The evolution of spacers and valved holding chambers

Journal of Aerosol Medicine and Pulmonary Drug Delivery

Volumn 27, Issue SUPPL. 1, 2014, Pages

  Nikander, Kurt ^a   Nicholls, Clare ^b   Denyer, John ^b   Pritchard, John ^c  

^a InDevCo AB   (Sweden)

^b PS5 Consultants Ltd   (United Kingdom)

^c PHILIPS RESEARCH LABORATORIES   (Germany)

Author keywords

adherence; electrostatic; inhalation delay; patent; pMDI accessory device; spacer; valved holding chamber

Indexed keywords

ADRENALIN HYDROGEN TARTRATE; BECLOMETASONE; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; BRONCHODILATING AGENT; BUDESONIDE; CHOLINERGIC RECEPTOR BLOCKING AGENT; CORTICOSTEROID; FLUORINATED HYDROCARBON; ISOPRENALINE; LOBELINE; ORCIPRENALINE; PLACEBO; SALBUTAMOL; SALBUTAMOL SULFATE; AEROSOL; DRUG;

ADULT; AEROSOL; AIRWAY; ASTHMA; BREATHING MOUTHPIECE; BREATHING PATTERN; CHILD; DRUG DELIVERY DEVICE; DRUG FORMULATION; DRUG SELF ADMINISTRATION; EPIDEMIC; EVIDENCE BASED MEDICINE; EVOLUTION; FACE MASK; FORCED EXPIRATORY VOLUME; HAND; HAND LUNG COORDINATION; HAND MOVEMENT; HISTORY OF MEDICINE; HUMAN; HYDROGEL; INFANT; INHALATION; INHALATION DELAY; INHALATION SPACER; ISOTOPE LABELING; LUNG; LUNG FUNCTION; MEDICAL NEBULIZER; METERED DOSE INHALER; MORTALITY; PATENT; PATIENT COMPLIANCE; PATIENT DEVICE INTERFACE; PATIENT MONITOR; PRACTICE GUIDELINE; PRESSURIZED METERED DOSE INHALER; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SMOKING CESSATION; STATIC ELECTRICITY; THRUSH; TOBACCO DEPENDENCE; VALVED HOLDING CHAMBER; AGE; CHEMISTRY; DEVICES; DRUG DELIVERY SYSTEM; EQUIPMENT DESIGN; HISTORY; INHALATIONAL DRUG ADMINISTRATION; MASK; MEDICINAL CHEMISTRY; PARTICLE SIZE; PRESCHOOL CHILD; PRESSURE; TRENDS;

ADMINISTRATION, INHALATION; AEROSOLS; AGE FACTORS; CHEMISTRY, PHARMACEUTICAL; CHILD; CHILD, PRESCHOOL; DRUG DELIVERY SYSTEMS; EQUIPMENT DESIGN; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; INFANT; MASKS; METERED DOSE INHALERS; PARTICLE SIZE; PATIENT COMPLIANCE; PHARMACEUTICAL PREPARATIONS; PRESSURE;

EID: 84904811025     PISSN: 19412711     EISSN: 19412703     Source Type: Journal    
DOI: 10.1089/jamp.2013.1076     Document Type: Review

References (169)

1. Chastanet L, inventor: Spray-inhaler. French patent FR 513,678. Priority date April 13, 1920; filed November 5, 1920; issued February 21, 1921.
2. Birch HM, and Gattone D, inventors: Means for administering medication orally into the respiratory organs. United States patent US 2,788,784. Filed August 23, 1955; issued April 16, 1957.
3. Thiel CG: From Susie's question to CFC free: an inventor's perspective on forty years of MDI Development and regulation. In: RN Dalby, PR Byron, and SJ Farr, (eds). Respiratory Drug Delivery, 5th ed. Interpharm Press, Buffalo Grove, IL; pp. 115-123, 1996.
4. Speizer FE, Doll R, and Heaf P: Observations on recent increase in mortality from asthma. Br Med J. 1968;1:335-339.
5. Speizer FE, Doll R, Heaf P, and Strang LB: Investigation into use of drugs preceding Death from asthma. Br Med J. 1968;1:339-343.
6. Committee on Safety of Drugs: Today's drugs: aerosols in asthma and vaccines. Br Med J. 1967;3:37.
7. Inman WHW, and ADelstein AM: Rise and fall of asthma mortality in England and Wales in relation to use of pressurized aerosols. Lancet. 1969;2(7615):279-285.
8. Fraser PM, Speizer FE, Waters SDM, Doll R, and Mann NM: The circumstances preceding Death from asthma in young people in 1968 to 1969. Br J Dis Chest. 1971; 65:71-84.
9. Esdaile JM, Feinstein AR, and Horwitz RI: A reappraisal of the United Kingdom epiDemic of fatal asthma. Arch Intern Med. 1987;147:543-549.
10. Pearce N, Crane J, Burgess C, Jackson R, and Beasley R: b-Agonists and asthma mortality: Déjà vu. Clin Exp Allergy. 1991;21:401-410.
11. O'Byrne PM, and Ä Delroth E: b-2 Déjà Vu. Chest. 2006; 129:3-5.
12. SaunDers KB: Misuse of inhaled bronchodilator agents. Br Med J. 1965;1:1037-1038.
13. Oprehek J, Gayrard P, Grimaud CH, and Charpin J: Patient error in use of bronchodilator metered aerosols. Br Med J. 1976;1:76.
14. Paterson IC, and Crompton GK: Use of pressurised aerosols by asthmatic patients. Br Med J. 1976;1:76-77.
15. Connolly OK: Methods of using pressurized aerosols. Br Med J. 1975;3:21.
16. Dolovich MB, Ruffin RE, Roberts R, and Newhouse MT: Optimal Delivery of aerosols from metered dose inhalers. Chest. 1981;80(Suppl 6):911-915. (Pubitemid 12222799)
17. Harper TB, and Strunk RC: Techniques of administration of metered dose aerosolized drugs in asthmatic children. Am J Dis Child. 1981;135:218-221. (Pubitemid 11106051)
18. Newhouse MT, and Dolovich MB: Control of asthma by aerosols. N Engl J Med. 1986;315:870-874. (Pubitemid 16028483)
19. Maison GL, inventor; Riker Laboratories, Inc., assignee: Aerosol Dispensing Apparatus. United States patent US 3,001,524. Priority date March 21, 1956; filed March 5, 1957; issued September 26, 1961.
20. Van Sickle WE, inventor: Enclosed Medicament Container and Atomizer. United States patent US 2,890,697. Filed March 15, 1957; issued June 16, 1959.
21. Franklin W, Lowell FC, Michelson AL, and Schiller IW: Aerosolized steroids in bronchial asthma. J Allergy. 1958;29:214-221.
22. Dennis M, and Itkin IH: Effectiveness and complications of aerosol Dexamethasone phosphate in severe asthma. J Allergy. 1964;35:70-76.
23. Freigang B: New method of beclomethasone administration to children unDer 4 years of age. Can Med Assoc J. 1977;117:1308-1309. (Pubitemid 8235512)
24. Childhood asthma and beyond [transcript]. Witness Seminar. The Wellcome Trust Centre for the History of Medicine, London, England; April 4, 2000. LA Reynolds, and EM Tansey, (eds). Wellcome Witnesses to Twentieth Century Medicine, Vol. 11; p. 57, November 2001.
25. Everard ML, Clark AR, and Milner AD: Drug Delivery from holding chambers with attached facemask. Arch Dis Child. 1992;67:580-585.
26. Bisgaard H: A metal aerosol holding chamber Devised for young children with asthma. Eur Respir J. 1995;8:856-860.
27. Amirav I, and Newhouse MT: Review of optimal characteristics of face-masks for valved-holding chambers (VHCs). Pediatr Pulmonol. 2008;43:268-274. (Pubitemid 351374459)
28. Rodriguez-Martinez CE, Sossa M, and Lozano JM: Commercial versus home-maDe spacers in Delivering bronchodilator therapy for acute therapy in children. Cochrane Database Syst Rev. 2008;(2):CD005536.
29. Silson JE, and Meshberg P, inventors; Revlon, Inc., assignee: Actuator for aerosol medication spray dispensers. United States patent US 3,107,670. Filed March 12, 1962; issued October 22, 1963.
30. Gorman JF, inventor: Aerosol inhalation apparatus. United States patent US 3,739,950. Filed April 5, 1971; issued June 19, 1973.
31. Ramis J, inventor: Aerosol apparatus. United States patent US 3,236,458. Filed February 14, 1963; issued February 22, 1966.
32. Hart SS, inventor; Aerosmoke Ltd., assignee: Aerosol Compositions. British patent GB 1,017,032. Priority date December 12, 1963; filed December 8, 1964; issued January 12, 1966.
33. Lewis D: Metered-dose inhalers: actuators old and new. Expert Opin Drug Deliv. 2007;4:235-245. (Pubitemid 46767626)
34. Coady TJ, Davies HJ, and Barnes P: Evaluation of a breath actuated pressurized aerosol. Clin Allergy. 1976; 6:1-6.
35. Kirk WF: In vitro method for comparing clouds produced from inhalation aerosols for efficiency in penetration of the airways. J Pharm Sci. 1972;61:262-265.
36. Sciarra JJ, and Cutie A: Simulated respiratory system for in vitro evaluation of two inhalation Delivery systems using selected steroids. J Pharm Sci. 1978;67:1428-1431. (Pubitemid 9031071)
37. Dolovich M, Ryan G, and Newhouse MT: Aerosol penetration into the lung; influence on airway responses. Chest. 1981;80(Suppl 6):834-836. (Pubitemid 12222774)
38. Morén F: Drug Deposition of pressurized inhalation aerosols. I. Influence of actuator tube Design. Int J Pharm. 1978;1:205-212. In: Morén F: Studies on pressurized aerosols for oral inhalation [doctoral thesis]. Abstracts of Uppsala Dissertations from the Faculty of Pharmacy. University of Uppsala, SweDen; 1980. (Pubitemid 9045932)
39. Newman SP, Morén F, Pavia D, Little F, and Clarke S: Deposition of pressurized suspension aerosols inhaled through extension Devices. Am Rev Respir Dis. 1981;124: 317-320. (Pubitemid 11003999)
40. Dolovich M, Ruffin R, Corr D, and Newhouse MT: Clinical evaluation of a simple Demand inhalation MDI aerosol Delivery Device. Chest. 1983;84;36-41. (Pubitemid 13073618)
41. Corr D, Dolovich M, McCormack D, Ruffin R, Obminski G, and Newhouse M: Design and characteristics of a portable breath-actuated particle size selective medical aerosol inhaler. J Aerosol Sci. 1982;13:1-7. (Pubitemid 12538643)
42. Newman SP, and Newhouse MT: Effect of add-on Devices for aerosol drug Delivery: Deposition studies and clinical aspects. J Aerosol Med. 1996;9:55-70. (Pubitemid 26119469)
43. Barry PW, and O'Callaghan C: The optimum size and shape of spacer Devices for inhalation therapy. J Aerosol Med. 1995;8:303-305.
44. Bisgaard H: Delivery options for inhaled therapy in children unDer the age of 6 years. J Aerosol Med. 1997; 10(S1):37-40.
45. NikanDer K: Challenges and opportunities in respiratory drug Delivery Devices. Expert Opin Drug Deliv. 2010;7: 1235-1238.
46. Mitchell JP, and Nagel MW: Valved holding chambers (VHCs) for use with pressurised metered-dose inhalers (pMDIs): a review of the causes of inconsistent medication Delivery. Prim Care Respir J. 2007;16:207-214. (Pubitemid 47281445)
47. Hess D: Aerosol Delivery Devices in the treatment of asthma. Respir Care. 2008;53:699-723.
48. Lavorini F, and Fontana GA: Targeting drugs to the airways: The role of spacer Devices. Expert Opin Drug Deliv. 2009;6:91-102.
49. Shim C: Spacer disuse. Am J Respir Crit Care Med. 2000;161:A320.
50. Brennan VK, Osman LM, Graham H, Critchlow A, and Everard ML: True Device compliance: The need to consiDer both competence and contriVance. Resp Med. 2005;99:97-102. (Pubitemid 40017391)
51. Mitchell JP, Nagel MW, and Rau JL: Performance of large volume versus small volume holding chambers with chlorofluorocarbon-albuterol and hydrofluoroalkane albuterol sulfate. Respir Care. 1999;44:38-44. (Pubitemid 29131902)
52. Dolovich M: Lung dose, distribution, and clinical response to therapeutic aerosol. Aerosol Sci Technol. 1993; 18:230-240. (Pubitemid 23106640)
53. Janssens HM, Krijgsman A, Verbraak TF, Hop W, De Jongste JC, and TidDens HA: Determining factors of aerosol Deposition for four pMDI-spacer combinations in an infant upper airway moDel. J Aerosol Med. 2004; 17:51-61. (Pubitemid 38520673)
54. Morén F, and Wetterlin K, inventors; Aktiebolaget Draco, assignee: Device for use with medicinal inhalation Devices. United States patent US 4,174,712. Priority date November 9, 1976; filed November 7, 1977; issued November 20, 1979.
55. Lindgren SB, Formgren H, and Morén F: Improved aerosol therapy of asthma: effect of actuator tube size on drug availability. Eur J Respir Dis. 1980;61:56-61. (Pubitemid 10043919)
56. Westwood M, Bourbeau J, Jones PW, Cerulli A, Capkun-Niggli G, and Worthy G: Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review. Respir Res. 2011;12:40.
57. Lankinen T, and Lehtinen M, inventors: Inhalation Device. International patent, WO 8,803,419. Priority date November 6, 1986; filed November 5, 1987; issued May 19, 1988.
58. Green E, Wohl B, and Ocejo-Torres S, inventors: Onepiece, foldable mask and holding chamber for use with aerosolized medications. United States patent US 2009/0032019. Priority date July 30, 2007; filed July 30, 2008; issued February 5, 2009.
59. Sackner M, and Watson H, inventors; Key Pharmaceuticals, Inc., assignee: Drug Delivery method and inhalation Device therefor. United States patent US 4,484,577. Filed May 12, 1982; issued November 27, 1984.
60. Epstein SW, Parsons JE, Corey PN, Worsley GH, and Reilly PA: A comparison of three means of pressurized aerosol inhaler use. Am Rev Respir Dis. 1983;128:253-255. (Pubitemid 13037033)
61. Tobin MJ, Jenouri G, Danta I, Kim C, Watson H, and Sackner MA: Response to bronchodilator drug administration by a new reservoir aerosol Delivery system and a review of other auxiliary Delivery systems. Am Rev Respir Dis. 1982;126:670-675. (Pubitemid 12001419)
62. PeDersen SP: Aerosol treatment of bronchoconstriction in children, with or without a tube spacer. N Engl J Med. 1983;308:1328-1330.
63. Bloomfield P, Crompton GK, and Winsey NJP: A tube spacer to improve inhalation of drugs from pressurised aerosols. Br Med J. 1979;2:1479. (Pubitemid 10162319)
64. Ellul-Micallef R, Morén F, Wetterlin K, and Hidinger KC: Use of a special inhaler attachment in asthmatic children. Thorax. 1980;35:620-623. (Pubitemid 10055769)
65. Hidinger K-G, and Kjellman NM: Childhood asthma. Improved efficacy of pressurized terbutaline aerosol by the use of a 750mL spacer (In manuscript). In: Hidinger K-G: Factors influencing bronchodilation induced by a b2-receptor agonist inhaled from a metered dose inhaler [doctoral thesis]. University of Gö teborg, SweDen; 1983.
66. Cushley MJ, Lewis RA, and Tattersfield AE: Comparison of three techniques of inhalation on the airway response to terbutaline. Thorax. 1983;38:908-913. (Pubitemid 14213231)
67. Gomm SA, Keaney NP, Winsey NJP, and Stretton TB: Effect of an extension tube on the bronchodilator efficacy of terbutaline Delivery from a metered dose inhaler. Thorax. 1980;35:552-556. (Pubitemid 10039565)
68. El-Kassimi FA: ''Aerosol-in-bag'' administration of inhaled bronchodilators. Eur J Respir Dis. 1987;70:234-238.
69. Lee H, and EVans HE: Evaluation of inhalation aids of metered dose inhalers in asthmatic children. Chest. 1987; 91:366-369. (Pubitemid 17027614)
70. Crimi N, Palermo F, Cacopardo B, Vancheri C, Oliveri R, Palermo B, and Mistretta A: Bronchodilator effect of Aerochamber and Inspirease in comparison with metered dose inhaler. Eur J Respir Dis. 1987;71:153-157. (Pubitemid 17155850)
71. Cates CJ, Crilly JA, and Rowe BH: Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006;(2): CD000052.
72. Newman SP, Woodman G, Clarke SW, and Sackner MA: Effect of InspirEase on the Deposition of metered dose aerosols in the human respiratory tract. Chest. 1986;89: 551-556. (Pubitemid 16133720)
73. König P: Spacer Devices used with metered dose inhalers. Breakthrough or gimmick? Chest. 1985;88:276-284. (Pubitemid 15005000)
74. Reilly PA, Levison H, Worsley GH, Mindorff C, and Rivlin J: Add on Devices for Delivery of aerosol drugs in children. In: SW Epstein, (ed). International Workshop on Metered Dose Inhaler. Astra Pharmaceuticals Canada Ltd., Missanga, Ontario, Canada; pp. 134-142, 1984.
75. Toogood JH, Jennings B, Greenway R, and Chuang L: Candidiasis and dysphonia complicating beclomethasone treatment of asthma. J Allergy Clin Immunol. 1980;65: 145-153. (Pubitemid 10131165)
76. Toogood JH, Jennings B, Baskerville J, Lefcoe N, and Newhouse M: Assessment of a Device for reducing oropharyngeal complications during beclomethasone treatment of asthma. Am Rev Respir Dis. 1981; 123:113. (Pubitemid 11069232)
77. Salzman GA, and Pyszczynski DR: Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate Delivered by metered-dose inhaler alone and with Aerochamber. J Allergy Clin Immunol. 1988;81:424-428. (Pubitemid 18060235)
78. British Thoracic Society, Scottish Intercollegiate GuiDelines Network: British guiDeline on the management of asthma. (SIGN 101). SIGN: Edinburgh, 2008, revised May 2012. Available at www.brit-thoracic.org.uk/Portals/0/ GuiDelines/AsthmaGuiDelines/sign101%20Jan%202012 .pdf. Accessed October 15, 2013.
79. Alavaikko S, Jaakkola SM, TjäDerhane L, and Jaakkola JKJ: Asthma and caries: a systematic review and metaanalysis. Am J EpiDemiol. 2011;174:631-641.
80. National Asthma Council Australia: Asthma Management Handbook 2006. Melbourne, 2006. Available at www .nationalasthma.org.au/uploads/handbook/370- amh2006- web-5.pdf. Accessed October 15, 2013.
81. National Asthma Education and Prevention Program, National Institutes of Health: Expert Panel Report 3: GuiDelines for the diagnosis and management of asthma. Bethesda, National Institutes of Health, 2007. Available at www.nhlbi.nih.gov/guiDelines/asthma/asthgdln.pdf. Accessed October 15, 2013.
82. Dolovich M: Spacer Design II: holding chambers and valves. Oral presentation at the International Symposium on Spacer Devices, Drug Information Association, Boston, MA, 1995. Proceedings unpublished. Cited by: Rau JL: The inhalation of drugs: adVantages and problems. Respir Care. 2005;50:367-382.
83. Newman SP, Millar AB, Lennard-Jones TR, Morén F, and Clarke SW: Improvement of pressurised aerosol Deposition with Nebuhaler spacer Device. Thorax. 1984;39:935-941. (Pubitemid 15211833)
84. Newhouse M, inventor: Inhalation Device. European patent 0,009,667. Priority date September 11, 1978; filed September 10, 1979; issued April 16, 1980.
85. Nowacki C, and Brisson AG, inventors; Trutek Research, Inc., assignee: Inhalation valve. United States patent US 4,470,412. Filed March 19, 1982; issued September 11, 1984.
86. Matthys H: Inhalation Delivery of asthma drugs. Lung. 1990;168 Suppl:645-652. (Pubitemid 20217708)
87. Holzner PM, and Muller BW: An in vitro evaluation of various spacer Devices for metered-dose inhalers using the Twin Impinger. Int J Pharm. 1994;106:69-75. (Pubitemid 24110066)
88. Chew NY, and Chan HK: The effect of spacers on the Delivery of metered dose aerosols of nedocromil sodium and disodium cromoglycate. Int J Pharm. 2000;200: 87-92. (Pubitemid 30177253)
89. Mitchell JP, Nagel MW, and Archer A: Mis-timing between actuation of a metered-dose inhaler (pMDI) and inhalation: experience with a valved holding chamber (VHC) compared with a spacer. Respir Care. 1998;43: 869.
90. Foss SA, and Keppel JW: In vitro testing of MDI spacers: a technique for measuring respirable dose output with actuation in-phase or out-of-phase with inhalation. Respir Care. 1999;44:1474-1485. (Pubitemid 30014146)
91. Nowacki C, Brisson AG, and Dela-Cruz E, inventors; TruDell Medical, assignee: Pediatric asthma medication inhaler. United States patent US 4,809,692. Priority date January 31, 1986; filed June 4, 1987; issued March 7, 1989.
92. Conner W, Dolovich M, Frame R, and Newhouse M: Reliable salbutamol administration in 6-to 36-month-old children by means of a metered dose inhaler and aerochamber with mask. Pediatr Pulmonol. 1989;6:263-267.
93. Kraemer R, Frey U, Sommer CW, and Russi E: Shortterm effect of albuterol, Delivered via a new auxiliary Device, in wheezy infants. Am J Respir Crit Care Med. 1991;144:347-351.
94. Clarke JR, Aston H, and Silverman M: Delivery of salbutamol by metered dose inhaler and valved spacer to wheezy infants: effect on bronchial responsiveness. Arch Dis Child. 1993;69:125-129. (Pubitemid 23233005)
95. Newman SP, Woodman G, Morén F, and Clarke SW: Bronchodilator therapy with Nebuhaler: how important is the Delay between firing the dose and inhaling? Br J Dis Chest. 1988;82:262-267.
96. Barry PW, Robertson CF, and O'Callaghan C: Optimum use of a spacer Device. Arch Dis Child. 1993;69:693-694. (Pubitemid 24009918)
97. Barry PW, and O'Callaghan C: Inhalational drug Delivery from seven different spacer Devices. Thorax. 1996;51: 835-840. (Pubitemid 26274087)
98. O'Callaghan C, Lynch J, Cant M, and Robertson C: Improvement in sodium cromoglycate Delivery from a spacer Device by use of an antistatic lining, immediate inhalation, and avoiding multiple actuations of drug. Thorax. 1993;48:603-606. (Pubitemid 23188432)
99. O'Callaghan C, inventor: Improvements in the administration of aerosol compounds. International patent WO 93/11817. Priority date December 16, 1991; filed December 16, 1992; issued June 24, 1993.
100. Barry PW, and O'Callaghan C: Poor output of salbutamol from a spacer Device: effect of spacer static charge and multiple actuations. Thorax. 1994;49:402P.
101. Berg E, and Nilsson H, inventors; Astra Aktiebolag, assignee: Spacer for use with a metered dose inhaler. United States patent US 6,435,176. Priority date January 27, 1994; filed January 23, 1995; issued April 19, 1996.
102. Berg E, Madsen J, and Bisgaard H: In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children. Eur Respir J. 1998;12:472-476. (Pubitemid 28389548)
103. Wildhaber JH, Devadason SG, HayDen MJ, James R, Dufty AP, Fox RA, Summers QA, and Le Souëf PN: Electrostatic charge on a plastic spacer Device influences the Delivery of salbutamol. Eur Respir J. 1996;9:1943-1946. (Pubitemid 26294768)
104. Pierart F, Wildhaber JH, Vrancken I, Devadason SG, and Le Souëf PN: Washing plastic spacers in household Detergent reduces electrostatic charge and greatly improves Delivery. Eur Respir J. 1999;13:673-678. (Pubitemid 29180184)
105. Lulla A, and Xerxes R, inventors; CIPLA Limited, assignee: Spacer Device for inhaler. European patent 1,137,452. Priority date December 9, 1998; filed March 18, 1999; issued October 4, 2001.
106. Mitchell JP, Coppolo DC, and Nagel MW: Electrostatics and inhaled medications: influence on Delivery via pressurized metered-dose inhalers and add-on Devices. Respir Care. 2007;52:283-300.
107. Dubus JC, and Anhøj J: Inhaled steroid Delivery from small volume holding chambers Depends on age, holding chamber, and interface in children. J Aerosol Med. 2004; 17:225-230. (Pubitemid 39299323)
108. Dompeling E, OuDesluys-Murphy AM, Janssens HM, Hop W, Brinkman JG, Sukhai RN, and De Jongste JC: Randomised controlled study of clinical efficacy of spacer therapy in asthma with regard to electrostatic charge. Arch Dis Child. 2001;84:178-182. (Pubitemid 32150340)
109. Janssens HM, Devadason SG, Hop WCJ, Le Souëf PN, De Jongste JC, and TidDens HAWM: Variability of aerosol Delivery via spacer Devices in young asthmatic children in daily life. Eur Respir J. 1999;13:787-791. (Pubitemid 29234779)
110. Kenyon CJ, Thorsson L, Borgstrom L, and Newman SJ: The effects of static charge in spacer Devices on glucocorticosteroid aerosol Deposition in asthmatic patients. Eur Respir J. 1998;11:606-610. (Pubitemid 28194851)
111. Amirav I, Mansour Y, Tiosano T, Chamny S, Chirurg S, Oren S, Grossman Z, Kahana L, Kahan E, and Newhouse MT: Safety of inhaled corticosteroids Delivered by plastic and metal spacers. Arch Dis Child. 2003;88:527-528. (Pubitemid 36648948)
112. Newman SP, Pavia D, Garland N, and Clarke SW: Effects of various inhalation moDes on the Deposition of radioactive pressurized aerosols. Eur J Respir Dis. 1982;63(Suppl 119): 57-65. (Pubitemid 12060356)
113. Roller CM, Zhang G, Troedson RG, Leach CL, Le Souëf PN, and Devadason SG: Spacer inhalation technique and Deposition of extrafine aerosol in asthmatic children. Eur Respir J. 2007;29:299-306. (Pubitemid 46231907)
114. Pool JB, Geenough A, Gleeson JGA, and Price JF: Inhaled bronchodilator treatment via the Nebuhaler in young asthmatic patients. Arch Dis Child. 1988;63:288-291. (Pubitemid 18094667)
115. Schultz A, Le Souëf TJ, Venter A, Zhang G, Devadason SG, and Le Souëf PN: Aerosol inhalation from spacers and valved holding chambers requires few tidal breaths for children. Pediatrics. 2010;126:e1493.
116. Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD, and Le Souëf PN: The influence of age on aerosol Deposition in children with cystic fibrosis. Eur Respir J. 1994;7:2185-2191.
117. Gleeson JGA, and Price J: Nebuhaler technique. Br J Dis Chest. 1988;82:172-174.
118. Agertoft L, and PeDersen S: Influence of spacer Device on drug Delivery to young children with asthma. Arch Dis Child. 1994;71:217-220. (Pubitemid 24298266)
119. Shore SC, and Wenberg EG: Administration of bronchodilator to young children. Br Med J. 1973;2:350.
120. Henry RL, Milner AD, and Davies JG: Simple drug Delivery system for use by young asthmatics. Br Med J. 1983;286:2021. (Pubitemid 13056509)
121. O'Callaghan C, Milner AD, and Swarbrick A: Spacer Device with face mask attachment for giving bronchodilators to infants with asthma. Br Med J. 1989;298: 160-161. (Pubitemid 19039677)
122. Amirav I, and Newhouse MT: Aerosol therapy with valved holding chambers in young children: importance of facemask seal. Pediatrics. 2001;108;389-394.
123. Esposito-Festen JE, Ates B, Van Vliet FJM, Verbraak AFM, De Jongste JC, and TidDens HAWM: Effect of a facemask leak on aerosol Delivery from a pMDI-spacer system. J Aerosol Med. 2004;17:1-6. (Pubitemid 38520667)
124. HayDen JT, Smith N, Woolf DA, Barry PW, and O'Callaghan C: A randomized crossover trial of facemask efficacy. Arch Dis Child. 2004;89:72-73. (Pubitemid 38122018)
125. Smaldone GC, Berg E, and NikanDer K: Variation in pediatric aerosol Delivery: importance of facemask. J Aerosol Med. 2005;18:354-363. (Pubitemid 41395736)
126. Everard ML: Trying to Deliver aerosols to upset children is a thankless task. Arch Dis Child. 2000;82:428. (Pubitemid 30307778)
127. Amirav I, Mansour Y, ManDelberg A, Bar-Ilan I, and Newhouse MT: ReDesigned face mask improves ''real life'' aerosol Delivery for Nebuchamber. Pediatr Pulmonol. 2004;37:172-177. (Pubitemid 38120988)
128. Iles R, Lister P, and Edmunds AT: Crying significantly reduces absorption of aerosolised drug in infants. Arch Dis Child. 1999;81:163-165. (Pubitemid 29349997)
129. Murakami G, Igarashi T, Adachi Y, Matsuno M, Adachi Y, Sawai M, Yoshizumi A, and Okada T: Measurement of bronchial hyperreactivity in infants and preschool children using a new method. Ann Allergy. 1990;64: 383-387. (Pubitemid 20118973)
130. NikanDer K, Berg E, and Smaldone GC: Jet nebulizers versus pressurized metered dose inhalers with valved holding chambers: effects of the facemask on aerosol Delivery. J Aerosol Med. 2007;20(Suppl 1):S46-S58.
131. Esposito-Festen J, Ates B, Van Vliet F, Hop W, and TidDens HAWM: Aerosol Delivery to young children by pMDI-spacer: is facemask Design important? Pediatr Allergy Immunol. 2005;16:348-353. (Pubitemid 40868491)
132. Ritson S, Everard ML, Denyer J, and Prince I: Comparison of carers' ability to use aerosol Delivery systems in young children. Eur Resp J. 2001;18(Suppl 33):494s.
133. Shah SA, Berlinski AB, and Rubin BK: Force-DepenDent static Dead space of face masks used with holding chambers. Respir Care. 2006;51:140-144. (Pubitemid 46888412)
134. Hinkle AJ, inventor: Face mask assembly and pacifier. United States patent US 4,896,666. Filed July 6, 1987; issued January 30, 1990.
135. Newhouse MT, and Amirav I, inventors: Pernasal application of aerosol medication. United States patent US 6,470,882 B1. Filed September 29, 1997; issued October 29, 2002.
136. Amirav I, LuDer A, Chleechel A, Newhouse M, and Gorenberg M: Lung aerosol Deposition in suckling infants. Arch Dis Child. 2012;97:497-501.
137. Xu Z, Hsu W, Von Hollen D, Viswanath A, NikanDer K, and Dalby R: Methodology for the in vitro evaluation of the Delivery efficiency from valved holding chambers with facemasks. J Aerosol Med Pulm Drug Deliv. 2014;27: S-44-S-54.
138. Devadason SG: Recent adVances in aerosol therapy for children with asthma. J Aerosol Med. 2006;19:61-66.
139. Zar HJ, Weinberg EG, Binns HJ, Gallie F, and Mann MD: Lung Deposition of aerosol-A comparison of different spacers. Arch Dis Child. 2000;82:495-498. (Pubitemid 30367063)
140. Ditcham W, Murdzoska J, Zhang G, Roller C, Von Hollen D, NikanDer K, and Devadason S: Lung Deposition of 99mTc-radiolabeled albuterol Delivered through a pressurized metered dose inhaler with spacer with facemask or mouthpiece in children with asthma. J Aerosol Med Pulm Drug Deliv. 2014;27:S-63-S-75.
141. Laube LS, Janssens HM, De Jongh FHC, Devadason SG, Dhand R, Diot P, Everard ML, Horvath I, Navalesi P, Voshaar T, and Chrystyn H: What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37:1308-1331.
142. Rau JL: Determinants of patient adherence to an aerosol regimen. Respir Care. 2005;50:1346-1356. (Pubitemid 46173321)
143. Everard ML: Role of inhaler competence and contriVance in ''difficult asthma,'' Paediatr Respir Rev. 2003;4:135-142. (Pubitemid 36665482)
144. Self TH, Brooks JB, Lieberman P, and Ryan MR: The value of Demonstration and role of the pharmacist in teaching the correct use of pressurized bronchodilators. Can Med Assoc J. 1983;128:129-131. (Pubitemid 13175245)
145. Kelling JS, Strohl KP, Smith RL, and Altose MD: Physician knowledge in the use of canister nebulizers. Chest. 1983;83:612-614. (Pubitemid 13109735)
146. Hanania N, Wittman R, Kesten S, and Chapman KR: Medical personnel's knowledge of and ability to use inhaling Devices. Metered-dose inhalers, spacing chambers, and breath-actuated dry powDer inhalers. Chest. 1994;105: 111-116.
147. Frew AJ, and MacFarlane JT: Poor inhaler technique may be perpetuated by clinical staff. Practitioner. 1984; 228:883.
148. NikanDer K, Turpeinen M, Pelkonen AS, Bengtsson T, Selroos O, and Haahtela T: True adherence with the Turbuhaler in young children with asthma. Arch Dis Child. 2011;96:168-173.
149. NikanDer K, ArheDen L, Denyer J, and Cobos N: Parents' adherence with nebulizer treatment of their children when using an Adaptive Aerosol Delivery (AAD) System. J Aerosol Med. 2003;16:273-281. (Pubitemid 37169638)
150. Lee HS, and EVans HE: Aerosol bag for administration of bronchodilators to young asthmatic children. Pediatrics. 1984;73:230-232. (Pubitemid 14188509)
151. Collingwood R, and Maitland R, inventors: Aerosol inhalation Device. European Patent Specification 0,089,070. Priority date February 23, 1982; filed February 8, 1983; issued November 20, 1986.
152. Newman SP, Clark AR, Talaee N, and Clarke SW: Pressurised aerosol Deposition in the human lung with and without an ''open'' spacer Device. Thorax. 1989;44:706-710. (Pubitemid 19243266)
153. Watt PM, Clements B, Devadason SG, and Chaney GM: Funhaler spacer: improving adherence without compromising Delivery. Arch Dis Child. 2003;88:579-581. (Pubitemid 36783035)
154. Burgess SW, Sly PD, Cooper DM, and Devadason SG: Novel spacer Device does not improve adherence in childhood asthma. Pediatr Pulmonol. 2007;42:736-739. (Pubitemid 47242872)
155. Haekkinen T, inventor: Flow indicator for respiration treatment apparatuses. International patent, WO 8802267. Priority date September 23, 1986; filed September 22, 1987; issued April 7, 1988.
156. Nowacki C, Brisson AG, and Dela-Cruz E, inventors; TruDell Medical, assignee: Pediatric asthmatic inhaler. United States patent US 4,832,015. Filed May 19, 1988; issued May 23, 1989.
157. Larson DA, and Danowki TJ, inventors; Healthscan Products, Inc., assignee: Metered dose inhalation unit with sliDe means. United States patent US 5,040,527. Filed December 18, 1990; issued August 20, 1991.
158. Scheuch G, and Sommerer K, inventors; GSF-Forschungszentrum, assignee: Device for controlled inhalational administration of controlled-dosage drugs into the lungs. United States patent US 6,401,710. Filed June 1, 1999; issued June 11, 2002. issued June 11, 2002
159. Denyer J, and NikanDer K, inventors; Medic-Aid Limited, assignee: Dosimetric spacer for calculating dosage administered. United States patent US 5,842,468. Priority date October 27, 1994; filed October 27, 1995; issued December 1, 1998.
160. Smith NJ, and O'Callaghan CO: Development of an MDI spacer data logger. In: Drug Delivery to the Lungs 10. The Aerosol Society, Portishead, Bristol, UK; pp. 127-130, 1999.
161. O'Callaghan C, Everard M, Smith N, and Denyer J: Feedback during treatment using a pressurized metered dose inhaler with valved holding chamber results in improved inhaler technique and adherence to therapy of paediatric patients with asthma. Eur Respir J. 2008; 32(Suppl 52):696s.
162. Apter AJ, Tor M, and Feldman HI: Testing the reliability of old and new features of a new electronic monitor for metered dose inhalers. Ann Allergy Asthma Immunol. 2001;86:421-424. (Pubitemid 32332321)
163. NikanDer K, Pearce L, Smith NJ, and Pritchard JN: The impact of electronic monitors on patients' adherence to inhaled medications. In: Proceedings of Respiratory Drug Delivery 2012; May 13-17; Arizona. Virginia Commonwealth University, Virginia; pp. 679-684, 2012.
164. Watt PM, inventor; Infamed Ltd., assignee: Drug Delivery Device and methods therefor. United States patent US 6,578,571. Priority date April 20, 1998; filed April 19, 1999; issued June 17, 2003.
165. Hedrick ND, Hughes AM, McKeehan PB, Thiel CG, inventors; Dart Industries Inc., assignee: Inhalation-responsive aerosol dispenser. United States patent US 3,598,294. Filed November 13, 1969; issued August 10, 1971.
166. Cleaver DF, inventor; Pfizer Limited., assignee: Medicament administering apparatus. British patent 975,754. Priority date May 15, 1961; filed August 2, 1962; issued November 18, 1964.
167. Pritchard J, inventor; United Kingdom Atomic Energy Authority, assignee: Aerosol dispenser with flow diverter. United States patent US 5,048,729. Priority date August 3, 1989; filed July 10, 1990; issued September 17, 1991.
168. Larson D, and Danowski, inventors; Healthscan Products, Inc., assignee: Medication inhaler mixer. United States patent US 5,297,543. Filed June 24, 1992; issued March 29, 1994.
169. Lieberman EA, and Von Hollen D, inventors: Aerosol Delivery mask. United States patent US 2008/0178886 A1. Priority date January 30, 2007; filed January 25, 2008; issued July 31, 2008.