLC, River Grove, Illinois, USA, 737–740 (2012).
   Google Scholar
• European Directorate for Quality in Medicines and Healthcare (EDQM). Preparations for nebulisation: characterisation, European Pharmacopeia, Strasbourg, France. General Chapter 2.9.44., 7th Edition (2012).
   Google Scholar
• United States Pharmacopeial Convention. United States Pharmacopeia/National Formulary USP 36:NF31, Rockville, MD, USA, <1601> Products for nebulization–characterization tests (2013).
   Google Scholar
• International Standards Organization, Geneva, Switzerland, ISO 27427:2010 Anaesthetic and respiratory equipment – nebulizing systems and components (2010).
   Google Scholar
• Mitchell JP , NagelMW, NicholsSCet al. Laser diffractometry as a technique for the rapid assessment of aerosol particle size from inhalers. J. Aerosol Med. 19(4), 409–433 (2006).
   PubMedGoogle Scholar
• Nagel MW , AvvakoumovaV, MacKayHet al. Medication delivery via infant and child valved holding chambers (VHCs) with facemask is aided with inhalation flow indicator. Presented at: 18th European Respiratory Society Annual Congress (ERS), Berlin, Germany, in Eur. Respir. J. 32S52: Poster P3497 (2008).
   Google Scholar
• Melani AS , ZancettaD, BarbatoNet al. Inhalation technique and variables associated with misuse of conventional metered-dose inhalers and newer dry powder inhalers in experienced adults. Ann. Allergy Asthma. Immunol. 93(5), 439–446 (2004).
   PubMed Web of Science ®Google Scholar
• Melani AS , BonaviaM, CilentiVet al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir. Med. 105(6), 930–938 (2011).
   PubMed Web of Science ®Google Scholar
• Dolovich M , MacIntyreNR, AndersonPJet al. Consensus statement: aerosols and delivery devices. Respir. Care 45(6), 589–596 (2000).
   PubMedGoogle Scholar
• Dolovich MB . In my opinion: interview with the expert. Pediatr. Asthma Allergy Immunol.17(4), 292–300 (2004).
   Google Scholar
• Connolly M . Inhaler technique of elderly patients: comparison of metered-dose inhalers and large volume spacer devices. Age Aging24(3), 190–192 (1995).
   PubMed Web of Science ®Google Scholar
• Rau JL . Practical problems with aerosol therapy in COPD. Respir. Care51(2), 158–172 (2006).
   PubMed Web of Science ®Google Scholar
• Rau JL , CoppoloDP, NagelMWet al. The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol. Respir. Care 51(5), 503–510 (2006).
   PubMed Web of Science ®Google Scholar
• Dolovich MB , RhemR. Impact of oropharyngeal deposition on inhaled dose. J. Aerosol Med.11(S1), S112–S115 (1998).
   PubMedGoogle Scholar
• O‘Connor D , AdamsW, Chen M-L et al. Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J. Aerosol Med. Pulmon. Deliv.24(3), 119–135 (2011).
   PubMedGoogle Scholar
• Stocks J , HislopAA. Structure and function of the respiratory system. In: Drug Delivery to the Lung. Bisgaard H, O‘Callaghan C, Smaldone GC. (Eds). Marcel Dekker, NY, USA, 47–104 (2002).
   Google Scholar
• Miller MJ , MartinRJ, CarloWAet al. Oral breathing in newborn infants. J. Pediatr. 107(3), 465–469 (1985).
   PubMed Web of Science ®Google Scholar
• Chua HL , CollisGG, NewburyAMet al. The influence of age on aerosol deposition in children with cystic fibrosis. Eur. Respir. J. 7(12), 2185–2191 (1994).
   PubMed Web of Science ®Google Scholar
• Berg E . In vitro properties of pressurized metered dose inhalers with and without spacer devices. J. Aerosol Med.8(S3), S3–S11 (1995).
   PubMedGoogle Scholar
• Velasquez DJ , GabrioB. Metered dose inhaler aerosol deposition in a model of the human respiratory system and a comparison with clinical deposition studies. J. Aerosol Med.11(S1), S23–S28 (1998).
   PubMedGoogle Scholar
• Newman SP , Chan H-K. In vitro/in vivo comparisons in pulmonary drug delivery. J. Aerosol Med.21(1), 1–8 (2008).
   Google Scholar
• Newman SP . How well do in vitro particle size measurements predict drug delivery in vivo. J. Aerosol Med.11(S1), S97–S104 (1998).
   PubMedGoogle Scholar
• Swift DL . Apparatus and method for measuring regional distribution of therapeutic aerosols and comparing delivery systems. J. Aerosol Sci.23(S1), S495–S498 (1992).
   Google Scholar
• Golshahi L , FinlayWH, OlfertJSet al. Deposition of inhaled ultrafine aerosols in replicas of nasal airways of infants. Aerosol Sci. Technol. 44(9), 741–752 (2010).
   Web of Science ®Google Scholar
• Golshahi L , VehringR, NogaMLet al. In vitro deposition of micrometer-sized particles in the extrathoracic airways of children during tidal oral breathing. J. Aerosol Sci.57(1), 14–21 (2013).
   Google Scholar
• McRobbie DW , PritchardS, QuestRA. Studies of the human oropharyngeal airspaces using magnetic resonance imaging. I. Validation of a three-dimensional MRI method for producing ex vivo virtual and physical casts of the oropharyngeal airways during inspiration. J. Aerosol Med.16(4), 401–415 (2003).
   PubMedGoogle Scholar
• Stapleton KW , GuentschE, HoskinsonMKet al. On the suitability of k-turbulence modeling for aerosol deposition in the mouth and throat: a comparison with experiment. J. Aerosol Sci. 31(6), 731–749 (2000).
   Web of Science ®Google Scholar
• Golshahi L , FinlayWH. An idealized child throat that mimics average pediatric oropharyngeal deposition. Aerosol Sci. Technol.46(5), i–iv (2012).
   Web of Science ®Google Scholar
• Grgic B , FinlayWH, BurnellPKPet al. In vitro intersubject and intrasubject deposition measurements in realistic mouth-throat geometries. J. Aerosol Sci.35(8), 1025–1040 (2004).
   Web of Science ®Google Scholar
• Copley M , MitchellJ, SolomonD. Evaluating the Alberta throat: an innovation to support the acquisition of more clinically applicable aerosol aerodynamic particle size distribution (APSD) data in oral inhaled product (OIP) development. Inhalation5, 12–16 (2011).
   Google Scholar
• Zhang Y , ChiaTL, FinlayWH. Experimental measurement and numerical study of particle deposition in highly idealized mouth-throat models. Aerosol Sci. Technol.40(5), 361–372 (2006).
   Web of Science ®Google Scholar
• Finlay WH . New validated extrathoracic and pulmonary deposition models for infants and children. In: Respiratory Drug Delivery 2012. Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM (Eds). Davis Healthcare International Publishing, LLC, River Grove, IL, USA, 325–336 (2012).
   Google Scholar
• Javaheri E , GolshahiL, FinlayWH. An idealized geometry that mimics average infant nasal airway deposition. J. Aerosol Sci.55(1), 137–148 (2013).
   Google Scholar
• Beron KL , GrabekCE, JungJAet al. Flow rate ramp profile effects on the emitted dose from dry powder inhalers. Presented at: Drug Delivery to the Lungs 19. The Aerosol Society, Edinburgh, UK, 10–12 December (2008).
   Google Scholar
• Foss SA , KeppelJW. In vitro testing of MDI spacers: a technique for measuring respirable dose output with actuation in-phase or out-of-phase with inhalation. Respir. Care44(12), 1474–1485 (1999).
   Google Scholar
• Finlay WH , ZuberbuhlerP. In vitro comparison of salbutamol hydrofluoroalkane (Airomir) metered dose inhaler aerosols inhaled during pediatric tidal breathing from five valved holding chambers. J. Aerosol Med.12(4), 285–291 (1999).
   PubMedGoogle Scholar
• Finlay WH , Gehmlich,MG. Inertial sizing of aerosol inhaled from two dry powder inhalers with realistic breath patterns versus constant flow rates. Int. J. Pharm.210(1–2), 83–95 (2000).
   PubMed Web of Science ®Google Scholar
• Janssens HM , De Jongste JC, Fokkens WJ et al. The Sophia anatomical infant nose-throat (Saint) model: a valuable tool to study aerosol deposition in infants. J. Aerosol Med.14(4), 433–441 (2001).
   PubMedGoogle Scholar
• Brockmann JE . Sampling and transport of aerosols. In: Aerosol Measurement: Principles, Techniques and Applications. Willeke K, Baron P. (Eds). Van Nostrand Reinhold, NY, USA, 77–111 (1992).
   Google Scholar
• Olsson B , BorgströmL, LundbäckHet al. Validation of a general in vitro approach for prediction of total lung deposition in healthy adults. J. Aerosol Med. Pulmon. Deliv. (2013) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Olsson B , BorgströmL, SvenssonMet al. Modeling oropharyngeal cast deposition to predict lung delivery from powder inhalers. In: Respiratory Drug Delivery 2008. Dalby RN, Byron PR, Peart J, Suman JD, Farr S, Young PM (Eds). Davis Healthcare International Publishing, LLC, River Grove, IL, USA, 197–205 (2008).
   Google Scholar
• Below A , BickmannD, BreitkreutzJ. Assessing the performance of two dry powder inhalers in preschool children using an idealized pediatric upper airway model. Int. J. Pharm.444(1–2), 169–174 (2013).
   PubMed Web of Science ®Google Scholar
• Bickmann D , WachtelH, KrögerRet al. Examining inhaler performance using a child‘s throat model. In: Respiratory Drug Delivery 2008. Dalby RN, Byron PR, Peart J, Suman JD, Farr S, Young PM (Eds). Davis Healthcare International Publishing, LLC, River Grove, IL, USA. 197–205 (2008).
   Google Scholar
• Brindley A , SumbyBS, SmithIJ. The characterisation of inhalation devices by an inhalation simulator: the Electronic Lung™. J. Aerosol Med.7(2), 197–200 (1994).
   PubMedGoogle Scholar
• Burnell PKP , MaltonA, ReavillKet al. Design, validation and initial testing of the Electronic Lung™ device. J. Aerosol Sci. 29(8), 1011–1025 (1998).
   Web of Science ®Google Scholar
• Smaldone GC , SangwanS, ShahA. Facemask design, facial deposition, and delivered dose of nebulized aerosols. J. Aerosol Med.20(s1), S66–S77 (2007)
   PubMedGoogle Scholar
• Janssens HM , TiddensHAWM. Facemasks and aerosol delivery by metered dose inhaler–valved holding chamber in young children: a tight seal makes the difference. J. Aerosol Med.20(s1), S59–S65 (2007).
   PubMedGoogle Scholar
• Everard ML , ClarkAR, MilnerAD. Drug delivery from holding chambers with attached facemask. Arch. Dis. Child.67(5), 580–585 (1992).
   PubMed Web of Science ®Google Scholar
• Everard ML , ClarkR, MilnerAD. Drug delivery from jet nebulizers. Arch. Dis. Child.67(5), 586–591 (1992).
   PubMed Web of Science ®Google Scholar
• Smaldone GC , BergE, NikanderK. Variation in pediatric aerosol delivery: importance of facemask. J. Aerosol Med.18(3), 354–363 (2005).
   PubMedGoogle Scholar
• Laube BL , SharplessG, ShermerCet al. Deposition of albuterol aerosol generated by pneumatic nebulizer in the Sophia Anatomical Infant Nose-Throat (SAINT) model. Pharm. Res. 27(8), 1722–1729 (2010).
   PubMed Web of Science ®Google Scholar
• Laube BL , SharplessG, ShermerCet al. Deposition of dry powder generated by Solovent in Sophia Anatomical Infant Nose-Throat (SAINT) model. Aerosol Sci. Technol. 46(5), 514–520 (2012).
   Web of Science ®Google Scholar
• Keller M , HugM, BucholskiAet al. Characterization of three inhalation products by the Sofia Anatomical Infant Nose Throat (SAINT) model upon nebulization by the eFlow® Baby electronic nebulizer. Presented at: 16th European Respiratory Society Annual Congress (ERS), Munich, Germany, 1–6 September. Poster P4100. Eur. Respir. J. 28S50, 713S (2006).
   Google Scholar
• Louca E , LeungK, CoatesALet al. Comparison of three valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face model. J. Aerosol Med. 19(2), 160–167 (2006).
   PubMedGoogle Scholar
• Cripps AL , DavisAM, PischelSMet al. In vitro performance of albuterol HFA formulation in two valved holding chambers at low inspiratory flow rates and extended delay times. Presented at: 64th Annual Meeting of the American Association for Allergy Asthma and Immunology (AAAAI), Philadelphia, PA, USA, 7–12 March. J. Allergy Clin. Immunol.121(2) S1, S9 (Abstract 38) (2008).
   Google Scholar
• Mitchell JP , NagelM, FinlayB. Advances in models for laboratory testing of inhalers: there‘s more to it than meets the nose or mouth – the ADAM face models. In: Respiratory Drug Delivery Europe 2011. Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM (Eds). Davis Healthcare International Publishing LLC, River Grove, IL, USA, 457–461 (2011).
   Google Scholar
• Storey-Bischoff J , NogaM, FinlayWH. Deposition of micrometer-sized aerosol particles in infant nasal airway replicas. J. Aerosol Sci.39(12), 1055–1065 (2008).
   Web of Science ®Google Scholar
• Tal A , GolanH, GrauerNet al. Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J. Pediatr. 128(4), 479–484 (1996).
   PubMed Web of Science ®Google Scholar
• Mitchell JP , MortonRW, EngelbrethDet al. Addressing the patient-device use interface: development and laboratory validation of a facemask with anatomically responsive face models. Inhalation 7(2), 10–15 (2013).
   Google Scholar
• Schuëpp K , StraubD, MöllerAet al. Deposition of aerosols in infants and children. J. Aerosol Med. 17(2), 153–156 (2004).
   PubMedGoogle Scholar
• Tobin MJ . Principles and practice of mechanical ventilation. McGraw Hill, NY, USA (2006).
   Google Scholar
• Ari A , FinkJB, DhandR. Inhalation therapy in patients receiving mechanical ventilation: an update. J. Aerosol Med. Pulmon. Deliv.25(6), 319–332 (2012).
   PubMed Web of Science ®Google Scholar
• Fink J , DhandR, DuarteAet al. Aerosol delivery from a metered-dose inhaler during mechanical ventilation: an in vitro model. Am. J. Respir. Crit. Care Med. 154(2pt.1), 382–387 (1996).
   PubMed Web of Science ®Google Scholar
• O‘Riordan TG , PalmerLB, SmaldoneGC. Aerosol deposition in mechanically ventilated patients: optimizing nebulizer delivery. Am. J. Respir. Crit. Care Med.149(1), 214–219 (1994).
   PubMed Web of Science ®Google Scholar
• Guerin C , FassierT, BayleFet al. Inhaled bronchodilator administration during mechanical ventilation: how to optimize it and for which clinical benefit? J. Aerosol Med. 21(1), 85–89 (2008).
   Google Scholar
• Esmond G , MickelsonsC. Non invasive respiratory support techniques. Wiley-Blackwell, Chichester, UK (2009).
   Google Scholar
• Hess DR . The mask for noninvasive ventilation: principles of design and effects on aerosol delivery. J. Aerosol Med.20S1, S85–S98 (2007).
   Google Scholar
• White CC , CrotwellDN, ShenSet al. Bronchodilator delivery during simulated pediatric noninvasive ventilation. Respir. Care (2013) (Epub ahead of print).
   PubMedGoogle Scholar
• Fuller HD , DolovichMB, TurpieFHet al. Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients: a study comparing four different actuator devices. Chest 105(1), 214–218 (1994).
   PubMed Web of Science ®Google Scholar
• Dellweg D , WachtelH, HohnEet al. In vitro validation of a Respimat® adapter for delivery of inhaled bronchodilators during mechanical ventilation. J. Aerosol Med.24(6), 285–292 (2011).
   Google Scholar
• Longest PW , GolshahiL, HindleM. Improving pharmaceutical aerosol delivery during noninvasive ventilation: effects of streamlined components. Ann. Biomed. Eng.41(6), 1217–1232 (2013).
   PubMed Web of Science ®Google Scholar
• Nagel MW , AvvakoumovaCC, DoyleCCet al. In vitro performance of a new collapsible holding chamber (CHC) for the delivery of aerosolized medication by pressurized metered-dose inhaler to patients receiving mechanical ventilation. Presented at: 21st European Respiratory Society Annual Congress (ERS), Amsterdam, NL. Eur. Respir. J. (conference abstract), 38S55:346s (2011).
   Google Scholar
• Young P , MackenzieIA. Management of the artificial airway. In: Core Topics in Mechanical Ventilation. Mackenzie I (Ed.). Cambridge University Press, Cambridge, UK, 54–87 (2008).
   Google Scholar
• Ricard J -D, Le Miére E, Markowicz P et al. Efficiency and safety of mechanical ventilation with a heat and moisture exchanger changed only once a week. Am. J. Respir. Crit. Care. Med.161(1), 104–109 (2000).
   PubMed Web of Science ®Google Scholar
• Fink JB . Opportunities and risks of using heliox in your clinical practice. Respir. Care51(6), 651–660 (2006).
   PubMed Web of Science ®Google Scholar
• Ari A , FinkJ. Aerosol drug delivery administration with helium-oxygen (heliox) mixtures: an overview. Curr. Respir. Med. Rev.6(2), 80–85 (2010).
   Google Scholar
• Svartengren M , AndersonM, PhilipsonKet al. Human lung deposition of particles suspended in air or in helium/oxygen mixture. Exp. Lung Res. 15(4), 575–585 (1989).
   PubMed Web of Science ®Google Scholar
• Mitchell JP , TougasTP, ChristopherJDet al. Challenges of sizing inhaler aerosols: bringing the methods into the 21st century. In: Respiratory Drug Delivery Europe 2013. Dalby RN, Byron PR, Peart J, Suman JD, Young PM, Traini, D (Eds). Davis Healthcare International Publishing LLC, River Grove, IL, USA, 363–368 (2013).
   Google Scholar
• Mitchell JP , NuttallM, Limbrick et al. The evaluation of aerosol delivery via a pressurized metered dose inhaler with valved holding chamber to an anatomical model of a small child face. In: Respiratory Drug Delivery Europe 2013. Dalby RN, Byron PR, Peart J, Suman JD, Young PM, Traini D (Eds). Davis Healthcare International Publishing LLC, River Grove, IL, USA, 379–382 (2013).
   Google Scholar

Patent

• Miller NC. Apparatus and process for aerosol size measurement at varying gas flow rates. US Patent 6,435,004-B1 (2002).
   Google Scholar

Websites

• Global Initiative for Asthma (GINA): global strategy for asthma management and prevention. www.ginasthma.org
   Google Scholar
• Devine AS. Endotracheal tubes. Medscape Reference. WebMD LLC (2011). http://emedicine.medscape.com/article/2044750-overview
   Google Scholar
• Copley M. Regulatory challenges of inhaler testing. Pharmaceutical Technology Europe. Advanstar Publishers. November 1st (2009). www.pharmtech.com/pharmtech/issue/issueDetail.jsp?id=18284
   Google Scholar