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Basset_edit.qxp 1/8/08 10:53 Page 10 Asthma Inhaler Technology—Improving Prevention and Reversal of Bronchospasm a report by C l i f f o rd W B a s s e t t , M D , FA A A A I , FAC A A I 1 and R a f a e l E d e l a H o z , M D , M P H 2 1. Medical Director, Allergy and Asthma Care of New York, Assistant Clinical Professor of Medicine and Otolaryngology, The Long Island College Hospital, and Faculty, New York University School of Medicine; 2. Assistant Professor, Department of Community and Preventive Medicine, Mount Sinai School of Medicine Bronchospasm is most commonly the result of asthma and chronic obstructive pulmonary disease (COPD). However, the disease can also be caused by anaphylactic shock or other chronic lung diseases. Asthma affects 16.1 million adults and an estimated 6.8 million children in the US1,2 and is clearly a major public health problem. Asthma-related direct and indirect medical costs exceed $12 billion.3 COPD is the fourth leading cause of death and affects an estimated one in 20 adults in the US.1,4 Thus, improving care through better physician and patient education, adding to the understanding of the diseases, and the development of new technologies will help to reduce the burden of asthma and COPD. Current Treatment Options Rescue therapy is generally first-line treatment for relieving acute bronchospasm associated with asthma and COPD. Rescue therapies are usually fast-response, short-acting medications administered through the inhalation route to maximize therapeutic effect and limit the number of adverse events.5 The aim of inhalation therapy is to reverse and minimize symptoms by delivering low doses of medication directly to the smooth muscle in the airways. There is a broad range of inhaler devices available, but many patients still use inhalers suboptimally. Thus, it is important that the device chosen for the patient can be used correctly and beneficially. Clifford W Bassett, MD, FACAAI, FAAAAI, is Medical Director of Allergy and Asthma Care of New York, an Attending in Allergy and Immunology at The Long Island College Hospital in Brooklyn, on the Faculty of New York University School of Medicine, and a Clinical Assistant Professor of Medicine and Otolaryngology at the State University of New York-Health Sciences Center at Brooklyn. He is a diplomate of the American Board of Allergy and Immunology and a Fellow of the American College and the American Academy of Allergy. He is Vice Chair of the Public Education committee of the American Academy of Allergy, Asthma and Immunology (AAAAI) and served on the National Anaphylaxis Task Force for the AAAAI. As an investigator in clinical trials, Dr Bassett has published papers in the Journal of Allergy and Clinical Immunology, Annals of Allergy, Pediatrics, and Chest. He is an expert on seasonal/indoor allergies, allergic skin disorders, asthma, pollen counting, exercise asthma, pet allergies, food allergies, and allergic emergencies. E: [email protected] Rafael E de la Hoz, MD, MPH, is an Assistant Professor in the Department of Community and Preventive Medicine at Mount Sinai School of Medicine in New York, and also Assistant Medical Director of the Mount Sinai World Trade Center Monitoring and Treatment Program. His primary clinical and research interests are pulmonary and occupational medicine. 10 Currently, there are two main drug classes of inhaled medication: bronchodilators and corticosteroids. Bronchodilators include short- and long-acting beta agonists and antimuscarinic drugs, which all act to reduce symptoms of bronchoconstriction. Corticosteroids are administered to reduce inflammation of the airways and to prevent the symptoms of asthma and COPD. For the purpose of this article, the focus will be on the use and delivery of short-acting beta agonists as a rescue medication. Short-acting Beta Agonists Several types of short-acting beta agonists (SABAs) are prescribed to patients with COPD and asthma, including albuterol, levalbuterol, metaproterenol sulphate, and pirbuterol acetate. The SABAs albuterol, levalbuterol, and pirbuterol acetate remain the cornerstone of rescue therapy for the prevention of exercise-induced bronchospasm (EIB).5 It is important to note that SABAs are not recommended for regularly scheduled, daily, long-term use.5 It is not within the scope of this article to provide an in-depth review of the current clinical evidence for SABAs in the treatment of acute symptoms, but a number of extensive reviews and guidelines have been published.5–11 In general, the selective SABAs albuterol, levalbuterol, and pirbuterol are comparable in efficacy on a per-puff basis. These SABAs also have few systemic and cardiovascular adverse effects, although care should be taken in patients with pre-existing cardiovascular disease, including ischemic heart disease, hypertension, or cardiac arrhythmias.5 Albuterol is a widely prescribed SABA. Several studies have shown that levalbuterol is safe and efficacious, and has similar effects on forced expiratory volume in one second (FEV1) to albuterol.12–15 Pirbuterol has also been used successfully as a drug taken when needed.16 Inhalation Devices There are a wide variety of inhalation devices available to patients. The most universally used and cheapest inhalation device is the conventional pressurized metered-dose inhaler (pMDI). However, evidence suggests that up to 75% of patients use traditional pMDIs incorrectly and that even after re-training roughly 50% revert to the wrong technique.17–19 Incorrect use leads to the greatest single limitation of the pMDI: inconsistent dosing. For ideal drug delivery, the MDI canister should be depressed at early to mid-inhalation. Unfortunately, hand–breath asynchrony, the most common form of suboptimal inhaler technique, has been noted as a particular problem in elderly patients and children.20,21 Incorrect use of pMDIs can also result from excessive inspiratory flow velocity and nose breathing. © TOUCH BRIEFINGS 2008 Graceway_ad.qxp 29/7/08 12:41 Page 11 For the prevention and reversal of bronchospasm THE BENEFITS OF A SPACER ...WITHOUT THE SPACER 1 The only rescue inhaler that eliminates the need to coordinate pressing with breathing (pirbuterol acetate inhalation aerosol) AVAILABLE BEYOND 2008 Just breathe in. Not subject to albuterol CFC deadline MAXAIR AUTOHALER is indicated for prevention and reversal of bronchospasm in patients aged 12 years and older with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or corticosteroid therapy. IMPORTANT SAFETY INFORMATION : MAXAIR AUTOHALER is contraindicated in patients with a history of hypersensitivity to pirbuterol or any of its ingredients. MAXAIR AUTOHALER, like other inhaled betaadrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and/or other symptoms. Although such effects are uncommon after administration of MAXAIR AUTOHALER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, MAXAIR AUTOHALER, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. MAXAIR AUTOHALER can produce paradoxical bronchospasm, which can be life threatening. If paradoxical bronchospasm occurs, MAXAIR AUTOHALER should be discontinued immediately and alternative therapy instituted.It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, eg, corticosteroids. The following adverse reactions were reported more frequently than 1 in 100 patients: nervousness (6.9%), tremor (6.0%), headache (2.0%), dizziness (1.2%), palpitations (1.7%), tachycardia (1.2%), cough (1.2%), and nausea (1.7%). Please see accompanying brief summary of full Prescribing Information. Reference: 1. Grossman J, Tinkelman DG, Ziment I. Pirbuterol acetate administered via breath-actuated inhaler compared with albuterol administered via MDI with a spacing device. Medscape General Medicine. 1999;1(2). http://www.medscape.com/viewarticle/408722. Accessed February 8, 2008. www.maxairautohaler.com ©2008 Graceway Pharmaceuticals, LLC, Bristol, TN MAX030830 Graceway_ad.qxp 29/7/08 12:42 Page 12 MAXAIR® AUTOHALER® (pirbuterol acetate inhalation aerosol) For Oral Inhalation Only Brief Summary of Prescribing Information See Package Insert for Full Prescribing Information INDICATIONS AND USAGE MAXAIR AUTOHALER is indicated for the prevention and reversal of bronchospasm in patients 12 years of age and older with reversible bronchospasm including asthma. It may be used with or without concurrent theophylline and/or corticosteroid therapy. CONTRAINDICATIONS MAXAIR AUTOHALER is contraindicated in patients with a history of hypersensitivity to pirbuterol or any of its ingredients. WARNINGS Cardiovascular: MAXAIR AUTOHALER, like other inhaled beta adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure and/or symptoms. Although such effects are uncommon after administration of MAXAIR AUTOHALER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, MAXAIR AUTOHALER, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Paradoxical Bronchospasm: MAXAIR AUTOHALER can produce paradoxical bronchospasm, which can be life threatening. If paradoxical bronchospasm occurs, MAXAIR AUTOHALER should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. Use of Anti-Inflammatory Agents: The use of beta adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding antiinflammatory agents, e.g., corticosteroids. Deterioration of Asthma: Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of MAXAIR AUTOHALER than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. PRECAUTIONS General: Since pirbuterol is a sympathomimetic amine, it should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, or cardiac arrhythmias, in patients with hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines or who have convulsive disorders. Significant changes in systolic and diastolic blood pressure could be expected to occur in some patients after use of any beta adrenergic aerosol bronchodilator. Beta adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. Information for Patients: The action of MAXAIR AUTOHALER should last up to five hours or longer. MAXAIR AUTOHALER should not be used more frequently than recommended. Do not increase the dose or frequency of MAXAIR AUTOHALER without consulting your physician. If you find that treatment with MAXAIR AUTOHALER becomes less effective for symptomatic relief, or your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using MAXAIR AUTOHALER, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor or nervousness. If you are pregnant or nursing, contact your physician about use of MAXAIR AUTOHALER. Effective and safe use includes an understanding of the way the medication should be administered. As with all aerosol medications, it is recommended to prime (test) MAXAIR AUTOHALER before using for the first time. MAXAIR AUTOHALER should also be primed if it has not been used in 48 hours. As described in the priming procedure, use the test fire slide to release two priming sprays into the air away from yourself and other people. (See “Patient’s Instructions For Use” portion of this package insert.) The MAXAIR AUTOHALER actuator should not be used with any other inhalation aerosol canister. In addition, canisters for use with MAXAIR AUTOHALER should not be utilized with any other actuator. Drug Interactions: Other short-acting beta adrenergic aerosol bronchodilators should not be used concomitantly with MAXAIR AUTOHALER because they may have additive effects. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Pirbuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of pirbuterol on the vascular system may be potentiated. Beta Blockers: Beta adrenergic receptor blocking agents not only block the pulmonary effect of betaagonists, such as MAXAIR AUTOHALER, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta blockers could be considered, although they should be administered with caution. Diuretics: The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium sparing diuretics. Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year study in Sprague-Dawley rats, pirbuterol hydrochloride administered at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) showed no evidence of carcinogenicity. In an 18-month study in mice at dietary doses of 1.0, 3.0, and 10 mg/kg (approximately 2, 5, and 15 times the maximum recommended daily inhalation dose for adults and children on a mg/m2 basis) no evidence of tumorigenicity was seen. Reproduction studies in rats administered pirbuterol hydrochloride at oral doses of 1, 3, and 10 mg/kg (approximately 3, 10, and 35 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) revealed no evidence of impaired fertility. Pirbuterol dihydrochloride showed no evidence of mutagenicity in in vitro assays and hostmediated microbial (Ames) assays for point mutations and in vivo tests for somatic or germ cell effects following acute and subchronic treatment in mice (cytogenicity assays). Teratogenic Effects – Pregnancy Category C: Pirbuterol was not teratogenic in rats administered oral doses of 30, 100, and 300 mg/kg (approximately 100, 340, and 1000 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Pirbuterol was not teratogenic in rabbits administered oral doses of 30 and 100 mg/kg (approximately 200 and 680 times the maximum recommended inhalation dose for adults on a mg/m2 basis). However, pirbuterol at an oral dose of 300 mg/kg (approximately 2000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis) caused abortions and fetal death. There are no adequate and well-controlled studies in pregnant women. Pirbuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of MAXAIR AUTOHALER for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Nursing Mothers: It is not known whether pirbuterol is excreted in human milk. Therefore, MAXAIR AUTOHALER should be used during nursing only if the potential benefit justifies the possible risk to the newborn. Pediatric Use: MAXAIR AUTOHALER is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness. ADVERSE REACTIONS The following rates of adverse reactions to pirbuterol are based on single- and multiple-dose clinical trials involving 761 patients, 400 of whom received multiple doses (mean duration of treatment was 2.5 months and maximum was 19 months). The following were the adverse reactions reported more frequently than 1 in 100 patients: CNS: nervousness (6.9%), tremor (6.0%), headache (2.0%), dizziness (1.2%). Cardiovascular: palpitations (1.7%), tachycardia (1.2%). Respiratory: cough (1.2%). Gastrointestinal: nausea (1.7%). The following adverse reactions occurred less frequently than 1 in 100 patients and there may be a causal relationship with pirbuterol: CNS: depression, anxiety, confusion, insomnia, weakness, hyperkinesia, syncope. Cardiovascular: hypotension, skipped beats, chest pain. Gastrointestinal: dry mouth, glossitis, abdominal pain/cramps, anorexia, diarrhea, stomatitis, nausea and vomiting. Ear, Nose and Throat: smell/taste changes, sore throat. Dermatological: rash, pruritus. Other: numbness in extremities, alopecia, bruising, fatigue, edema, weight gain, flushing. Other adverse reactions were reported with a frequency of less than 1 in 100 patients but a causal relationship between pirbuterol and the reaction could not be determined: migraine, productive cough, wheezing, and dermatitis. The following rates of adverse reactions during three-month controlled clinical trials involving 310 patients are noted. The table does not include mild reactions. PERCENT OF PATIENTS WITH MODERATE TO SEVERE ADVERSE REACTIONS Reaction Pirbuterol Metaproterenol N=157 N=153 Central Nervous System tremors 1.3% 3.3% nervousness 4.5% 2.6% headache 1.3% 2.0% weakness .0% 1.3% drowsiness .0% 0.7% dizziness 0.6% .0% Cardiovascular palpitations 1.3% 1.3% tachycardia 1.3% 2.0% Respiratory chest pain/tightness 1.3% .0% cough .0% 0.7% Gastrointestinal nausea 1.3% 2.0% diarrhea 1.3% 0.7% dry mouth 1.3% 1.3% vomiting .0% 0.7% Dermatological skin reaction .0% 0.7% rash .0% 1.3% Other bruising 0.6% .0% smell/taste change 0.6% .0% backache .0% 0.7% fatigue .0% 0.7% hoarseness .0% 0.7% nasal congestion .0% 0.7% Electrocardiograms: Electrocardiograms, obtained during a randomized, double-blind, cross-over study in 57 patients, showed no observations or findings considered clinically significant, or related to drug administration. Most electrocardiographic observations, obtained during a randomized, double-blind, cross-over study in 40 patients, were judged not clinically significant or related to drug administration. One patient was noted to have some changes on the one hour postdose electrocardiogram consisting of ST and T wave abnormality suggesting possible inferior ischemia. This abnormality was not observed on the predose or the six hours postdose ECG. A treadmill was subsequently performed and all the findings were normal. OVERDOSAGE The expected symptoms with overdosage are those of excessive beta-stimulation and/or any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. As with all sympathomimetic aerosol medication, cardiac arrest and even death may be associated with abuse of MAXAIR AUTOHALER. Treatment consists of discontinuation of pirbuterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage. The oral median lethal dose of pirbuterol dihydrochloride in mice and rats is greater than 2000 mg/kg (approximately 3400 and 6800 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Note: The indented statement below is required by the Federal government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC’s). WARNING: Contains trichloromonofluoromethane and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere. A notice similar to the above WARNING has been placed in the “Patient’s Instructions For Use” portion of this package insert under the Environmental Protection Agency’s (EPA’s) regulations. The patient’s warning states that the patient should consult his or her physician if there are questions about alternatives. This is only a brief summary of important information regarding MAXAIR AUTOHALER. For more information please visit www.maxairautohaler.com or call 1-800-328-0255. Rx only Manufactured by Distributed by 3M Pharmaceuticals Graceway™ Pharmaceuticals, LLC Northridge, CA 91324 Bristol, TN 37620 654800 US19 Rev0407-1 Basset_edit.qxp 1/8/08 10:53 Page 13 Inhaler Technology—Improving Prevention and Reversal of Bronchospasm Inhalation therapy has recently moved away from the use of chlorofluorocarbon (CFC)-propelled devices and toward HFA inhalers due to CFC gases causing ozone depletion. Newer CFC-free devices are now being replaced with inhalers that use hydrofluoroalkanes (HFAs) as a propellant. All DPIs are already CFC-free. Spacer/Holding Chamber Devices To overcome the administration problem, spacers have been developed that avoid the need to co-ordinate inhaler actuation and inhalation.22 Spacers/holding chambers are simple tube extensions to the actuator mouthpiece, one-way valved holding chambers (VHCs), or reversed-flow devices. The rationale for spacers is that by increasing the distance between the point of aerosol generation and the patient’s mouth, the oropharyngeal deposition is reduced, thus increasing lung deposition.23 Current guidelines recommend VHCs as a viable alternative to nebulizers for delivering large bronchodilator doses to patients with severe acute asthma or COPD.24 A Cochrane review showed that the relative risk for hospitalization in children over two years of age and adults with acute asthma was not significantly different whether they received beta-agonists through a nebulizer or pMDI with spacer/VHC.25 While spacers have proven clinical benefits, they may not be ideal for all patients, particularly those with active lifestyles, because they are cumbersome and may cause embarrassment. Dry Powder Inhalers Dry powder inhalers (DPIs) are activated through inhalation by the patient. The asthma medication comes in a dry powder formulation inside a small capsule that is placed inside the inhaler. DPIs do not require a propellant, but 1. Pleis JR, Lethbridge-Çejku M, Summary health statistics for US adults: National Health Interview Survey, 2006. National Center for Health Statistics, Vital Health Stat, 2007:10(235). 2. Bloom B, Cohen RA, Summary Health Statistics for US Children, National Health Interview Survey, 2006. National Center for Health Statistics, Vital Health Stat, 2007;10(234). 3. Weiss KB, Sullivan SD, The health economics of asthma and rhinitis: assessing the economic impact, J Allergy Clin Immunol, 2001;107:3–8. 4. Minino AM, Heron MP, Smith BL, Deaths: Preliminary Data for 2004, National Vital Statistics Reports, 2006;54. 5. National Asthma Education and Prevention Program (NAEPP), Expert panel report 3: guidelines for the diagnosis and management of asthma, National Heart, Lung, and Blood Institute, Bethesda (MD), 2007:213–76. 6. Walters EH, Walters J, Gibson P, et al., Inhaled short acting beta2-agonist use in chronic asthma: regular versus as needed treatment, Cochrane Database Syst Rev, 2003;1:CD001285. 7. Salpeter SR, Ormiston TM, Salpeter EE, Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma, Ann Intern Med, 2004;140(10):802–13. 8. Qaseem A, Snow V, Shekelle P, et al., Clinical Efficacy Assessment Subcommittee of the American College of Physicians, Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians, Ann Intern Med, 2007;147(9):633–8. 9. Rabe KF, Hurd S, Anzueto A, et al., Global Initiative for Chronic Obstructive Lung Disease, Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary, Am J Respir Crit Care Med, 2007;176(6):532–55. 10. American Thoracic Society/European Respiratory Society Task US RESPIRATORY DISEASE 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. do require a relatively rapid rate of inhalation in order to provide the energy necessary for drug aerosolization.24 This type of device is currently used with long-acting beta agonists (LABAs) and anticholinergics (tiotropium), or inhaled corticosteroids (ICS). Breath-actuated Inhalers Like DPIs, breath-activated pMDIs overcome the problem of co-ordinating inhalation and actuation. Inhalation at the mouthpiece activates the release of the dose.26 As the patient inhales through the mouthpiece of the device, a triggering mechanism releases the drug. The device has a pressurized propellant system that is actuated with an inspiratory flow of 30l/minute.27 Studies have demonstrated that the breath-actuated device can be used successfully in patients with severe airflow limitations28 and is simple to use, particularly in elderly treatment-naïve patients.29–31 The most common reason for unsuccessful use was an inadequate inspiratory volume to activate the canister due to participants halting their inspiration early or not beginning their inspiration at functional capacity or residual volume.29 Summary and Conclusions SABAs remain the gold standard for treating acute bronchospasm and for the prevention of EIB. However, the suboptimal use of conventional pMDIs remains a problem, and can result in inconsistent dosing. A major limitation associated with pMDIs is patients being unable to co-ordinate inspiration with pressing the button to release medication. Assessing a patient’s ability to handle a pMDI, properly prepare and actuate the pMDI, and co-ordinate actuation, and providing suitable patient training are essential. ■ Force, Standards for the Diagnosis and Management of Patients with COPD, Version 1.2, New York: American Thoracic Society, 2004, 2005. Available at: www.thoracic.org/go/copd Op’t Holt TB, Inhaled beta agonists, Respir Care, 2007;52(7): 820–32. Carl JC, Myers TR, Kirchner HL, et al., Comparison of racemic albuterol and levalbuterol for treatment of acute asthma, J Pediatr, 2003;143(6):731–6. Skoner DP, Greos LS, Kim KT, et al., Evaluation of the safety and efficacy of levalbuterol in two to five-year-old patients with asthma, Pediatr Pulmonol, 2005;40(6):477–86. Milgrom H, Skoner DP, Bensch G, et al., Levalbuterol Pediatric Study Group, Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol, J Allergy Clin Immunol, 2001;108(6):938–45. Handley DA, Tinkelman D, Noonan M, et al., Dose-response evaluation of levalbuterol versus racemicalbuterol in patients with asthma, J Asthma, 2000;37(4):319–27. Tinkelman DG, Brandon ML, Grieco M, et al., Comparison of safety and efficacy of inhaled pirbuterol with metaproterenol, Ann Allergy, 1990;64:202–6. Epstein SW, Manning CP, Ashley MJ, et al., Survey of the clinical use of pressurized aerosol inhalers, Can Med Assoc J, 1979;120(7):813–16. Bailey WC, Richards JM, Brooks CM, et al., A randomized clinical trial to improve self-management practices of adults with asthma, Arch Intern Med, 1990;150:1664–8. Goodman DE, Israel E, Rosenberg M, et al., The influence of age, diagnosis, and gender on proper use of metered-dose inhalers, Am J Respir Crit Care Med, 1994;150:1256–61. Todd MA, Baskett JJ, Richmond DE, Inhaler devices and the elderly, N Z Med J, 1990;103:43–6. 21. Kamps AW, Brand PL, Roorda RJ, Determinants of correct inhalation technique in children attending a hospital-based asthma clinic, Acta Paediatr, 2002;91(2):159–63. 22. Currie GP, Douglas JG, Oxygen and inhalers, BMJ, 2006;333: 34–6. 23. Newman SP, Spacer devices for metered dose inhalers, Clin Pharmacokinetics, 2004;43(6):349–60. 24. Dolovich MB, Ahrens RC, Hess DR, et al., Device selection and outcomes of aerosol therapy: evidence-based guidelines, Chest, 2005;127(1):335–71. 25. Cates CJ, Crilly JA, Rowe BH, Holding chambers (spacers) versus nebulizers for beta-agonist treatment of acute asthma, Cochrane Database Syst Rev, 2006;(2):CD000052. 26. O’Callaghan C, Wright P, The metered-dose inhaler. In: Bisgaard H, O’Callaghan C, Smaldone GC (eds), Drug Delivery to the Lung, New York: Marcel Dekker, 2002;337–70. 27. Marshik PL, Larsen JS, Leach CL, et al., A novel breath actuated device (Autohaler™) consistently actuates during the early phase of inspiration, J Aerosol Med, 1995;8:187–95. 28. Fergusson RJ, Lenney J, McHardy GJ, et al., The use of a new beath-actuated inhaler by patients with severe airflow obstruction, Eur Respir J, 1991;4(2):172–4. 29. Chapman KR, Love L, Brubaker H, A comparison of breath-actuated and conventional metered-dose inhaler inhalation techniques in elderly subjects, Chest, 1993;104(5):1332–7. 30. Diggory P, Bailey R, Vallon A, Effectiveness of inhaled bronchodilator delivery systems for elderly patients, Age Aging, 1991;20:379–82. 31. Arthur V, Pushkin S, Emery P, Inhaler use in patients with arthritic hands, Clin Trials Meta-analysis, 1992;28:23–8. 13