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* From the Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to: Bruce K. Rubin, MD, FCCP, Professor and Vice-Chair, Department of Pediatrics, Professor of Biomedical Engineering, Physiology, and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1081; e-mail: brubin{at}wfubmc.edu
Key Words: adherence • aerosol therapy • asthma • children • corticosteroids • dry powder inhalers • nebulizers • pressurized metered-dose inhalers • valved holding chambers
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Introduction |
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 TOP Introduction The Patient Who Does...The Patient Who Does...The Patient Who Is...The Patient Who Cannot...The Patient With Unrealistic...The Patient Who Incorrectly...The Patient Who Does...The Patient Who Really...Implications for Asthma...References |
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In this article, many of the reasons for patient reports that "medications not working" are discussed with suggestions that may help to improve patient understanding and adherence. For the purposes of this discussion, asthma medications will be limited to those delivered as an aerosol by jet nebulizer (JN), pressurized metered-dose inhaler (pMDI), or dry powder inhaler (DPI), however, many of these issues also hold true for orally administered medications.5 Recommendations for addressing these problems are offered at the end of each section, recognizing that these suggestions come from the author’s clinical experience. There are few data assessing the effectiveness of suggested interventions. Although the greatest emphasis in this manuscript is on the child with asthma, most of these issues can be just as important in adults.
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The Patient Who Does Not Want To Take Medication |
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Patients with chronic disease may not accurately perceive their limitations. Many adults with myopia recall getting their first set of glasses when they were in grade school and being amazed to discover that objects do not naturally blur in the distance for persons with normal vision. Similarly, patients with long-standing chronic asthma will limit their own activity and may perceive chronic cough, exercise, and air flow limitation as being "normal." These patients may recognize their limitation only after a course of asthma therapy.
Other patients perceive that a large part of asthma is psychological, so they may think that if they believe that they are well, they will be well. These patients may refuse home measurement of airflow or symptom diaries, making it even more difficult to assess asthma severity. Unfortunately, even in the best of cases, during a carefully monitored clinical trials,891011121314 adherence to recording in peak flow diaries has been shown to be highly inaccurate. Even patients who profess adherence often fabricate written records, making peak flow diaries very unreliable. These studies have clearly documented the overreporting of medication use with fabricated diary entries.11121314 When canister weight was measured at each visit, drug dumping (ie, actuating inhalers > 100 times in a 3-h interval immediately before visits to the physician) was documented by chronolog records14 with the overreporting of usage generally exceeding 50% of doses in published reports.1011121415
These patients can benefit from asthma education and careful objective measurement of pulmonary function to document the effectiveness of medications. Children, adolescents, or the elderly may benefit from the monitored administration of medications.
Secondary Gain
There is sometimes secondary gain to having a chronic illness. During exacerbations of asthma, children are sometimes kept home from school and are given special attention by parents. The act of going to the doctor or emergency department for more intensive asthma therapy is generally perceived to be an unpleasant experience by most patients, but the occasional child will find this additional attention and concern to be so satisfying that they deliberately do not take medication, knowing that this is likely to bring on an asthma attack.16 These children need to be identified so that they and their families can receive appropriate intervention.
Parents also can use their child’s illness for secondary gain. In the most severe form of this, Munchausen syndrome by proxy, children can experience serious injury and even death as a result of the parent’s psychopathology.17 However, a parent will sometimes overstate the seriousness of their child’s illness for attention, personal gain, and occasionally for financial gain. When this happens, there is a risk that medication will not be taken as prescribed.18
Social services must be called to actively intervene if nonadherence threatens the health of the patient. Often, problems such as these can be clarified only with a monitored hospital admission and therapy.
Too Expensive
Sometimes medication is so expensive for a family that the parent will only use it when they feel that they absolutely must, such as when symptoms become limiting.1920 This problem can be made worse if their physician responds to this complaint of the "medication not working" by prescribing even more medication. Not only will this increase medication costs, as discussed below, it will also increase confusion, especially if the mediations are to be taken at different times and by using different devices. Patients are occasionally given several different medications with limited data to support synergistic or additive effectiveness. Costs can sometimes be decreased by changing the dosage form (eg, using a pMDI or DPI instead of a JN). Finally, many pharmaceutical companies sponsor programs to provide medications at lower cost for patients who qualify on the basis of need.
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The Patient Who Does Not Understand How or When To Use Medication |
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Words used and explanations given in the health-care setting should be selected carefully, and should be used in the context of the patient’s understanding as these can influence beliefs about asthma, sometimes in unforeseen ways. For example control medications are defined as those treating underlying inflammation. Therefore, many physicians call these controller medications or long-term controller medications. However, when having an asthma attack, patients reach for the medication that is most likely to control wheezing, cough, and shortness of breath. Many patients understand that controller medications control symptoms, not inflammation. The unintended result is that patients may use the wrong medication during attacks, get no immediate relief, and therefore believe that the medication is not working. Similar problems are encountered with the what are called preventer medications. Inhaled corticosteroids (ICSs), for example, prevent inflammation, however, inhaled bronchodilators can prevent exercise-induced asthma.
Another potentially confusing term that is used by many physicians is rescue medication. Many patients incorrectly believe that this term means that the medication should be used only when they are in need of emergency services. Telling a patient that a rescue medication opens the airways may convey two unintended messages: First, use the rescue medication to treat only life-threatening conditions, and second, the force of the medication leaving the inhaler will inflate the airways.
Asthma education must include clear communication. There is no substitute for a written action plan as long as the patient is able to read. Do not take literacy for granted. It helps to review understanding, goals, and action plans periodically, and to revise them as necessary.
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The Patient Who Is Concerned About Medication Side Effects |
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There is a concern among some patients that any medication that is taken daily will lead to the body becoming "dependent" or "addicted" to that medication.4719 Some patients believe that all medications taken on a regular basis can lead to the same physiologic or psychological addiction as narcotics. Therefore, they may not wish to take medications like ICSs every day.
Some patients "don’t believe in medications." Although some of these patients prefer complimentary or alternative therapies, which are perceived to be more natural than prescription medications, there are others who feel that the body is best with no medications at all. These patients may only appear in the clinic at times of crisis.
Psychological disorder in asthma is associated with poor control and poor adherence to therapy with ICSs, although in cross-sectional studies it can be difficult to determine whether the psychological dysfunction preceded (or caused) the nonadherence to therapy or whether the psychological problems were the result of poor asthma control.21 In a study designed to evaluate patient characteristics associated with nonadherence to nebulizer therapy, The St. George Respiratory Questionnaire was administered to a cohort of patients with COPD who had been prescribed daily aerosol therapy using a JN. The total scores on the St. George Respiratory Questionnaire (ie, greater psychosocial dysfunction) were negatively correlated with therapy adherence, and this association was particularly strong for patients whose scores suggested clinical depression.22
Although education and good communication can often correct misconceptions, occasionally these are so ingrained as to be difficult to change. In cases in which the patient or parent puts themselves or their child at great risk by refusing to take medications, social service or psychiatric intervention may be a necessity.
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The Patient Who Cannot Feel the Medication Working |
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When patients say they do not feel the medication, this may mean that they do not feel the cold chlorofluorocarbon (Freon; DuPont; Wilmington, DE) effect or the dry powder in the back of their throat with some of the newer asthma inhalers, or that they do not feel a quick physiologic effect, particularly with ICSs. It has been said that ß-agonist bronchodilators are sometimes overused by patients because they can feel them work. This perception of effectiveness includes not only decreased respiratory effort but also the tachycardia and tremor that sometimes accompanies the inhalation of ß-agonists. Patients can sometimes appreciate these physiologic responses more easily than they can understand that the long-term use of ICSs will have no immediate or rapid physiologic effect but will prevent exacerbations of asthma and improve lung function over the long term.
Clear communication or treatment goals supported by regular monitoring of airflow at home can help to change these perceptions. In some cases, it may be helpful to use a medication that has a distinct taste (eg, flunisolide) to see whether this will improve adherence.
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The Patient With Unrealistic Expectations |
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Patients can also have unrealistically high expectations of their medication, and falling short of these expectations might suggest that the medication is not working as it should. In the patient’s mind a preventer medication might be expected to completely prevent asthma attacks and to do this as soon as therapy with the medication is started. This is sometimes reinforced by advertising messages, for example, if you use a certain medication you do not need to worry about exposure to the cat. Similarly, a reliever medication should bring immediate and complete relief, and if it does not, the problem must be that the medication is not working. More subtle are the unrealistic expectations that we give to our patients or that we practitioners hold. These expectations can be based on personal prejudices or may be influenced by pharmaceutical marketing. Although legally physicians can only be given information about a product by a company sales representative based on Food and Drug Administration-approved claims of safety or efficacy, marketing efforts can be worded to suggest that one brand or type of ICS or ß-agonist has fewer side effects (eg, less tachycardia or hyperactivity), or is more effective for certain types of patients (eg, the only form of ICS that is effective in treating infants with asthma). These claims are generally made without supporting clinical data.
As before, the clear communication of goals and expectations can counter misconceptions. However, a more sinister problem is caregiver misconceptions of medication safety or effectiveness. If the physician incorrectly believes that medication administration by nebulization is more effective than pMDI or DPI administration, or that certain newer bronchodilators may have fewer side effects (despite package insert information to the contrary), then it will be impossible to present accurate information to the patient.
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The Patient Who Incorrectly Thinks That They Are Inhaling Medication |
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JNs can vary significantly in performance characteristics and durability. In a study performed over 10 years ago,25 half of the nebulizer models tested showed visible signs of malfunction, including spraying of large droplets, leaking of solution, and air leaks that prevented nebulization. The model with the largest variability of nebulization rate also was associated with an unacceptably large variability in particle size. Inadequate cleaning can decrease nebulizer output by 50%.26 The Centers for Disease Control and Prevention recommends that nebulizers should be disassembled, cleaned with sterile water, rinsed, and air dried after each use.27
Aerosol droplet size and nebulization times are both inversely proportional to gas flow through the jet. The higher the flow to the nebulizer, the smaller the particle size generated and the shorter the time required to nebulize the full dose.2829 In a lung model simulating tidal breathing at volumes of 50 to 400 mL, when the driving air flow was increased from 4 to 8 L/min the drug output was increased by 264%.30 The mass median aerodynamic diameter (MMAD) of an aerosol depends on compressor air flow. At a flow of 4 L/min, the MMAD was 7.0 µm with 26.8% of the particles in the aerosol < 5 µm in size, a size that is generally referred to as the respirable fraction. At a flow of 6 L/min, the MMAD was 4.9 µm (50.1% of particles were < 5µm), and at a flow of 8 L/min the MMAD was 3.6 µm (70.8% of particles were < 5 µm).27 There is also significant variability in the flow generated by different compressors used for home nebulization.31 The mean flow for the nebulizer-compressor combinations ranged from 2.08 to 5.42 L/min. The interaction between flow and device was significant (p < 0.001) for the percentage of particles in the respirable range. A nebulizer that produces a MMAD of 2.5 µg, when driven by a gas source pressure of 50 lb per square inch at 8 L/min, may produce a MMAD of > 8 µm when operated on a home compressor developing pressure of 10 lb per square inch. This can result in negligible respirable output to the patient.
For medication administered by aerosol to be deposited in the airway, children must use either a mouthpiece or a mask that is sealed tightly against the face and must inhale quietly, slowly, and deeply. A slow, deep inhalation allows the medication to enter the lower airway by minimizing turbulence. Medication then can be deposited in the airway by sedimentation. There is no difference in clinical response between mouthpiece and close-fitting mask treatment, so patient preference should guide the selection of the device.32 Amirav and Newhouse33 have shown that even small breaks in the mask can significantly reduce medication delivery. In this study,33 all children > 2 years old could consistently perform quiet tidal breathing with a closely fitting mask in place after careful training of parents and patients.
If the patient will not wear the mask closely to the face, an alternative commonly employed is a "blow-by" technique in which the aerosol from the nebulizer is directed toward the patient’s nose and mouth from a distance. Although this may be more convenient, deposition studies confirm that almost no drug enters the lower airway with this technique. In a simulation of breathing from a facemask at a tidal volume of 50 mL, Everard and colleagues30 showed that when tubing or facemask was applied to the filter "face," 1.21 mg drug was deposited of a 20-mg sodium cromoglycate fill. At 1 cm from the filter, 0.49 mg drug was deposited (a 60% reduction), and at a 2-cm distance only 0.18 mg drug was deposited (an 85% reduction).30
Some caregivers counsel the parents of infants to "make them cry," with the mistaken belief that this will lead the child to inhale the medication more deeply. However, crying is a long exhalation followed by a very rapid inhalation for the child to catch their breath. Nebulization during crying deposits almost nothing into the lower respiratory tract because of this. Thus, aerosols should never be administered to a crying child.3435 In vitro studies suggest that more medication can be delivered to a sleeping child than to one who is awake and breathing quietly or to the child who is crying.36
Nebulizer cups have a residual volume of medication that is unavailable for nebulization, and this volume varies from 0.5 to 1.5 mL, depending on the device.29 The greater the fill volume of the nebulizer cup, the more medication is available to the patient. For example, if there is a residual volume of 1 mL in the nebulizer cup with a fill volume of 2 mL, half of the medication will be unavailable to the patient, but if this volume is increased to 4 mL, only 25% of the medication will be unavailable for nebulization. Many patients use a 2-mL unit dose of medication in the nebulizer without adding additional saline solution to optimize the fill volume. Newer nebulizer cups allow the recirculation of medication during exhalation and have smaller residual volumes, minimizing these effects.
DPIs and pMDIs also must be used correctly for effective medication deposition.37 Because pMDIs usually require the coordination of actuation with inhalation, we always recommend that they be used with a valved holding chamber to decrease coarse particle deposition in the oral pharynx and the need to coordinate canister actuation with inhalation. The exception to this is the Maxair (pirbuterol) Autohaler (3M; St. Paul, MN), which is a breath-activated pMDI that produces a lower velocity aerosol stream. To this date, the Autohaler has been marketed only using the ß-agonist pirbuterol.
In most polycarbonate holding chambers, the half-life of respirable particles is < 10 s, but this time can be increased after reducing the electrostatic charge by washing the holding chamber with a small amount of detergent and then air drying before first use.3738
A large dead space in some valved holding chambers reduces the amount of medication available, especially to small infants with low tidal volumes. As well, an inefficient valve design that prevents the holding chamber valves from opening and closing with quiet breathing will also severely limit the amount of medication available to the patient. Multiple actuations of the pMDI into the holding chamber also decrease the amount of medication available to the patient.38
For DPIs to work, the medication must be released and then deaggregated to an aerosol while being inhaled. Since the energy from the patient’s inspiratory flow disperses the drug powder, the magnitude and duration of the patient’s inspiratory effort influences aerosol generation from a DPI.39 Some of the earlier devices such as the Spinhaler or the Rotahaler (these were manufactured by GlaxoSmithKline; [Research Triangle Park, NC] but are not available now) required very high inspiratory flow and were inefficient at delivering medication to most children.40 More modern DPIs require a much lower flow to be effective. Differences still exist among DPI devices. The Turbuhaler (AstraZeneca; Wilmington, DE) is most effective with an inspiratory flow of 
60 L/min.41 Most adults and healthy children over the age of 5 years can inhale at 60 L/min and have no difficulty using a Turbuhaler,4243 but many of those below this age have lower peak inspiratory flow and thus are unable to use this device well.44 Dry powder devices such as the Diskus (GlaxoSmithKline) have a fairly uniform performance at an inspiratory flow of > 30 L/min,45 but it has not been clearly demonstrated that this device is more effective than the Turbuhaler in any patient group including small children or patients with acute asthma.
All of the currently available multidose DPIs have a dose counter that lets the patient know when they are out of medication. Unfortunately, dose counters have not been incorporated into pMDIs, and therefore it is left to the patient to determine when the medication is gone. In a survey of 50 asthmatic patients who presented for the first time at our pediatric asthma center and who were using a pMDI for asthma therapy, we found that 41 of these patients (82%) thought that their pMDI still had medication if they were able to hear the noise of air flow when they depressed the canister in the actuator boot. We also showed that medication canisters of ICSs or ß-agonists with a nominal dose of 60 actuations continue to make a noise for a mean (± SD) of 113 ± 7 actuations, or nearly twice the nominal dose.46 Aerosol canisters usually have a 15% overfill, and there is a significant dropoff of medication emitted, so that patients who continue to use the pMDI until it no longer makes a sound when depressed, actually inhale > 40 puffs with very little medication. In describing patients who think that they are taking their medication when they actually are activating a nearly empty canister, we have coined the term pseudo-adherence. Until dose counters are routinely incorporated into pMDIs, we teach our patients to divide the number of actuations printed on the canister by the total number of actuations they require for medication each day in order to determine the number of days that the canister will contain active medication. They record the last day of canister use and affix this date to the actuator boot. For example, if a typical ICS canister has 120 actuations at the nominal dose and the patient is receiving two inhalations twice a day (or four puffs per day), each canister should last 1 month. Patients are then taught to discard the medication at the end of the month and start a new canister at that time.
Key problems with the proper use of aerosol devices are summarized in Table 1 . Education programs must evaluate how patients are using a prescribed device, and the physician should periodically reassess their understanding. As always, the caregiver must first know in order to teach.
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The Patient Who Does Not Have Asthma |
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Many infants with small airways are more likely to wheeze transiently with viral infection and to not respond to therapy with bronchodilators.47 These recurrent obstructive symptoms remit in most children who develop these symptoms during the first 3 years of life. Low lung function seems to be the primary risk factor for these transient episodes, as described by Dodge et al48 in the prospective Tucson Children’s Respiratory Study. Not only are these infants unlikely to respond to asthma medication, but they also appear to be at no greater risk for the development of asthma in later life than children who do not wheeze.48
It has been well-documented that infants with bronchiolitis do not respond to therapy with ICSs,49 and that most do not benefit from inhaled bronchodilators, although some may benefit from inhaled epinephrine.50 Most infants who have wheezing with a viral infection have a self-limited disease that will not improve with the use of aerosols that are designed to treat asthma.
Patients with chronic rhinitis can have chronic cough, resulting from postnasal drip, and this can be confused with the presence of cough-variant asthma. As well, when small children have upper airway congestion, these sounds (poetically called ruttles by Dr. Mark Everard) can be transmitted into the chest and be mistakenly recognized as chest congestion or wheeze.
The relationship between gastroesophageal reflux and wheezing in infants is not clear, and is complicated by the fact that children with airflow obstruction swallow air and that distension of the stomach can exacerbate gastroesophageal reflux. A trial of therapy for gastroesophageal reflux disease may be warranted, particularly in infants with chronic cough and other respiratory complaints with or without failure to thrive.51 In infants (ie, < 1 year of age) a barium swallow (sometimes called an upper GI series) is useful to evaluate for esophageal abnormalities, vascular rings compressing the trachea, and perhaps to demonstrate gastroesophageal reflux.
There are some older children who have wheezing that is referred to variously as vocal cord dysfunction, psychogenic wheeze, or functional wheezing. Although the parent and occasionally the patient may suspect that this is the result of stress, pulmonary function testing and visual airway evaluation is often necessary to confirm the diagnosis.52 A trial of an inhaled asthma medication such as corticosteroids or bronchodilators will sometimes confuse the diagnosis further, as some of these patients will initially respond either to medication or to placebo with symptom improvement, only to have symptoms recur later. The recognition of this condition, and appropriate treatment with behavioral and breathing therapy is usually effective.
An additional problem, which is more common in the young infant, is the patient to whom either the wrong medication has been prescribed or who has been prescribed a medication that will have limited or no effect on outcome. For example, studies50 have demonstrated that aerosolized ß-agonists do not improve clinical outcome in most patients with bronchiolitis. Paradoxically, changes in the osmolarity of some nebulizer solutions can exacerbate wheezing and can lead to reduced pulmonary function in some infants.53 The use of ß-agonists in infants with tracheomalacia, which is a fairly common problem in prematurely born infants who have required intubation and mechanical ventilation, can even lead to increased airway collapse and deterioration in pulmonary function.54 In general, the younger the child or the greater the number of other abnormalities such as neuromuscular problems, cardiac problems, or congenital abnormalities, the more likely it is that noisy breathing is due to airway abnormalities rather than to asthma.
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The Patient Who Really Needs More Medicine |
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Exposure to new allergens or increased exposure to allergens can exacerbate asthma. A significant reduction in glucocorticoid receptor-binding affinity was reported in ragweed-allergic asthmatic patients during ragweed pollen season.55 Exposure to irritants such as tobacco smoke or volatile inhalants (eg, glue from a new hobby of painting or model building) can increase airways hyperresponsiveness. Airway irritation also has been reported to have occurred as a result of preservatives in aerosol nebulizer solutions of medications for asthma.56
Infection also can exacerbate asthma both acutely and, probably, chronically. The development of allergic bronchopulmonary aspergillosis57 and chronic infection with Chlamydia58 have been reported to be associated with cases of difficult-to-manage asthma. Gastroesophageal reflux disease has been associated with difficult-to-control asthma. Therapy for gastroesophageal reflux disease in children with both gastroesophageal reflux and persistent asthma has resulted in a significant reduction in the in the use of short-acting and long-acting bronchodilators, as well as ICSs.59 Asthma also has been reported60 to increase in severity during menstrual periods in some women. This may be a factor to consider in the case of an adolescent girl with worsening asthma.
Steroid resistance has been invoked as a possible cause of some case of difficult-to-treat asthma. Steroid-resistant asthma has been subclassified as eosinophilic or noneosinophilic. Patients with persistent asthma symptoms and bronchial lavage evidence of airway eosinophilia, despite receiving high-dose steroid therapy, may have rare congenital alterations in the steroid receptor61 or perhaps decreased steroid receptor binding induced by allergen exposure.62 Such patients may respond to therapy with cyclosporin A.63 It is thought, however, that most patients with eosinophilic, steroid-resistant asthma are nonadherent to steroid therapy, and thus a trial of IM triamcinolone may be warranted to determine the accuracy of the diagnosis.64
A second phenotype of steroid-resistant asthma has a neutrophilic predominance in bronchial biopsy or lavage fluid samples.65 Although therapy with corticosteroids rapidly induces eosinophilic apoptosis (ie, programmed cell death), it prolongs the survival of neutrophils, and this may shift the inflammatory predominance to this class of cells, especially in the airway of patients with the most severe asthma. Success with continuous subcutaneous terbutaline infusion in some of these patients has been reported.66
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Implications for Asthma Management |
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To improve adherence, maintenance aerosol therapy should be administered along with some easily remembered activity of daily living. For twice-daily administration, medications can be kept with the toothbrush and can be inhaled just before brushing the teeth. Rinsing the mouth after brushing the teeth will also wash away residual drug that deposited in the oropharynx. It is best to avoid the regular use of medication at school as the inconvenience can significantly reduce adherence and may be an embarrassment to some children. However, the availability of rescue medication at school (or daycare or in another caretaker’s home) must be assured. It helps to prepare written guidelines for medication use, and these guidelines should be available in all places where the child stays, such as home, school, or at the residence of both parents when there is divorce or separation.67 When prescribing aerosol medications, it is important that the patient or the parent be carefully taught to use the device.24 It is usually inappropriate for children to have the responsibility for their own medication administration. This has been associated with increased asthma morbidity and mortality.268
Many of these problems can be managed by careful patient education.69 Taking the time to first understand why the patient does not want to use the medication will allow the caregiver to understand whether this reticence to take medication is due to a fear of side effects or of medications in general, or to a misunderstanding about how the medication is supposed to work in preventing or treating asthma. For the most effective patient education, caregivers must also be knowledgeable about the appropriate use of aerosol therapy in children.70
Asthma is a potentially life-threatening disease, a fact that is lost on many asthma patients. Just as children are taught to look both ways before crossing the street and to wear a seat belt when riding in a car, the parents of children with asthma and adults with asthma must be told the truth about the condition and treatment options, and must be involved in developing a written management plan that is based on mutually agreed on goals, objectives, and expectations. The written asthma management plan should include specific actions and times, and should eliminate open-ended directives. Focus on the medication brand name, what the patient should expect as a result of using it, and what the patient should do if the medication does not achieve the intended effect. Education and understanding what our patients tell us is often as important as the use of the medications that we prescribe.
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Footnotes |
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Received for publication July 24, 2003. Accepted for publication April 6, 2004.
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  B. K. Rubin Pediatricians Are Not Just Small Internists Chest, May 1, 2006; 129(5): 1118 - 1121. [Full Text] [PDF]
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 C. R. Jenkins, F. C. K. Thien, J. R. Wheatley, and H. K. Reddel Traditional and patient-centred outcomes with three classes of asthma medication Eur. Respir. J., July 1, 2005; 26(1): 36 - 44. [Abstract] [Full Text] [PDF]
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B. K. Rubin and L. Durotoye How Do Patients Determine That Their Metered-Dose Inhaler Is Empty? Chest, October 1, 2004; 126(4): 1134 - 1137. [Abstract] [Full Text] [PDF]
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