Technology Review

Metered Dose Inhaler Therapy for Asthma, Bronchitis, and Emphysema James M. Hofford, MD Wilmington, Delaware

This review addresses die use o f the metered dose in­ creasing the recommended dosage of medication for haler (M DI) to administer aerosol therapy in the treat­ those receiving /8-adrenergic, anticholinergic, and glu­ ment o f asthma, bronchitis, and emphysema. Studies cocorticoid drugs. A consensus now recommends that have shown that physicians’ prescribing patterns for aerosol glucocorticoids be considered the primary use o f the inhaler have been inconsistent with optimal method of therapy for asthma; however, the effective­ therapy. Furthermore, the medical literature suggests ness of glucocorticoids in the treatment of bronchitis that the metered dose inhaler should replace the jet and emphysema has not been determined. Although nebulizer in hospital and outpatient settings as a more available data do not prove that drugs used in the efficient and cost-effective treatment method. treatment o f asthma increase mortality, further study is All classes o f aerosol drugs are now available for ad­ recommended in view of the potential toxicity of these ministration by the M DI. Reports suggest that patients drugs. whose conditions do not respond to treatment admin­ Key words. Administration, inhalation; nebulizers and istered by the M D I may improve following instruction vaporizers; asthma; bronchitis; lung diseases, obstruc­ in the proper method o f using the inhaler or by in­ tive. / Fam Pract 1992; 34:485^192.

Asthma and chronic obstructive pulmonary disease Therapeutic Aerosols (CO PD), eg, bronchitis and emphysema, afflict 24 mil­ All classes o f therapeutic aerosol drugs are currently lion Americans; these patients spend more than $1 bil­ available for administration by the M DI. An understand­ lion annually on treatment.1 These chronic pulmonary ing of their pharmacological actions is prerequisite to diseases continue to pose a serious problem to the health improving the therapy o f patients with asthma and care system in the United States, despite medical research that has improved our understanding of their pathophys­ COPD. iology and led to the development o f an extensive array o f effective medications.2-4 A survey o f physician prescribing patterns demon­ /3-Adrenenjic Drujjs strates that aerosol drugs represent the most commonly /3-Adrenergic drugs stimulate /3-receptors in the airway, used treatment o f obstructive lung diseases in hospitals.5 resulting in smooth muscle relaxation and bronchodila- Increased awareness of the potential benefits that can be tion, enhancement of mucociliary clearance, and attenu­ derived by more effective use of the metered dose inhaler ation of prostaglandin-induced bronchospasm. lhc mo­ (M DI) to administer aerosol therapy in both hospital and lecular mechanisms by which relaxation is induced have outpatient settings has the potential to simultaneously been well studied: an increase in cyclic AMP activates decrease the cost o f medical care and reduce the morbid­ specific kinases, leading to a decrease in intercellular ity and mortality o f these diseases. calcium ion concentration and an inhibition o f myosin phosphorylation.6’7 Effective doses o f these drugs result in very low

Submitted, revised, November 21, 1991. blood levels (billionths of a gram), and, consequently, the chance o f developing systemic side effects is remote. From Jefferson Medical College. Thomas Jefferson University, Philadelphia. Pennsylva­ nia, and the Medical Center o f Delaware, Wilmington. Requests for reprints should be Potential side effects occurring at higher dosage levels arc- addressed to Jam es M. Hofford, MD, 211 Oakrnod Road, Fairfax, Wilmington, DE sympathetic stimulation, decreases in arterial oxygen ten- 19803.

1992 Appleton & Lange ISSN 1,094 3509 485 it Journal o f Family Practice, Vol. 34, No. 4, 1992 MDI Therapy for Asthma Hofford

I able 1. Therapeutic Agents Available in Metered P a t i e n t S e l e c t i o n Dose Inhaler Pulmonary- function studies performed before and after Duration Average bronchodilator administration are helpful in selecting Peak of Cost per Pregnane)’ Effect* Effect* Inhaler** Category responsive patients. Evidence o f a 12% to 25% improve­ Drug (minutes) (hours) ($) (EDA) ment in forced expiratory volume in 1 second is consid­ /3-Adrenergic ered a valid predictor o f therapeutic success.17 In addi­ Isoproterenol 5-15 1-2 23.63 C tion, measurement o f the peak expiratory' How rate Isoctharine 15-60 2-3 26.98 C attainable during a forced expiratory' volume with a peak Metaproterenol 30-60 3—4 20.23 c Terbutalinc 60 4 22.10 B expiratory- flow meter may also be used to monitor the Albuterol 3 0 -6 0 4 24.16 C status and response o f patients to therapy at home and in Bitolterol 30-60 5 18.00 C the office. Furthermore, the observations o f decreased Pirbuterol 30-60 5 18.82 C dyspnea and improved exercise tolerance following bron­ Anticholinergic chodilator therapy also suggest that such therapy is ben­ Ipratropium 60-120 3 -6 26.80 B eficial.18 Biscromones Some patients whose pulmonary- function testing Cromolyn 1 5 -3 0 2 -6 37.15 B demonstrates a positive response are clinically unrespon­ 'D ata from Physicians’ Desk Reference,13 Drug Evaluations,15 and llar-Yishay et al.16 sive because o f improper M D I use. Characteristics that * * Derived from pharmacy price quotes. Pregnancy Category B denotes no evidence o f risk in humans. (Fetal risk evaluation: identify such patients include lack o f prior instruction animal studies + , human studies or animal studies human studies not done.) and poor knowledge of the correct technique of MDI Category C denotes that risk cannot be ruled out. (Fetal risk evaluation: animal studies use.19 + or lacking; human studies lacking.) FDA denotes Federal Drug Administration.

Anticholinergic Drugs sion in the immediate post-therapy period, cardiac ar­ rhythmias, and hypoglycemia.6-8 The inhalation o f atropine is avoided in therapy since it is These agents are indicated for the short-term relief associated with significant systemic side effects owing to of bronchoconstriction and are the treatment of choice a high rate o f absorption across the respiratory tract for acute exacerbations o f asthma. Increased dosages are mucosa into the bloodstream.20-21 Ipratropium, a new particularly useful in acutely ill patients. For example, synthetic derivative, is poorly absorbed into the circula­ some have treated such patients by prescribing two to tion and has been shown to have an important role in four puffs o f a /3-adrenergic drug up to six times daily. aerosol therapy and to cause few side effects.22-23 Life-threatening episodes in the emergency department The rationale for using anticholinergic agents rests may require four puffs over 2 minutes followed by one- on the knowledge that, in healthy persons, bronchomo- puff per minute until dyspnea is relieved or side effects tor tone is predominantly cholinergically mediated limit further use. Increased doses may seem better justi­ through the parasympathetic nervous system. Atropine fied when one considers that doses delivered by jet neb­ and other anticholinergic drugs are parasympatholytic because o f their marked affinity for acetylcholine receptor ulizer are fivefold to tenfold greater than the usual two sites on postganglionic parasympathetic nerves, where puffs from an M D I.9-10 Patients receiving increased dos­ they act as acetylcholine blockers. The most significant ages should be monitored closely for the presence o f side- pulmonary- parasympathetic outflow occurs through the effects. Ideally, elective measurement o f cumulative or vagus nerve and is directed to receptors located in the noncumulativc dose response curves in the pulmonary larger airways and submucosal glands, while (3-adrener­ function laboratory will provide an estimate o f a patient’s gic drugs exert their greatest effect on small airways. The maximal tolerable dosage.11-12 activity o f the vagus nerve is influenced by central stim­ The prescribing o f higher than usual dosages raises ulation induced by emotional states; consequently, ipra­ questions o f safety. One must consider, however, that tropium is reported to be especially beneficial in those problems related to inadequate treatment with low dos­ with a strong emotional component in the disease.24-25 ages probably exceed the toxic problems associated with Anticholinergic agents have a slower onset o f action higher, more effective dose levels. and a longer duration o f effect than most /f-adrenergic The Food and Drug Administration’s rating of the drugs (Table 1). Some report ipratropium to be as risk o f use o f these drugs in pregnant women and the effective in treating asthma as the newer /3-adrenergic literature provide guidance concerning the teratogenic agents; however, the subject remains controversial. The potential of these drugs13-14 (Table 1). patients with COPD who are most likely to respond to

486 The Journal of Family Practice, Vol. 34, No. 4, 1992 MDI Therapy for Asthma HofFord

ipratropium arc bronchitic patients and those who fail to Chronic complicated asthma mav require that aero­ respond to a /3-adrenergic bronchodilator during pulmo­ sol glucocorticoid dosages be increased to 16 to 32 nary function testing.26 Gross has suggested that the inhalations (42 /xg per inhalation) dailv.36 A recent re­ optimal response in stable COPD is achieved by using an view suggests that a fbur-times-a-day regimen o f an aero­ M D I dose o f ipratropium that may be two times the sol steroid is more effective than a two-times-a-day reg­ commonly recommended dose of 36 /ug.22 Ipratropium imen when using high doses.37 Side effects are minimal, is especially indicated when treating patients with myas­ and the need for oral glucocorticoids is reduced.35-38 thenia gravis whose pulmonary symptoms have wors­ Adrenal suppression and hvpercortisolism are virtu­ ened because o f therapy with cholinesterase inhibitors ally nonexistent when lower doses o f the inhaled gluco­ and patients with asthma who are receiving /3-blocking corticoids are used. One exception, dexamethasone MDI, drugs.22-27 is associated with a high degree o f absorption into the Ipratropium may cause unexpected broncho- blood and can eventually result in hvpercortisolism.35 spasm.28’29 Unlike atropine, ipratropium is free o f inhib­ Glucocorticoids are known teratogens. Before they itory' effects on mucous secretion and mucociliary trans­ are used by a pregnant woman, the physician should port, has no effect on the urinary sphincter, is less likely consider the risk-benefit ratio to mother and child. A than j3-adrenergic agonists to cause arterial hypoxemia, Food and Drug Administration pregnancy category for and has no effect on intraocular pressure in narrow-angle prescribing glucocorticoids is not listed.13 glaucoma unless sprayed into the eye, or if it is used in combination with albuterol. The ocular side effects can be prevented by using swimming goggles, standing in Biscromones front o f a mirror to observe the path o f the inhaled spray, Aerosolized cromolyn sodium inhibits degeneration o f continuing antiglaucoma measures, and using ipratro­ mast cells by antigen and blocks release o f the chemical pium and albuterol separately.22’30 mediators o f allergy' from sensitized cells. Once the me­ diators have been released, the drug is rendered ineffec­ Glucocorticoid Drugs tive; hence, it is useful in preventing, but not treating, acute paroxysms o f asthma after they have developed. The effectiveness o f glucocorticoids is attributed to their Cromolyn is most effective in treating exercise-in­ ability to suppress allergic bronchial inflammation; in­ duced asthma and should be the first choice in control­ hibit intermediate (type 3) hypersensitivity reactions, ling allergic bronchial asthma when an immediate asth­ while having little influence on immediate (type 1) reac­ matic response to allergen plays a predominant role.39 tions; and restore responsiveness to /3-adrenergic drugs. Cromolyn is available for administration by MDI The molecular mechanism of glucocorticoid action pro­ (800 n g per inhalation) and also as an aerosol powder poses steroid diffusion through the cell membrane caus­ inhaled from a 20-mg capsule.40-41 Maximum effect in ing the formation o f a messenger RNA and subsequent the treatment o f chronic disease is achieved if two inha­ synthesis o f lipocortin, which reduces the release o f ara- lations by M DI are taken four times daily and several chidonic acid, a substrate for prostaglandins and lcuko- weeks are allowed for response. Administration 15 to 30 tricnes.6’31 minutes before exercise or exposure to cold dry air or Based on recent evidence that asthma is a result o f a environmental agents effectively prevents the onset o f unique type o f airway inflammation, Barnes32 has sug­ asthma (Table 1). gested that “asthma is therefore much more than bron- The powder form of aerosol cromolyn, introduced choconstriction, and treatment must be directed toward for use in the United States in 1973, has been associated reducing this inflammation as well as promoting bron- with serious side effects in a few reported cases.42-48 chodilation.” Aerosol glucocorticoids used early in the Cromolyn, as an MDI aerosol, became available in Flu- course o f asthma improve control o f the disease and rope in 1981 and in the United States in 1986. This decrease the need for oral steroids. There have been no formulation seems to be gaining general acceptance with well-controlled studies reporting the use o f aerosol glu­ minimal side effects. cocorticoids in COPD.33-34 The potent, longer-acting aerosol glucocorticoids, such as bcclomethasonc, have a high potency to toxicity' Drug Combination Therapy ratio. High-dose bcclomethasonc or budesonide (250 /xg per inhalation) is available in Europe, while in the United The clinical presentation o f asthma is quite diverse, mak­ States the standard inhaler delivers 42 /xg per inhala­ ing it unwise to be too dogmatic with regard to treat­ tion.35 ment. Obviously, patients should be advised to avoid

The Journal of Family Practice, Vol. 34, No. 4, 1992 487 MDI Therapy for Asthma Hoffbrd

Table 2. Therapy Strategies for Mild, Moderate, and Severe Asthma

Mild Asthma Moderate Asthma Severe Asthma

1. Aerosol fl-adrenergic 1. Increase dose o f aerosol /3- 1. Add systemic steroid adrenergic

2. Add aerosol cromolyn or 2. Increase dose o f aerosol steroid aerosol steroid

3. Short course o f systemic steroid 3. Add theophylline

4. Add aerosol anticholinergic

N ote: Glucocorticoid lung deposition is improved by using a (5-adrenergic agent 5 minutes before administering the glucocorticoid. Adapted from Dolovich and Newhouse31 allergens and occupational sensitizers; sinus disease and struction, followed by a time during which the patient esophageal reflux must be treated; and drug-induced practices proper use o f the inhaler, improves patient asthma due to nonsteroidal anti-inflammatory agents and performance.55-56 f3-adrenergic antagonists should be eliminated. Recent authoritative research suggests that the M DI A suggested plan for the treatment o f mild, moder­ should be administered by the open-mouth method o f ate, and severe asthma based on present day reports has Newhouse and Dolovich10 (Table 3). This technique is been outlined in Table 2. It is important to note that an considerably more effective than the closed-mouth aerosol steroid achieves maximal efficacy and decreases method recommended by drug manufacturers. Using the need for systemic steroid therapy once the acute radioactively labeled MDI-gcneratcd aerosols, the open- asthmatic episode has been controlled. During periods of mouth method has been demonstrated to deliver twice as stress or a recurrent asthmatic attack, systemic steroids much medication to the lower respiratory tract with should be resumed.13-33 significantly improved bronchodilation.57 /3-Adrenergic agonists are superior to ipratropium The rationale for the open-mouth technique is that in status asthmaticus, but the combined use o f each may about 80% of an MDI aerosol dose deposits in the result in greater improvement.22 Exercise-induced oropharynx and only 10% reaches the lung. The particle- asthma is effectively managed by combining ipratropium size o f the therapeutic aerosols generated varies from 0.5 and cromolyn or a ^-adrenergic agonist and cromolyn.49 /am to 35 /am, but only the particles between 1 yam and The combination o f a /f-adrenergic and an anticho­ 5 /am are deposited in the lower respiratory tract. The linergic agent in COPD provides the rapid onset o f deposition o f these particles depends on impaction, sed­ action o f the former and the sustained activity o f the imentation, and diffusion. Impaction causes particles latter with the increased potency o f their combined ac­ greater than 5 yam to deposit in the upper airways; this tions. Theophylline potentiates the side effects o f /3-ad­ effect increases at high inspirator)' flow rates. Particles 1 renergic agonists only when they are present in substan­ to 5 yam in size are deposited in the small airways by tial blood levels. Ipratropium can be combined with sedimentation (a gravitational effect), where the main sympathomimetic and theophylline therapy without any therapeutic effect is achieved. Their deposition is in­ increase in side effects.50 Theophylline, with a half-life of creased by slow inspiratory flow rates (less than 1 L/scc) 7 to 9 hours, is superior in the control of nocturnal and a 4- to 10-second period of breath-holding, which asthma. The longer acting /3-adrenergic bronchodilators, allows time for sedimentation. The therapeutic value o f bitolterol and formotcrol (under investigation), show promise for the use in the treatment o f this illness.51- 54 Table 3. Open-Mouth Method of Using the Metered Dose Inhaler

Using the Metered Dose Inhaler Personnel supendsintf treatment should instruct patients in the recommended open-mouth procedure as follows: 1. Shake the metered dose inhaler three or four times. Recommended Procedure 2. Hold the mouthpiece 4 cm in front o f the widely opened mouth. 3. Exhale to resting end expiration (end tidal volume). Fifty percent o f patients with asthma and 62% o f adult 4. Actuate the inhaler and slowly inhale for 5 seconds to total lung outpatients with CO PD use the M DI incorrectly.19 It has capacity. 5. Hold breath at total lung capacity for as long as possible or up to been shown, however, that following a single instruction 10 seconds. in correct use, 77% to 80% demonstrate the correct 6. Slowly exhale. technique for using the inhaler. Additional verbal in­ Adapted from Newhouse and Dolovich.10

488 The Journal of Family Practice, Vol. 34, No. 4, 1992 MDI Therapy for Asthma Hotford

Table 4. Using a Spacer with the Metered Dose Inhaler

1. Insert the inhaler mouthpiece into the chamber. 2. Shake the inhaler a few times. 3. Place the chamber mouthpiece in the mouth and close the lips. 4. Exhale to resting end expiration (end tidal volume). 5. Spray one put!' from the inhaler into the chamber. 6. Inhale tor 5 seconds to total lung capacity. 7. Hold breath at total lung capacity for as long as possible, up to 10 seconds. 8. Slowly exhale. Adapted from Physicians' D ale Rcfrretice.11

inability to inhale slowlv and hold a breath; arthritis and stroke with poor hand-breath coordination; or age, eg, children under 5 years. It is in such patients that a spacer will enhance the use o f the MDI. Spacers also decrease Figure 1. Demonstration of a patient using a spacer (Aero- the side effects o f inhaled glucocorticoids, namely, sy s­ Chamber) attached to a metered dose inhaler. (Photograph temic effects sometimes seen with high dosages, and the courtesy o f Forest Pharmaceuticals, Inc.) occurrence of thrush, reported in 5% to 15% of pa­ tients.63-64 Recently, manufacturers have attempted to improve particles less than 0.1 /urn in size, the movement o f which the performance o f the MDI by developing powder is controlled by diffusion, has not been clearly de­ inhalers that do not require hand-lung coordination for fined.10-58 inhalation. These powder devices have not shown any The most common patient errors encountered are better patient acceptance or therapeutic benefit than the inability' to coordinate firing the aerosol with inhalation, MDI aerosol unit.40-41-65-66 to inhale slowly, and to hold a breath adequately.57-58 Prewarming the M DI canister to body temperature when atmospheric temperatures are low increases the lower Replacement of the Jet Nebulizer bv airway deposition from 17% to 32% as the temperature the MDI rises from 4°C to 32°C (39.2°F to 89.6°F).59 The mouthpiece o f the M DI canister should be Current studies demonstrate that the MDI is as effective inspected before use to prevent accidental inhalation o f as the jet nebulizer when used to treat moderate and foreign bodies lodged in the mouthpiece (mouthpiece severe airflow obstruction in both hospital and outpa­ caps, coins, capsules).60 tient settings.67-70 Replacement of the jet nebulizer with the MDI in hospitals has the potential to contribute to more cost- Spacers and Delivery Systems effective medical care. Jasper et al71 state that self-admin­ Spacers are extensions in the form of a tube that serve as istration o f a bronchodilator by MDI in all adult patients a holding chamber for the drug released from the MDI not in an intensive eare setting would save $253,487 per canister and from which the patient can more easily year in their institution alone. Summer et al72 report a inhale the medication (Figure 1). These devices over­ study in which the use o f the jet nebulizer resulted in come a patient’s lack o f hand-lung coordination, decrease patient eharges o f $4159 and respiratory therapist time oropharyngeal deposition, and improve lung deposition o f 3808 minutes; comparative values for the MDI were by enhancing propellant vaporization, which results in $1024 and 840 minutes, respeetivcly. more respirable particles.10-61-62 The M DI releases the The MDI can be used to administer the whole range aerosol into the chamber, and the patient inhales as o f available aerosol medications and has the additional described in Table 4. Children may simply put the cham­ attributes o f simplicity, portability, and protection o f ber in the mouth and breathe normally for 20 to 30 medications from contamination. Also, an MDI may be seconds, after which the MDI aerosol is released into the used to successfully treat severe asthma in the emergency chamber, and normal breathing is continued for 3 or 4 department. Although previously the standard method o f more breaths. eare, administration o f aerosols by intermittent positive A significant number o f patients are unable to prop­ pressure breathing remains useful only in the treatment erly use an M D I because of: severe asthma with an o f croup with epinephrine and laryngeal candidiasis with

The Journal of Family Practice, Vol. 34, No. 4, 1992 489 MDI Therapy for Asthma Hofford

nystatin since high inspiratory flow rates are needed to other factors should be considered; for example, patients increase delivery o f these drugs to the larynx.73-74 taking the greatest amount o f drug might also have the most severe asthma. Further study is needed.

Mechanical Ventilation and the MDI

Intubated patients can effectively receive aerosol medica­ Conclusions tions through the endotracheal tube.75 The MDI is more Asthmatic patients who are free o f disease for extended efficient and interferes less with the patient’s respiration periods usually respond to a /3-adrenergic M D I when than the jet nebulizer in treating ventilator patients.76-78 symptoms arise, and persistent symptomatology requires The efficient use o f the M DI with a mechanical ventilator a prophylactic regimen including an aerosol glucocorti­ depends on a slow flow, a deep inspiration, and a sus­ coid with the addition o f a /3-adrenergic, anticholinergic, tained peak inspiratory pause delivered by the ventilator or cromolyn as appropriate. or in using bag-assisted ventilation. The use o f bron- The newer aerosol /3-adrenergic drugs (albuterol, chodilating agents in this manner serves to decrease the tcrbutalinc, pirbuterol, bitoltcrol) arc /32 selective, pro­ work o f breathing, lessens patient dyspnea, and reduces ducing bronchodilation with less cardiac stimulation weaning time.79 than the older /3-adrenergic drugs (epinephrine, isopro­ terenol, isoctharine, mataproterenol). The longer acting /3-adrcncrgic bronchodilators bitoltcrol and formotcrol Concerns About Asthma Mortality and (investigational) may prove to be helpful in treating Drug Toxicity nocturnal asthma. Aerosol /3-adrcnergic drugs have value in replacing oral theophylline as first-line therapy since Despite the clinical reports o f the effectiveness o f using they are more potent bronchodilators and considerably higher dosages of aerosol drugs, the drug manufacturers less toxic. have not offered any official comment or ordered any sanction to increase recommended dosage levels. There is an ongoing concern about the potential Acknowledgments cardiac effects o f inhaled /3-adrenergic drugs and fluoro­ The writer wishes to thank Gail Gill, Librarian of the Delaware Acad­ carbon propellants. emy o f Medicine in Wilmington, Delaware, and Marianne Sodoski, Evaluations o f propellant toxicity have led to the Librarian of the Geisinger Wyoming Valley Hospital in Wilkes- speculation that humans would have to use an inhaler 20 Barre, Pennsylvania, for their assistance. times over a period of 2 minutes without exhaling before myocardial fluorocarbon concentrations become critical. The Asthma Mortality Task Force concluded that “the References role o f cardiac pathology in death from asthma remains 1. Yulsman T. Allergies. New York Times Magazine 1988 Apr 17: uncertain,” and that “the clinical importance o f the ar- 10. 2. Sheffer AL, Buist AS, cds. Proceedings of the Asthma Mortality rhythmogenic potential of bronchodilator drugs (and Task Force. J Allerg Clin Immunol 1987; 80(suppl 3 ):3 6 1 -5 1 4 . combinations thereof) used in the acute and chronic- 3. Evans R, Mullaly DI, Wilson RW , et al. National trends in the treatment o f asthma remains unresolved.”80 morbidity and mortality o f asthma in the US: prevalence, hospi­ talization, and death from asthma over two decades: 1 9 6 5 -1 9 8 4 . Overall, the Task Force concluded in 1987 that Chest 1987; 91(suppl 6):65S-74S. “there are no experimental data to show that any o f the 4. Buist AS. Is asthma mortality increasing? Chest 1988; 9 3 :4 4 9 -5 0 . drugs used to treat asthma are responsible for the in­ 5. O’Driscoil BR, Cochrane GM. Emergency use o f nebulised bron­ creases in deaths reported in various parts o f the world”; chodilator drugs in British hospitals. Thorax 1987; 4 2 :4 9 1 -3 . 6. Barnes PJ. Arw ay pharmacology. In: Murray JF, Nadel JA, eds. however, some asthma medications do have toxic poten­ Textbook of respiratory medicine. Philadelphia: WB Saunders, tial, and “deaths are still reported in circumstances that 1988:249-68. suggest treatment has proved inadequate.”81 7. Georgopoulos D, Giulckas D, Ilonidis G, Sichletidis L. Effect of salbutamol, ipratropium bromide, and cromolyn on prostaglandin The topic has been refueled by a recent report that a P' 2 alpha-induced bronchospasm. Chest 1989; 9 6 :8 0 9 -1 4 . pharmaceutical company wrote a confidential letter to 8. Lim R, Walshaw MJ, Saltissi S, Hind CR. Cardiac arrhythmias the Food and Drug Administration alerting it to a Ca­ during acute exacerbations o f chronic airflow limitation: effect of fall in plasma potassium concentration induced by nebulized beta2- nadian study reporting that asthma patients using twice agonist therapy. Postgrad Med J 1989; 65:449-52. the recommended daily dosage o f adrenergic drugs 9. Morgan M DL, Singh H BV, Fraim H , Williams SJ. Terbutaline aerosol given through pear spacer in acute asthma. Br Med J 1982; faced double the risk o f a fatal or near-fatal asthma 285:849-50. attack.82 The report must be viewed with caution since 10. Newhouse MT, Dolovich M. Aerosol therapy of reversible air flow

490 The Journal of Family Practice, Vol. 34, No. 4, 1992 MDI Therapy for Asthma Hotford

obstruction— concepts and clinical correlations. Chest 1987; 35. Ziment I. Respiratory pharmacology. Steroids. Clin Chest Med 91(suppl S):58S—64S. 1986; 7:341-54. 11. Jenkins SC, Heaton RW, Fulton TJ, Moxham J. Comparison or 36. Reed CE. Aerosols in chronic airway obstruction. N Engl I Med domiciliary nebulized salbutamol and salbutamol from a metered 1986; 15:888-9. dose inhaler in stable chronic airflow limitation. Chest 1987; 37. Malo JL, Cartier A, Merland N, et al. Four-times-a-day dosing 9 1 :8 0 4 -7 . frequency' is better than a twice-a-day regimen in subjects requiring 12. Britton J, Tattersfield A. Comparison o f cumulative and non- a high dose inhaled steroid, budesonide, to control moderate to cumulative techniques to measure dose response curves tor beta severe asthma. Am Rev Respir Dis 1989; 140:624—8. agonists in patients with asthma. Thorax 1984; 3 9 :5 9 7 -9 . 38. Li JT, Reed CE. Proper use of aerosol corticosteroids to control 13. Physicians’ Desk Reference. 45th ed. Oradell, NJ: Medical Eco­ asthma. Mavo Clin Proc 1989; 6 4 :2 0 5 -1 0 . nomics Co, 1991:668,669,951,969,970,1279,1407,1777,2017, 39. Pelikan Z, Peiikan-Filipek M, Schoemaker MC, Berger MP. Effects 2029,2331,2332,2493. of disodium cromogly'cate and beclomethasone dipropionate on 14. Schatz M, Zeiger RS, Harden KM, Hoffman CP, et al. The safety the asthmatic response to allergen challenge I Immediate response of inhaled beta-agonist bronchodilators during pregnancy. J Allerg (1AR). Ann Allergy 1988; 6 0 :2 1 1 -6 . Clin Immunol 1988; 82:686-95. 40. Lai S, Malhotra SM, Gribben MD. Comparison of sodium cro­ 15. Drug evaluations. 6th ed. Chicago: American Medical Association, moglycate pressurized aerosol and powder in the treatment ot 1986:393-418. asthma. Clin Allergy 1982; 1 2 :1 9 7 -2 0 1 . 16. Bar-Yishav E, Levy 1GM, Volozni D, Godfrey S. Duration of 41. Sclcow JE, Mcndelson IM, Rosen JP. Clinical benefits o f cromolyn action o f sodium cromoglycate on exercise induced asthma: com­ sodium aerosol (MDI) in the treatment o f asthma in children. Ann parison of 2 formulations. Arch Dis Child 1983; 58:624—7. Allergy 1989; 6 2 :1 9 5 -9 . 17. Morris AH. Clinical pulmonarv function testing— a manual ot 42. Lobcl H , Maehtcy I, Eldor MY. Pulmonary infiltrates with eosin- uniform laboratory procedures. 2nd ed. Salt Lake City: Inter­ ophiiia in an asthmatic patient treated with disodium cromogly'­ mountain Thoracic Society, 1984:24. cate. Lancet 1972; 2:1032. 18. Pratter M R, Irwin RS. Predicting response to bronchodilator 43. Burgher LW , Kass I, Schenken JR. Pulmonary' allergic granulo­ thcrapv in chronic obstructive pulmonarv disease. Arch Intern matosis: a possible drug reaction in a patient receiving cromolyn Med 1988; 148:1909-10. sodium. Chest 1974; 6 6 :84—6. 19. DeBlaquicre P, Christensen DB, Carter WB, Martin TR. Use and 44. Repo UK, Nieminen P. Pulmonary infiltrates with cosinophilia misuse o f metered-dose inhalers by patients with chronic lung and urinary' symptoms during disodium cromoglycate treatment. disease. Am Rev Respir Dis 1989; 140 :9 1 0 -6 . A case report. Scand J Respir Dis 1976; 5 7 :1 —4. 20. Mann JS, George CF. Anticholinergic drugs in the treatment of 45. Slater EE. Cardiac tamponade and peripheral eosinophilia in a airways disease. Br J Dis Chest 1985; 79:209. patient receiving cromolyn sodium. Chest 1978; 7 3 :8 7 8 -9 . 21. Berdy GJ, Berdy SS, Odin LS, Hirst LW. Angle closure glaucoma 46. Shcffer AL, Rocklin RE, Goetzl F.J. Immunologic components ot precipitated by aerosolized atropine. Arch Intern Med 1991; 151: hypersensitivity reactions to cromolyn sodium. N Engl J Med 1 6 5 8-60. 1975; 293:1220-4. 22. Gross NF. Ipratropium bromide. N Engl J Med 1988; 319:486— 47. Rosenow EC. The spectrum o f drug-induced pulmonary disease. 94. Ann Intern Med 1972; 7 7 :9 7 7 -9 1 . 23. Ziment I, Au JP. Respiratory' pharmacology. Anticholinergic- 48. Leynardier F, Pujadc-Laurame MD, Cornaillc G, Dry J. Death agents. Clin Chest Med 1986; 7:355—66. after cromogly'cate [letter]. Allergy' 1985; 4 0 :5 4 0 . 24. Gross NJ, Co E, Skorodin MS. Cholinergic bronchomotor tone in 49. Wooley M, Anderson SD, Quigley BM. Duration o f protective- COPD. Estimates of its amount in comparison with that in normal effect o f terbutaline sulfate and cromolyn sodium alone and in subjects. Chest 1989; 9 6 :9 8 4 -7 . combination on exercise induced asthma. Chest 1990; 97:39—45. 25. Gross N F, Skorodin MS. Role of the parasympathetic system in 50. Rebuck AS, Gent M, Chapman KR. Anticholinergic and sympath­ airway obstruction due to emphysema. N Engl J Med 1984; omimetic combination therapy o f asthma. J Allergy Clin Immunol 3 1 1 :4 2 1 -5 . 1983; 71:317-23. 26. Braun SR, McKenzie WN, Copeland DK, Knight L, Ellersieck 51. Rossing TH. Methylxanthines in 1989. Ann Intern Med 1989; MK. A comparison o f the effect of ipratropium and albuterol in the 110 :5 0 2 -4 . treatment of chronic obstructive airway disease. Arch Intern Med 52. Martin RJ, Cicutto LC, Ballard RD, Goldcnheim PD, Cherniack 1989; 149:544-7. RM. Circadian variations in theophylline concentrations and the 27. Liggett SB, Daughaday CC, Senior RM. Ipratropium in patients treatment o f nocturnal asthma. Am Rev Respir Dis 1989; 139: with COPD receiving cholinesterase inhibitors. Chest 1988; 94: 4 7 5 -8 . 210- 2 . 28. Barnes PJ. Muscarinic autoreceptors in airways. Their possible role 53. Zwillich CW, Neagley SR, Cicutto L, White DP, Martin RJ. Nocturnal asthma therapy: inhaled bitolterol versus sustained re­ in airway disease. Chest 1989; 9 6 :1 2 2 0 -1 . 29. Patel KR, Tullett WM. Bronchoconstriction in response to iprat­ lease theophylline. Am Rev Respir Dis 1989; 139:470—4. ropium bromide. Br Med J 1983; 286:1318. 54. Larsson S, Lofdahl CG, Arvidsson P. Twelve hours bronchodilat- 30. Kalra LK, Bone MF. The effect of nebulized bronchodilator ther­ ing effect duration of inhaled formoterol in asthma. Am Rev apy on intraocular pressures in patients with glaucoma. Chest Respir Dis 1990; 141(suppl 4):A 27. 55. Lee H , Evans H E. Aerosol inhalation teaching device. J Pediatr 1988; 93:739^1. 31. Dolovich MB, Newhouse MT. Aerosols: generation, methods of 1987; 110:249-52. administration, and therapeutic applications in asthma. In: Mid­ 56. Lee FI, Evans H E. Evaluation o f inhalation aids o f metered dose- dleton E Jr, Reed C E, Ellis E F, Adkinson NF Jr, Yunginger JW, inhalers in asthmatic children. Chest 1987; 9 1 :3 6 6 -9 . eds. Allergy' principles and practice. 3rd ed. St Louis: CV Mosby, 57. Dolovich M, Ruffin RE, Roberts R, Newhouse MT. Optimal delivery' of aerosols from metered dose inhalers. Chest 1981; 1988:559-78. 32. Barnes PJ. A new approach to the treatment of asthma. N Engl J 80(suppl 6):911-5. 58. Newman SP. Aerosol deposition considerations in inhalation ther­ Med 1989; 321:1517-27. 33. Sahn SA. Corticosteroids in chronic bronchitis and pulmonary apy. Chest 1985; 88(suppl 2 ):1 5 2S -160S . 59. Wilson AF, Mukai DS, Ahdout JJ. Effect o f canister temperature emphysema. Chest 1978; 73:389-96. 34. Hall TG, Kasik JE, Bedell GN, Schaiff RA. The efficacy of inhaled on performance of metered-dose inhalers. Am Rev Respir Dis beclomethasone in chronic obstructive airway' disease. Pharmaco­ 1991; 143:1034-7. 60. Schultz CH , Hargartcn SW, Babbitt J. Inhalation o f a coin and a therapy 1989; 9:232-9.

491 The Journal of Family Practice, Vol. 34, No. 4, 1992 MDI Therapy for Asthma Hotford

capsule- from metcred-dose inhalers. N Engl J Med 1991; 325: ulizer vs spacer for bronchodilator delivery in patients hospitalized 4 3 1 -2 . for acute exacerbations of COPD. Chest 1989; 96:1241—6. 61. Newman SP, Millar AB, Ixnnard jones TR , Moren F, Clarke SW. 71. Jasper AC, Mohsenifar Z, Kahan S, Goldberg HS, Koerner SK. Improvement o f pressurized aerosol deposition with nebuhaler Cost-benefit comparison o f aerosol bronchodilator delivery meth­ spacer device. Thorax 1984; 39:935-41. ods in hospitalized patients. Chest 1987; 91:614—8. 62. Salzman GA. Spacer devices for aerosol therapy. In: Sbarbaro JA, 72. Summer W, Elston R, Tharpe L, Nelson S, Haponik EE. Aerosol ed. Clinical challenge in cardiopulmonary medicine. Park Ridge, bronchodilator delivery methods. Arch Intern Med 1989; 149: 111: American College of Chest Physicians, 1986; 6(3): 1-8. 6 1 8 -2 3 . 63. l’rahl P, Jensen T . Decreased adrenocortical suppression utilizing 73. IPPB Trial Group. Intermittent positive pressure therapy of the nebuhaler for inhalation o f steroid aerosols. Clin Allergy 1987- chronic obstructive pulmonary disease. Ann Intern xMcd 1983; 1 7 :3 9 3 -8 . 99r6 1 2 -2 0 . 64. Salzman GA, Pyszczynski DR. Oral pharyngeal candidiasis in 74. Singer OP, Wilson WA. Laryngotracheobronchitis: two years’ patients treated with beclomethasone dipropionate delivered bv experience with racemic epinephrine. Can Med Assoc J 1976; MDI alone and with aerochamber. J Allergy Clin Immunol 1988' 1 1 5 :1 3 2 -4 . 8 1 :4 2 4 -8 . 75. Steedman DJ, Robertson CE. Emergency endotracheal drug ad­ 65. Gimino F, van Veened R, Berg WC, Steenhuis F.J. A placebo ministration using aerosol. Resuscitation 1987; 1 5 :1 3 5 -9 . controlled comparison between the bronchodilatory effects o f ip­ 76. Fernandez A, Lazaro A, Garcia A, Aragon C, Cerda E. Bronchod- ratropium bromide inhaled as a dry powder and by metered dose- ilators in patients with chronic obstructive pulmonary disease on inhaler in chronic obstructive pulmonary disease. Ann Allergy mechanical ventilation. Am Rev Respir Dis 1990; 1 4 1 :1 6 4 -8 . 1988;61:341-3. ' 77. Fuller HD, Dolovich MB, Posmituck G, Pack WW, Newhouse 66. Newman SP, Moren F, Trofast E, Talaee N, Clarke SW. Deposi­ MT. Pressurized aerosol versus jet aerosol delivery to mechanically tion and clinical efficacy o f terbutaline sulfate from turbuhaler, a ventilated patients. Am Rev Respir Dis 1990; 1 4 1 :4 4 0 -4 . new multidose powder inhaler. Eur Respir J 1989; 2 :2 4 7 -5 2 . 78. Beaty CD, Ritz RH . Benson MS. Continuous in-line nebulizers 67. Salzman GA, Steele M T, Pribble JP, Elenbaas RM, Pyszczynski complicate pressure support ventilation. Chest 1989; 9 6 :1 3 6 0 -3 . DR. Aerosolized metaproterenol in the treatment o f asthmatics 79. Mancebo J, Piedade A, Hubert L, Lemaire F, Harf A, Brochard L. with severe airflow obstruction— comparison o f two delivery Effects o f albuterol inhalation on the work o f breathing during methods. Chest 1989; 95:1017-20. weaning from mechanical ventilation. Am Rev Respir Dis 1991; 68. Dolovich M, Ruffin R, Corr D, Newhouse MR. Clinical evalua­ 144:95-100. tion o f a simple demand inhalation MDI aerosol delivers' device 80. Schoen FJ. Cardiac pathology in asthma. J Allerg Clin Immunol Chest 1983; 84:36-41. 1987; 80(3 pt 2 ) 4 1 9 - 2 2 . 69. Calcutt LE, Leech JA, Hodder RV. Metered dose inhaler with 81. Poynter D. Fatal asthma— is treatment incriminated? J Allerg Clin spacer is superior to jet nebulization for emergency room treat­ Immunol 1987; 80(3 pt 2)423-6. ment of acute, severe asthma. Chest 1988; 94(suppl 1 ):52S. 82. Meier B. Company tells of dangers in overusing asthma drugs. 70. Berry RB, Shinto RA, Wong EH, Despars JA, Light RW. Neb­ New York Times 1991 Aug 8:A14(col 5,6).

April 25-29, 1992

The Society of Teachers of Family Medicine

25TH ANNIVERSARY ANNUAL SPRING CONFERENCE

“Celebrating Our Past, Creating Our Future”

Adam’s Mark Hotel St. Louis, Missouri

Audience: Full-time and part-time family medicine educators, practicing physicians with an interest in educational issues, researchers. Special focus of meeting will be on the beginnings o f family medicine, with a look to our past, our present, and our future. For more information, contact the STFM Program Department, 800-274-2237 or 816-333-9700, ext. 4510, PO Box 8729, Kansas City', MO 64114.

4 9 2 The Journal of Family Practice, Vol. 34, No. 4, 1992