Asthma: A Practical Approach for the Adult Patient

    Author: Richard L. Sheldon, MD, FACP, FCCP, Clinical Professor of Medicine at Loma Linda University; Staff Pulmonologist/Intensivist, Beaver Medical Group, Redlands, CA.

    Peer Reviewers: Felipe A. Rubio, MD, Clinical Chief, Department of Medicine, Kettering Medical Center; and Theodore Shankel, MD, Pulmonary and Critical Care Medicine, Beaver Medical Clinic, Redlands, CA.

Editor's Note-Asthma is a chronic inflammatory disease of the airways that affects approximately 15 million persons in the United States. As about one-third of these are children, asthma is the most common chronic disease of the pediatric age group.

Although it is so commonly seen in the ambulatory setting, primary care physicians (PCPs) have in recent years received poor marks from specialists for properly diagnosing and treating this condition. National attention has identified increasing mortality rates in asthma, and PCPs have been criticized for using improper and often inadequate prescribing protocols. Theophylline, once a mainstay of asthma therapy, has recently fallen from favor because of its toxicity and the availabilty of more effective and safer agents.

In recent years, several newer drugs have come to the market, and these drugs provide the clinician with more choices. These newer and more potent agents (such as leukotrie ne-blocking agents) have targeted other avenues to reverse or modify the primary causative factor in asthma-inflammation.

Managed care has taken greater interest in asthma because of the high cost and complications associated with hospitalization for status asthmaticus. Many of these admissions could and should have been averted through wider education of patients and family, use and monitoring of peak flow meters, and prompt recognition and physician intervention to anticipate exacerbations and inciting events. The National Asthma Education and Prevention Program has identified classification of asthma severity and has recommended a step-wise therapeutic approach for long-term control and quick relief. Advances in home therapy for interventions in asthma excacerbations have also been developed.

The lay press has recently highlighted several deaths due to the inappropriate use of over-the-counter asthma remedies, which has led to the reemphasis on the importance of early identification of the asthma patient and the necessity of prompt and rational medical therapy. This issue addresses these concerns and underscores the etiology, pathogenesis, and effective treatment options for asthmatic patients in our practices.

Epidemiology

Among disease entities, concern about asthma has managed to dominate the last decade due to its remarkable increase in incidence, mortality, and, thus, economic importance.1 Epidemiologists, in frustration, report on this increase despite a better understanding of asthma's pathogenesis and better means of treatment.

Most asthma begins in childhood and early teens. However, the 64 years and older population is the fastest growing population in the United States and represents the second most important group at risk for asthma-related morbidity and mortality. The presence of coexisting diseases requires the elderly to take, on the average, 6-8 different medications, making the addition of asthma medications a serious complicating factor to their health care.2 More than 14 million U.S. citizens are afflicted, with 450,000 hospital admissions and 5000 deaths reported annually.3 Primary care physicians provide 65% of the ambulatory care to asthmatics. Allergists and pulmonologists deliver 30% of the outpatient care.4

It is useful to compare methods of treatment, outcomes, and cost within different national systems (see Table 1). It will be interesting to see how costs have changed when the year 2000 data are published.

Etiology ('Triggers')

There are many culprits implicated in the etiology of asthma (see Table 2). Among them are the following interesting ideas: there may be synergy between air pollution and allergies to dust mites, pollens, cats, and mold,5 lower socioeconomic status,6 occupational dust exposure,7 attitudes of adolescents about smoking,8 race and gender (blacks and males having a higher incidence of asthma,)9 and harsh climatic conditions.10

Special mention should be made of the relationship between viruses and wheezing. In infants, the respiratory syncytial virus (RSV) is responsible for recurrent but transient wheezing. Early viral infections may affect the developing immune system, thereby modifying the subsequent risk of asthma. In children and adults with asthma, the common cold viruses can trigger an acute attack of asthma.11

The genetics of asthma are being studied more intensely. Currently, it is felt that there are strongly inherited components of the asthma phenotype. Specific genes responsible for the phenotype have not been identified. It is anticipated that discovery of primary asthma genes, asthma severity-modifying genes, and asthma treatment-modifying genes will provide tools that can improve diagnosis and management.12

Exposure of asthma patients to irritants to which they are sensitive will increase asthma symptoms and cause exacerbations. All patients with asthma, regardless of its severity, should avoid: exposure to allergens to which they have a known sensitivity, tobacco smoke, exercise when air pollution is significant, use of beta-blockers, and eating foods containing sulfites.3

Patients with asthma, nasal polyps, and sensitivity to aspirin/non-steroidal anti-inflammatory drugs (NSAIDs) should refrain from using these drugs. Furthermore, patients with rhinitis, sinusitis, and gastroesophageal reflux should be vigorously treated for these disorders since they can cause exacerbations of wheezing.3

Table 1. Comparison of Direct & Indirect Costs of Asthma from Five Countries, Adjusted to 1990 U.S. Dollars

Country, Year of Data
Asthma Prevalence in 1990
Direct Medical Costs
Indirect Costs Total Costs
Cost per Patient per Year
Australia, 1991
8.5%
$250 million
$207 million
$457 million
$326  
Canada, 1989
2.5%
$355 million
$181.1 million
$536.1 million
$1021
Sweden, 1975
3.0%
$90.8 million
$257.5 million
$348.3 million
$1315
United Kingdom, 1988
3.0%
$722.5 million
$1.07 billion
$1.79 billion
$1043
United States, 1990
4.0%
$3.6 billion
$2.6 billion
$6.4 billion
$640  

Adapted from: Am J Respir Crit Care Med. Supplement on National Asthma Education and Prevention Program Task Force Report on the Cost Effectiveness, Quality of Care and Financing of Asthma Care 1996;154:S87.

Definition

The definition of asthma has expanded as the understanding of the inciting factors, pathophysiology, and new treatment modalities have expanded. The current working definition from the Expert Panel Report of the National Asthma Education and Prevention Program (NAEPP) of the National Institutes of Health (NIH) is as follows:

"Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular: mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and ephithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Moreover, recent evidence indicates that subbasement membrane fibrosis may occur in some patients with asthma and that these changes contribute to persistent abnormalities in lung function."3

Pathophysiology

The description of the pathophysiology of asthma now includes new ways to characterize this disorder-upper airway and lower airway, mild, moderate, and severe, childhood onset and adult onset, and early and late phase-all making the old concept of "extrinsic" vs. "intrinsic" mostly inadequate.

Table 2. Common Asthma Triggers

    Allergic
      · House dust mites
      · Mold or yeast spores
      · Pollen
      · Cat hair, saliva, and urine
      · Dog hair and saliva
      · Cockroach particles
      · Aspirin and other NSAIDS
      · Metabisulfite, used as a food and drink preservative
    Non-Allergic
      · Tobacco smoke
      · Smog
      · Natural gas, propane, or kerosene
      · Wood smoke
      · Coal smoke
      · Gas, wood, coal, and kerosene heating units
      · Paint fumes
      · Viral respiratory infections
      · Exercise
      · Weather with climatic changes
    Adapted from: Managing Asthma Today: Integrating New Concepts. American Medical Association Publication 1997:4.

The factors that lead to the chronic inflammation of the airways are multiple but involve a variety of different inflammatory cells and "mediators." The implicated cells are mast cells, eosinophils, epithelial cells, macrophages, and activated T-lymphocytes. Resident cells of the airways, such as fibroblasts and endothelial and epithelial cells, can also release mediators. No single cell or "mediator" is involved, but, rather, a complex interaction between cells and their preformed mediators. Additionally, "on the spot," newly produced mediators react to inflame the airways and sensitize smooth muscle lining the airway.

Cell derived mediators alter airway smooth muscle tone, increase vascular permeability, activate neurons, and increase mucus secretion. The mediators involved include histamine, leucotrienes, chemokines, cytokines, chemotactic factors, and platelet activating factor.13 Virus-induced wheezing is due to the ability of viruses to coordinately activate epithelial cells and endothelial cells and leukocytes to cause airway edema, obstruction and increased airway responsiveness by producing pro-inflammatory cytokines and mediators.14

Once the asthma "cascade" is initiated by one or more triggers, the pathophysiologic process can be seen as three phases-the early (acute), subacute, and late (chronic) phases. The early phase almost always leads to the later phases if it is left to proceed untreated.

Chronic asthma, with inadequate control of inflammation, will lead to lung remodeling, chronic airway edema, and increased mucus viscosity and secretion. The net effect of these actions is permanent changes in lung function, mucosal thickening, and persistent airway plugging.

Newly described "adhesion proteins" found in the bronchial epithelium, vascular tissue, and lung parenchyma play an important role in maintaining the inflammation found in the airways.15

S-nitrosothiol concentrations in the trachea of asthmatic children is lower than in the trachea of normal children. Low concentrations of airway S-nitrosothiols may represent a distinct metabolic consequence of asthmatic inflammation and provide an easy way to measure nitric oxide in asthmatics. This could help to identify sub-groups of asthmatics needing specific interventions.16

Table 3. Occupational Triggers and At-Risk Workers

Agents Workers
· Di-isocyanates Plastics, floor varnishers, spray painters
· Anhydride Plastics, resins
· Trimelitic anhidrides Plastics, epoxy resins
· Amines Photographers, shellac
· Wood dust or bark Carpenters, furniture makers
· Metals (nickel & cobalt) Metal platers and grinders, diamond polishers
· Fluxes Electronics
· Drugs (PCN, psyllium, TCN) Pharmaceuticals
· Enzymes Pharmaceutical and detergent
· Latex Health care
· Plants Tea and herbal processors
· Insects Farmers, entomologists
· Lactoserum Diary
· Crabs and prawns Fisherman, processors
· Animal urine Handlers and research labs

Clinical Features and Differential Diagnosis

"All that wheezes is not asthma," is an often-repeated axiom. The diagnosis is usually not difficult and should be entertained when there are episodic symptoms of airflow obstruction that are at least partially reversible.

The differential diagnosis should include chronic obstructive pulmonary disease, recurrent aspiration, congestive heart failure, pulmonary embolism, upper airway obstruction, laryngeal and vocal cord dysfunction, cystic fibrosis, lung involvement of vasculitites, drug-induced cough (ACE inhibitors), industrial bronchitis, carcinoid syndrome, and hysteria.

Most of the diseases making up the differential diagnosis are easily ruled out by a complete history and physical, but complex laboratory and radiographic studies may be required when dealing with some of the more unusual diseases.

History. In the adult, the most important presenting symptom is intermittent cough. This is usually accompanied by a complaint of recurrent dyspnea and chest tightness (wheezing). The symptoms frequently occur at night, prompting a concern that recumbancy and the clinical situations accompanying recumbancy, such as congestive heart failure and aspiration, are present. Further investigation helps to clarify these issues.

Symptoms tend to present or be made worse with exposure to pollens, tobacco and wood smoke, animals with fur or feathers, molds, dust, chemicals (perfumes, etc.), or industrial pollution (may or may not be job related). Other inciting historical events include exercise, viral infections, changes in weather, menses, and intense emotional shifts.

The pattern of symptoms is important but may be misleading. Despite a lack of seasonal, diurnal variation, or episodic history, asthma should be high on the diagnostic list in the consideration of undiagnosed cough or wheezing.

Care should be exercised when considering family history of asthma, hay fever, eczema, or other atopic disease since these are not strong indicators of the presence of asthma. None-the-less, close relatives with allergies, rhinitis, sinusitis, and nasal polyps should be noted.

Injury of the airways by way of pneumonia (especially if recurrent) and exposure to parental smoking as a youth are important pieces of historical data.

Other important historical data include social aspects of the patient-where they are employed and, thus, to what substances they are exposed (see Table 3). Home environmental issues (including heating and cooling systems, carpeting, pets, hobbies, and vacation habits) are all important pieces of information.

If there is a smoking history present and the patient is a current and active smoker, considerable time should be taken to obtain details of this part of the patient's life. Extensive questioning by the physician of the patient's smoking habits will start a process whereby the physician can let the patient know that smoking must immediately stop.

Physical Examination. The major physical findings in the asthmatic will occur in the thorax, upper airway, and skin. Since asthma is described in terms that stress the episodic nature of the symptoms, the examiner must be prepared for a normal physical exam, even in a patient with significant disease.

Thorax. Chronic air-trapping will result in a permanently hyper-expanded chest that is seen as an increase in the anterior-posterior diameter. With acute and severe airway obstruction, findings may include the use of accessory muscles. More subtle findings of respiratory muscle distress include abdominal paradox and respiratory alternans.17 Normally, the abdomen moves outward with inspiration and inward with expiration. When the diaphragm fatigues, the opposite occurs causing abdominal paradox. Also, periods may occur when the accessory muscles serve as the main respiratory muscles while the diaphragm rests. Then, the diaphragm resumes its work while the respiratory muscles rest. This is called respiratory alternans. These last two are indicators of a failing respiratory "pump" and should be clues to advanced disease needing hospitalization.

The most compelling finding in the physical examination of the asthmatic is wheezing. This "continuous" near musical sound is caused by narrowing of the bronchi and bronchioles by spasm, airway edema, mucus plugging, or pressure on the airways from the surrounding lung, resulting in fluttering of the airway walls. To be asthmatic wheezing, it should be involuntary, with the normal person being able to produce a wheeze voluntarily with forced expiration. Asthmatic wheezing is usually heard in expiration, but, as the attack worsens, it can be heard throughout the entire respiratory cycle. Ominously, wheezing may dissolve as the attack worsens, so that the chest becomes quiet as the patient in near respiratory collapse struggles to breathe.18

Upper Airway. The asthmatic's respiratory mucus lining from top to bottom can be viewed as a continuum, with inflammation being the common denominator. An increase in mucosal swelling in the nose along with increased secretions are common. The presence of clear, jelly-like masses starting in the farthest reaches of the nasal passages seen with a otoscope indicate nasal polyps. Use of aspirin, NSAIDs, and tartazine have been implicated as causative factors in their development. In private discussions with fellow clinicians, there is agreement that nasal polyps are seen less often these days. It is suspected that the reason is due to the increased use of nasal steroids and nasal cromolyn.

Skin. Atopic dermatitis and eczema are common problems for the asthmatic.

Special Tests

Pulmonary Function Testing. Part of the basic work-up of the suspected asthmatic should be a measurement of the FVC, FEV1, and FEV1/FVC before and after inhaling a beta-agonist. The response to the inhaled beta-agonist helps to establish the reversibility aspect of asthma. The American Thoracic Society guidelines require an increase of more than 12% and 200 mL in FEV1 to indicate significant reversibility.

Primary care clinics should have access to spirometry for diagnosis and monitoring. Office spirometry for this purpose should be performed using equipment and techniques that conform to the standards published by the American Thoracic Society.

Methacholine, Histamine, and Exercise Challenge. The baseline pulmonary function test may be normal in a patient highly suspected of having asthma. In such cases, the patient's airway can be challenged with methacholine, histamine, or exercise, and then the pulmonary function test is performed again in order to see the effects of the challenge. This test has the potential for being dangerous and, therefore, should only be done in a lab trained in its use and using tightly controlled protocols. The test should not be done if the patient's FEV1 is less than 65%.

Allergy Testing. Skin tests and other forms of in-vitro tests should be considered for patients with persistent asthma and who are exposed to perennial indoor allergens.

Bronchoscopy. Within the usual clinical setting, this important diagnostic tool has not been useful in the diagnosis and therapy of asthma. It has proven invaluable in the research setting-tracking the pathophysiology of asthma with bronchoalveolar lavage (BAL) and studying the effects of medications on many aspects of asthma.

Peak Flow Meters. These hand-held devices are simple to understand and operate. They have become important tools and are used at home for the day-by-day monitoring of airway hyper-responsiveness. Initially, the patient uses the meter over a 2-3 week period to establish his or her "personal best" peak expiratory flow rate (PEFR). Daily monitoring of the PEFR is then compared to his or her personal best. If the daily PEFR stays in the 80-100% range of his or her personal best PEFR, then usual dosing of their condition continues or tapering can be advanced. If the PEFR falls to 60-80% of his or her personal best, worsening of their symptoms will follow and will require an increase in medications. A drop in PEFR to 60% or less requires immediate intervention and perhaps a visit to his or her physician.

Management

Controlling Exposure. Factors that can be controlled fall into four categories: 1) inhaled allergens, such as molds, animal danders, etc., house-dust mites, and cockroaches; 2) occupational exposures; 3) irritants, such as pollution and tobacco smoke; and 4) other factors, such as rhinitis/sinusitis, GERDS, respiratory viral infections, aspirin and NSAIDs sensitivity, and beta-blockers. Tartrazine sensitivity is no longer considered an important trigger for asthma symptoms.

Metered Dose Inhalers and Spacers. Metered dose inhalers (MDIs) have become the favored way to deliver aerosols to the airways of patients with inflammation and bronchospasm. MDI technology is moving in the direction of replacing the ozone depleting propellants, chlorofluorocarbons (CFC), with hydrofluoroalkane (HFA), which does not deplete stratospheric ozone. The plume emitted from current MDIs contains 95% CFC (Freon), which is metabolically stable. The small portion inhaled is immediately exhaled unchanged.

The major problems with MDIs center around the patient's technique while using these devices. Many of the problems inherent in the use of MDIs (impaction in the oropharynx, poor plume development, timing, Freon dispersment, etc.) can be eliminated by the use of a "spacer." Spacers come in many shapes and sizes. They will significantly improve the delivery of medication to the lower airway and, thus, should be used routinely with the MDI.19

There is concern that in the case of inhaled steroids, spacers may increase the risk of steroid complications because of the improved delivery of the medication. If this is a problem, the spacer device is eliminated and more frequent dosing is substituted.20

Table 4. Inhaled Steroids

Generic Brand inhalations/canister mcg/puff Usual Adult Dose
Beclomethasone Vanceril 200 (16.8 g) 42 mcg 84 mcg 3-4 times daily
Vanceril DS 200 84 mcg daily
Fluticasone Flovent 60, 120, 120 44, 110, 220 mcg 88-880 mcg twice daily
Flovent Rotadisk 120 50, 100, 250 mcg 50-250 mcg twice daily
Flunisolide AeroBid 250 mcg 500 mcg twice daily
AeroBid-M 100
Budesonide Pulrnicort 200 mcg 200-800 mcg twice daily
Turbuhaler 200
Triamcinolone Azmacort 240 100 mcg 200 mcg 3-4 times daily

Pharmacology

The new nomenclature classifies medications into long-term controllers and quick-relief medications. The most effective long-term controllers are those that are shown to primarily have anti-inflammatory actions.

Long-term Controllers

Corticosteroids (see Table 4). Because of their profound anti-inflammatory effect, inhaled corticosteroids are the most effective medications available to treat the chronic inflammation of asthma. If the patient uses an MDI without a "spacer" and applies appropriate technique, only 10-20% of the aerosol reaches the lung. The rest is either swallowed, remains in the device, or is exhaled.

The benefits of corticosteroids are slow to develop and require 6-12 hours in order to be manifested.21 The mechanisms of action of steroids are complex, but the net effect of their actions is to reduce airway blood blow and, thus, causes exudation of plasma into the wall of the airway and reduction of mucus production. Steroids also limit the migration of inflammatory cells into the area of damage and the release of mediators.22

Inhaled steroids are most effective as long-term controllers of symptoms, whereas the systemic steroids are best used to gain rapid control of symptoms. Usually, a twice-a-day dosing schedule of inhaled steroids is enough to control asthma and even once a day use can control mild but persistent asthma. The use of inhaled steroids will dramatically reduce the use of oral steroids and, thus, lessen the side-effects of these drugs in patients with severe disease.

Systemic steroids used over a 3-10 day period are an effective "ace up the sleeve" when symptoms break through a well-controlled patient. My personal favorite is an intra-muscular injection of 40 mg of triamcinolone. This method assures dosing compliance and a smooth taper over a three-day period. Also, the patient is assured that the treating physician realizes how uncomfortable they are by responding with a potent "shot."

Table 5. Predicting Fatal Asthma

      · Respiratory failure requiring intubation
      · Hypoxic seizures during an asthma attack
      · Reduction in prednisone dosage by more than 50% during hospitalization or one month prior to the fatal attack
      · Use of inhaled beclomethasone upon discharge
      · Increased asthma symptoms in the week prior to discharge
      · Disregard of asthma symptoms by the patient
      · Deficient self-care with noncompliance to the treatment program
      · Conflicts among the patient, parents, and staff regarding treatment
      · Life changes resulting in depression
      · Low IQ
    Adapted from: Lee-Chiong T. Predicting fatal asthma. Asthma Management 1994;3:1-2.
     

Complications of inhaled steroid therapy in usual doses include oral thrush, cough, and dysphonia. These problems can be reduced by the patient rinsing their mouth after using the medication. Only at high-doses do inhaled steroids have the potential of causing adrenal suppression, osteoporosis, thinning of the skin, and easy bruisablity.

Complications that can occur with long-term use of systemic steroids include abnormal glucose metabolism, increased appetite, fluid retention, weight gain, mood shifts, peptic ulcers, hypertension, adrenal axis suppression, thinning of the skin with eccymhosis, accelerated osteoporosis with compression fractures of vertebral bodies, Cushing's syndrome, cataracts, myopathy, aseptic necrosis of the femur, and impairment of the immune system. There are co-morbidities that can worsen as steroids are used. These co-morbidities include tuberculosis, herpes virus infections, Varicella, peptic ulcer disease, hypertension, and Strongyloides.

Every-other-day steroid oral dosing continues to be a useful way to reduce steroid use. The patient will comment that on the "off day," they will be more inclined to have symptoms but if tolerated, the steroids will be a useful technique in both tapering off higher doses and subsequent maintenance.

Presumed steroid sparing drugs, such as TAO, methotrexate, cyclosporin A, and gold, may be helpful in severe disease but the side effects of some of these medications make them dangerous, and they should be used only in extreme situations.

Steroid resistance in asthma has been identified. This state makes an already unhappy situation worse. The diagnosis of steroid resistance should only be arrived at when it is determined that adequate doses of steroids are being delivered and other confounding problems (obstructive sleep apnea, gastro-esophageal reflux, beta-blockers, etc.) have been eliminated or reduced. The diagnosis of steroid-resistant asthma is entertained when there has been poor control of symptoms after six months of strict adherence to a treatment plan and despite 2 mg of inhaled steroids per day regardless of the amount of oral steroids ingested. Management of asthma in this situation calls for a trial of medications, such as methotrexate, cyclosporin, and intravenous immunoglobulins. The efficacy of these drugs is unproven and the side effects dangerous, but, in this small population with severe disease, these drugs may serve as the last resort.23

Finally, a short burst of oral steroids is the most effective way to control wheezing during the course of a viral respiratory infection.24

Cell Stabilizers (Cromolyn Sodium and Nedocromil). These compounds block mast cell degranulation and eosinophil recruitment. The net effect is to reduce inflammation in the mild-to-moderate asthmatic. There is both an early and a late effect and an unexplained moderation in exercise-induced bronchospasm. These medications are less effective in adult onset asthma than in asthma seen in children.

Side effects are rare, and dosing can be a problem. Inhalation four times a day is required until adequate lung levels are attained. This usually requires 2-3 weeks, and then the medication dosing can be reduced to 1-2 times a day.

Long-Acting Beta2-Agonists. Salmeterol and formoterol are considered partial agonists without any anti-inflammatory activity. Both will provide effective bronchodilation over a 12-hour period. Those with more severe asthma tend not to respond to salmeterol. For the mild-to-moderate asthmatic, using these long-acting medications at bed-time is beneficial. Since these drugs have no anti-inflammatory action, they must be used with inhaled steroids.

Methylxanthines. This group of drugs were once the mainstay of asthma therapy. With the advent of techniques to measure blood levels of xanthines, their toxic effects were better appreciated and, with the improved technology of MDIs, xanthines soon became a second-line, if not third-line, medication.

Currently, theophylline is recognized as a mild-to-moderate bronchodilator with possible mild anti-inflammatory effects. In the sustained release form, it can be used with inhaled steroids to prevent nocturnal wheezing and cough. Serum levels of 5-10 mcg/mL are sufficient to achieve theophylline's desired effect.

Table 6. Indicators Suggesting That Hospitalization may be Needed

      · Decreased level of consciousness or extreme agitation (panic)
      · Can't complete sentences without stopping to breathe
      · Silent chest on auscultation
      · Persistent tachypnia or tachycardia despite treatment
      · Pulsus paradoxus
      · Abdominal paradox and respiratory alternans
      · Cyanosis
      · Peak flow rate less than 50% of "personal best" or FEV1 less than 1 L despite treatment
      · Hypoxemia and hypercarbia (SaO2 less than 88%), especially with acidosis 
      · Chest x-ray showing infiltrate, atalectasis, or pneumothorax

In the mechanically ventilated patient in the ICU, methylxanthines may be required in order to maximize treatment. In this setting, lower doses are suggested. Here too, one should aim for serum levels in the 5-10 mcg/mL range, since roughly two-thirds of the bronchodilating effects are achieved at the 10 mcg/mL level and anti-inflammatory effects are achieved at the 5-10 mcg/mL level. This level of dosing will reduce side effects, which are a major problem in a patient receiving multiple drugs at high doses.

Leukotriene Blockers. When mast cells, eosinophils, and basophils become activated, leukotrienes are released. These biochemical mediators contract smooth muscle in the airways, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells.

A new group of drugs, leukotriene inhibitors (blockers), have proven to be effective in the out-patient management of mild-to-moderate asthmatics. Taken as a pill, these medications have been noted to promptly reduce the need for inhaled beta-agonists and steroids. The side effect profile is minimal, with elevated liver enzymes being reported.

Immunotherapy. This important form of therapy should be considered when there is clear evidence of a relationship between exposure to an unavoidable allergen and symptoms, when symptoms occur all year long or for long parts of a year, and when there is difficulty controlling symptoms with standard drugs.3

Table 7. Weaning from the Ventilator is Probably Safe When . . .

    W Work of breathing is near normal
    E Electrolytes are normal*
    A Alert patient, not sedated
    N Nutritionally improved
    I Infections controlled
    N Negative inspiratory pressure is -20 to 25 cm 
    G "GASES": normal pH, PaCO2, & adequate PaO2
      *Low potassium may be due to beta-agonists

Quick-Relief Medication

Short-Acting Beta2-Agonists. The short-acting beta2-agonists are the most often used medication in the treatment of asthma. The airway smooth muscle from the trachea to the terminal bronchioles relaxes when this medication is applied. Their intracellular effect is to stimulate adenyl cyclase. They prevent and reverse the bronchoconstrictor effects of mediators such as histamine, acetylcholinne, leukotrienes, bradykinin, prostaglandins, and endothelins. These medications can inhibit cholinergic neurotransmission and increase ciliary beat frequency.

Albuterol is the most useful and frequently used drug of this class. It is most effective when inhaled and, in recommended dosages, has few side effects. When taken orally, adverse effects include restlessness, tachycardia, palpitations, and muscle tremor. When used in the acute setting, albuterol is pushed to high doses and, on occasion, can be used as a continuous aerosol until either the symptoms lessen or severe tachycardia occurs.

The adverse effects of beta2-agonists are not usually encountered in asthmatic patients. Tolerance sometimes develops with these drugs for reasons that are unclear. It is seen most commonly in asthmatics whose triggers act by way of mast-cell activation and with exercise. Tolerance may be avoided if inhaled steroids are used with the beta2-agonists and if a long-acting beta2-agonist is used at nighttime.25

Recently, a controversy has developed regarding increased mortality seemingly related to the frequent use of beta2-agonists. The essence of the controversy centers around whether there is a real increased risk of death from frequent use of these drugs or whether these drugs are used more often by the more severely afflicted asthmatic and, thus, more prone to die from their disease. Another concept is that since these medications are so effective, the severely afflicted patient may unwisely try to resolve their attack at home before presenting to the emergency room.

Anticholinergics. These drugs (ipratropium bromide and oxitropium bromide) effectively block the vagal cholinergic tone of airway smooth muscle. There is evidence that inhaled anticholinergics will also inhibit mucus secretion in the airways. Since ipratropium bromide and oxitropium bromide are such large molecules, they are not appreciably absorbed into the bloodstream. Side-effects are negligible. Their onset is slow, but they have a long duration of action. When used with beta2-agonists, they have a greatly appreciated synergistic effect.

These drugs have firmly established themselves as first-line medications in the treatment of emphysema and chronic bronchitis (COPD) but not in treating asthma. However, nebulized ipratropium has been reported to be nearly as effective as nebulized beta2-agonists in the treatment of severe, acute asthma.26

Corticosteroids. There is growing information to support the concept that high and cumulative doses of inhaled steroids in the emergency room (ER) setting, administered by metered dose inhalers with spacers along with beta agonists, have a prompt effect on acute asthma.27

Miscellaneous. Finally, patients with persistent asthma should be given the yearly influenza vaccine.28

In the future, PCPs will see more leukotriene inhibitors, hand-held nebulizers, dry-powder inhalers, and a switch away from ozone-depleting chlorofluorocarbons used as propellants in MDIs. Antibodies that block the early allergic reaction are in clinical trials.

When to Admit to Hospital

Because of the nature of the disease, hospital ERs rarely experience a night without treating at least one severe asthmatic unable to gain relief with home treatments (see Table 5). In the ER, continuous oxygen via nasal cannula at 1-3 L/min flow is standard. Albuterol with ipratropium given by inhaled aerosol every 30 minutes for three doses is frequently needed. Continuous aerosols of these medicines are sometimes given but only with careful monitoring of heart rate so that if the patient develops a tachycardia in the 160-180 beats/min range, the aerosols are stopped. Intravenous methylpredisolone, 40-125 mg, is given along with intravenous hydration.

The use of IV magnesium sulfate is controversial. Studies have shown that 1-2 mg of magnesium sulfate are helpful in severe exacerbations and is usually well tolerated. The 1 mg dose is given over 20 minutes and can be repeated 20 minutes later but should be monitored by serum levels to avoid toxicity.

There have been other therapies tried in the ER that have no place in the management of acute asthma exacerbations. These therapies are inhaled furosemide, helium/oxygen (heliox), and acetylcysteine.

Table 8. When to Refer the Asthma Patient to a Specialist

      · Patient has had a life-threatening asthma exacerbation
      · Patient is unresponsive to therapy
      · Is it something other than asthma?
      · Other disorders complicating asthma or its treatment
      · Additional diagnostic testing is needed
      · More patient education is needed
      · Patient is being considered for immunotherapy
      · The presence of severe and persistent asthma
      · Patient requires continuous oral steroids or increasingly higher doses of inhaled steroids
      · Questionable history of inhaled or ingested asthma triggers contributing to repeated exacerbations
    Adapted from: Spector SL, Nicklas RA, et al. Practice parameters for the diagnosis and treatment of asthma. J Allergy Clin Immunol 1995;96:729-731.

In-Hospital Treatment

When the patient's asthma has become so severe that hospitalization is deemed necessary, there is now an option to intubation and mechanical artificial ventilation with a standard ventilator (see Table 6). Noninvasive ventilation (NIV) is available using continuous positive airway pressure (CPAP) delivered by mask. A preferred modification of this form of ventilation is BiPAP. NIV should only be used in patients who are alert and are capable of cooperating with the treatment. Minute-by-minute attention is required to manage these patients and it should be attempted only if a skilled respiratory care practitioner (respiratory therapist) is available to attend to the details of these CPAP or BiPAP devices and monitor the patient's response. Frequently, the reward for applying BiPAP is avoiding the "slippery slope" of intubation and all that goes with it. When NIV is attempted, all oral medications should be switched to the intravenous route.

If intubation cannot be avoided, the largest diameter possible endotracheal tube should be placed orally, along with a naso-gastric tube into the stomach. Medication delivery via an MDI with an adapter inserted in the ventilator circuit is easier than using a nebulizer and does not alter inspiratory flow patterns in the ventilator's circuit. High doses of beta-agonists are tolerated, but careful monitoring for side-effects, especially serum potassium reduction, is critical.

Improvement in bronchodilation can be tracked while the patient is on a ventilator. This technique is accomplished by noting a fall in inspiratory airway resistance. Inspiratory airway resistance can be measured by calculating the difference between the peak pressure (Ppeak) and the plateau, or static, pressure (Pplat) (Ppeak minus Pplat pressure). The Ppeak is the highest pressure seen on the ventilator's pressure gauge when the machine drives the breath into the patient. The Pplat is determined by placing one's hand briefly over the expiratory limb during expiration. The ventilator's pressure gauge will drop and will come to rest at the Pplat. Removing the hand allows the pressure in the circuit to drop further to baseline before the next breath starts.

Sedation for asthmatic patients intubated and on ventilators is mandatory and sometimes paralysis is needed. Morphine sulfate should be avoided because of its tendency to cause hypotension, vomiting, and to release of histamine.

Midazolam is useful as a sedating agent because of rapid onset (2-3 minutes should be allowed), short half-life, and lack of bronchoconstrictor effect. It can be rapidly reversed by flumazenil if severe toxic reactions are seen or if the patient is to be weaned from the ventilator. The effect of midazolam can be increased by interacting with drugs commonly used to manage intubated patients-cimetidine, erythromycin, verapamil, diltiazem, ketoconazole, and itraconazole. Midazolam can be administered by either continuous infusion or small boluses. If the patient is to be mechanically ventilated for weeks, lorazepam may be a better sedating agent.

Desynchronous breathing during the early stages of intubation and mechanical ventilation increases the potential for barotrauma, hypoventilation, and poor oxygenation. When this occurs, paralysis may be needed. Beneficial effects of paralysis in this setting may include reduction of lactic acid and carbon dioxide production and reduced oxygen consumption. The neuromuscular blocker of choice is either vecuronium or pancuronium since these agents don't cause histamine release. These agents can be delivered as a continuous drip, which should be periodically stopped to evaluate the patient and to lessen the myopathy associated with extended use of these drugs. The myopathy associated with neuromuscular blockers is worsened with concomitant use of steroids. Neuromuscular blockers should only be used with adequate sedation, since patients conscious enough to be aware they are paralyzed will experience fear best described as terror.

An unconventional treatment for the intubated patient who continues to be severely obstructed is the use of Heliox (helium and oxygen mixture). Heliox is less dense than air and will decrease airway resistance and, thus, respiratory muscle fatigue. This should only be tried where skilled respiratory care practitioners are available and with careful monitoring. As stated previously, this is not a recommended therapy for ER management.

While in the ICU, high-dose steroids, IV hydration, and antibiotics are standards of care along with ventilatory support. Mechanical ventilation must end at some time. Weaning the patient from the ventilator can be accomplished by various techniques. The most often modalities used are: T-piece, continuous positive airway pressure (CPAP), pressure support ventilation (PSV), or synchronous intermittent mechanical ventilation (SIMV). When patient is deemed ready to wean (see Table 7), the clinician should pick one of the techniques listed above and apply it to the patient. Despite much research, no one weaning technique has shown superiority over the others. If superiority is seen, it is probably related more to the skill of the ICU personnel involved, rather than the modality used.

Alternative Medicine

Methods of alternate medicine (acupuncture, homeopathy, herbal medicine, transcendental meditation, and yoga) are sometimes applied to the treatment of asthma. The only published data showing any scientific support are acupuncture in exercise-induced bronchospasm.28 It is estimated that one-third of the U.S. population uses alternative medicine modalities. Therefore, it is important to ask patients for their experience with past and current forms of therapy with any of these methods in order to safely apply "non-alternative" (i.e., standard) treatment.

Special Problems

Surgery and Asthma. Patients with moderate-to-severe asthma are at an increased risk following a major surgical procedure, especially if the surgery is to the chest or upper abdomen. In these surgeries, respiratory mechanics can be altered to a degree that cough and deep breathing will be difficult, leaving the patient open to an increased risk of post-operative atalectasis and pneumonia.

If the asthma is so severe that the patient has been on systemic steroids, the surgeon will be rightly concerned that wound infection will be more likely and wound healing will be delayed. The use of systemic steroids in the post-operative asthma patient who has exacerbated as a result of the surgery is also problematic for the same reasons.

There are several strategies that can prove helpful in reducing post-operative complications in the asthmatic. The best way to avoid post-operative set-backs is to maximize the patient's airway control by loading the lung prior to surgery with long-term controllers such as inhaled steroids. Pre-operative culture of the sputum, if the patient has large amounts of secretions, is helpful. Then, if acute bronchitis or pneumonia occurs post-operatively, a helpful clue as to which antibiotic would be most beneficial is already in the chart. Increased pulmonary toilet of the lung will reduce post-operative secretions and lessen the risk of infection.

Elderly.29 This large and growing population has special problems that can complicate their asthma. General problems of the elderly can make asthma treatment difficult, such as arthritis or weakness severe enough to limit their ability to accuate a MDI. Vision and memory may be impaired to the degree that reading directions and remembering dosing schedules is problematic. There are seven specific areas that need to be mentioned.

Musculoskeletal. Between 10% and 20% of asthmatics have a reaction to aspirin.30 Thus, patients sensitized will develop prompt worsening of their wheezing after ingesting aspirin. The cyclooxygenase-mediated conversion of arachidonic acid to prostaglandins is blocked by aspirin and, thus, shunting arachidonic acid toward the formation of leukotrienes responsible for bronchoconstriction.

NSAIDS are also responsible for causing worsening bronchospasm in susceptible patients. Since degenerative joint disease is so common in this age group and NSAIDS are effective in managing the pain of arthritis, great care must be used in the use of these drugs in the elderly.

Central Nervous System Diseases. In the treatment of migraine headaches, beta-blockers are frequently used. Calcium channel blockers would be a better choice in treating the asthmatic with migraine. In treating transient ischemic attacks (TIA), aspirin is a drug of choice. Again, great care must be used when prescribing aspirin in this group. Other anti-platelet aggregating medications are preferred.

Gastrointestinal Disease. Reflux esophagitis presents a double issue in the elderly asthmatic. Not only is this condition causative of asthma symptoms, but drugs used to treat both asthma (theophylline) and reflex esophagitis (H2 blocks) can negatively interact and, thereby, increase the risk that theophylline will accumulate in the blood stream to toxic levels. Since H2 blockers are now available without prescription, a carefully done history of drug use is crucial. The better choice for treating reflux in this group is famotidine or nizatidine.

Endocrine Disorders. Corticosteroids are potent anti-inflamatory agents of proven efficacy in asthma. The oral use of steroids can cause well-documented endocrine dysfunction, glucose intolerance, fluid imbalance, and electrolyte abnormalities, to name a few. These effects are rare with inhaled steroids if used in standard doses. The most distressing problems center around noninsulin-dependant diabetes mellitus, osteoporosis in approximately 50% of asthmatics on long-term oral therapy,31 and pituitary-adrenal suppression. If a corticotropin-releasing hormone stimulation test is normal, then a rapid wean from steroid therapy will be successful.

Ophthalmic Disorders. Eye drops containing NSAIDs have been reported to cause asthma attacks.32 Ketorolac has been blamed for causing an asthma attack in a patient with nasal polyps.33 One ophthalmic beta-blocker has been reported to have caused a case of fatal asthma.34 Acute angle-closure glaucoma has occurred with the use of the combination ipratropium and beta-agonist aerosol when the mist from the treatment came in contact with the eye.35 This was not a systemic effect.

Cardiopulmonary Disorders. As mentioned before, the treatment of hypertension and asthma can be complicated when beta-blockers are used. Angiotensin converting enzyme (ACE) inhibitors are famous for causing cough and, on occasion, tip a patient with preexisting bronchial hyperactivity into full-blown bronchospasm. Calcium channel blockers are generally safer in treating asthmatics with hypertension.

ENT Disorders. Sinusitis is an important trigger for asthma attacks. Patients experiencing chronic sinusitis and pulmonary symptoms should be highly suspect for occult asthma. Many of the antibiotics used to treat sinusitis have the potential to be triggers in producing asthma attacks. This can be an especially dangerous problem if the patient is not suspected of having asthma.

Exercise

Many asthmatics find exercise will trigger bronchospasm so predictably that they give up exercising-to the detriment of their general physical well-being. The mechanisms associated with this form of bronchospasm are poorly understood, however, and air pollution and loss of heat from the airways are suspect.

If the asthma patient is to maintain a life-long exercise program, he may need to follow a few rules. Exercising when air pollution is significant and exercising in the cold should be avoided. Also, premedication with cromolyn or a beta2-agonist prior to exercise will eliminate or reduce exercise-induced bronchospasm.

Pregnancy

Low birth weight, increased perinatal mortality, and increased prematurity have all been associated with poorly controlled asthma. Whereas decongestants, live virus vaccines, immunotherapy, iodines, certain antibiotics (tetracycline, sulfonamides, and ciprofloxacin), brompheniramine, epinephrine, and alpha-adrenergic compounds are deemed potentially hazardous to the fetus, the usual medications used to treat asthma are safe.36

Disposition

Home Care. At the time of discharge from the hospital, the patient enters into a different arena where asthma becomes a foe that lurks in all parts of his or her life. Help is frequently needed to manage the patient so as to eliminate unnecessary ER visits and, thus, re-hospitalization.

Most communities have established home visitation programs that will check on the patient on a regular basis at home. These home visits are important to determine the level of safety and cleanliness that exists in the home, how well the patient is eating, and how well they are adhering to their treatment program.

Although there is no absolute proof of the cost effectiveness for such programs, it is generally felt that this type of home-care reduces costly returns to the hospital and improves overall patient care. For many senior citizens, the visits are much looked forward to social events in an otherwise lonely existence, and thus may be therapeutic on that basis alone.

There may come a time when the asthma patient needs the help of a specialist (see Table 8). Highly intense out-patient care will result in fewer costly ER visits and subsequent hospital admissions. Patient satisfaction is increased when the patient feels that he or she has the expanded resources of the community's health delivery system involved in his or her care.

Summary

Asthma is the most underdiagnosed and undermanaged disease with which primary care physicians contend. Older U.S. physicians approach asthma patients with outdated assumptions-not realizing that this disorder is a chronic inflammatory disease rather than an intermittent spasm of airway smooth muscle.

Currently, asthma is being used as a model for other chronic diseases. Lessons being learned now on how to manage and finance this disease are being applied to other chronic, difficult-to-manage diseases, such as congestive heart failure and emphysema.

References

    1. Global Initiative for Asthma. National Heart, Lung, and Blood Institute/World Health Organization Workshop Report. Bethesda, Md: National Institutes of Health; 1995;95:3659.

    2. Bardana EJ Jr. Is asthma really different in the elderly patient? J Asthma 1993;30:77-79.

    3. Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report II. Bethesda, Md: National Institutes of Health; 1997;97:4051.

    4. Weiss KB, et al. An economic evaluation of asthma in the United States. N Engl J Med 1992;326:862-866.

    5. Corbo GM, et al. Effects of environment in atopic status and respiratory disorders in children. J Allergy Clin Immunol 1993;92:16-23.

    6. Willies-Jacobo LJ. Socioeconomic status and allergy in children with asthma. J Allergy Clin Immunol 1993;92:630-632.

    7. Xiping X, et al. Occupational exposures and physician-diagnosed asthma. Chest 1993;104:1364-1370.

    8. Brook U, et al. Attitudes of asthmatic and nonasthmatic adolescents toward cigarettes and smoking. Clin Pediatr 1993;32(11):642-646.

    9. Gold DR, et al. Race and gender differences in respiratory illness prevalence and their relationship to environmental exposures in children 7 to 14 years of age. Am Rev Respir Dis 1993;148:10-18.

    10. Larsson K. High prevalence of asthma in cross country skiers. BMJ 1993;307:1326-1329.

    11. Folkerts G, et al. Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 1998;157:1708-1720.

    12. The genetics of asthma. Supp Am Rev Respi Dis 1997;156:4.

    13. Beasley R, et al. Pathology of asthma and its clinical implications. J Allergy Clin Immunol 1993;92:148-154.

    14. Folkerts G, et al. Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 1998;157:1708-1720.

    15. Albelda SM. Endothelial and epithelial cell adhesion molecules. Am J Respir Cell Mol Biol 1991;4:195-203.

    16. Gaston B, et al. Bronchodilator S-nitrosothil deficiency in asthmatic respiratory failure. Lancet 1998;351:1317-1319.

    17. Wilkins RL, et al. Clinical Assessment in Respiratory Care. 3rd ed. St. Louis, MO: Mosby-Year Book; 1995.

    18. Pasterkamp H, et al. Respiratory sounds: Advances beyond the stethoscope. Am J Respir Crit Care Med 1997;156:974-984.

    19. Kim CS, et al. Oropharyngeal deposition and delivery aspects of metered-dose inhaler aerosols. Am Rev Respir Dis 1987; 135:157-164.

    20. Toogood JH, et al. Use of spacers to facilitate inhaled-corticosteroid treatment of asthma. Am Rev Respir Dis 1984;129: 723-729.

    21. Fanta CH, et al. Glucosteroids in acute asthma: A critical controlled trial. Am J Med 1983;74:845-851.

    22. McFadden ER. Inhaled glucocorticoids and acute asthma: Therapeutic breakthrough or nonspecific effect. Am J Respir Crit Care Med 1998;157:677-678.

    23. Woolcock AJ. Corticosteroid-resistant asthma. Am J Respir Crit Care Med 1996;154:S45-S47.

    24. Brunette MG, et al. Childhood asthma: Prevention of attacks with short-term corticosteroid treatment of upper respiratory tract infections. Pediatrics 1988;81:624-629.

    25. Barnes P. Current therapies for asthma. Chest Supp 1997;111: 17S-26S.

    26. O'Driscoll BR, et al. Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet 1989; 1:1418-1420.

    27. Rodrigo G, Rodrigo C. Inhaled flunisolide for acute severe asthma. Am J Respir Crit Care Med 1998;157:698-703.

    28. Fung KP, et al. Attenuation of exercise-induced asthma by acupuncture. Lancet 1986;2:1419-1422.

    29. Anderson CJ, Bardana EJ. Asthma in the elderly: Interactions to be wary of. J Respir Dis 1995;11:965-976.

    30. Pleskow WW, et al. Aspirin-sensitive rhinosinusitis/asthma: Spectrum of adverse reactions to aspirin. J Allergy Clin Immunol 1983;71:574-580.

    31. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 1983;309:265-268.

    32. Sheehan GJ, et al. Acute asthma attack due to ophthalmic indomethacin. Ann Intern Med 1989;111:337-338.

    33. Isaacs R, McShary R. Ketorolac, nasal polyposis and bronchial asthma: A cause for concern. Anaesth Analg 1993;76:420-422.

    34. Odeh M, et al. Timolol eye-drop induced fatal bronchospasm in an asthmatic patient. J Fam Pract 1991;32:97-98.

    35. Hall SK. Acute angle-closure glaucoma as a complication of combined beta-agonist and ipratropium therapy in the emergency department. Ann Emerg Med 1994;23:884-887.

    36. Report of the Working Group on Asthma and Pregnancy. Management of Asthma During pregnancy. Bethesda, MD: National Institutes of Health; 1993;93:3279.


Readers are Invited . . .

Readers are invited to submit questions or comments on material seen in or relevant to Primary Care Reports. Send your questions to: Robin Mason-Reader Questions, Primary Care Reports, c/o American Health Consultants, P.O. Box 740059, Atlanta, GA 30374. Or, you can reach the editors and customer service personnel for Primary Care Reports via the Internet by sending e-mail to robin.mason@medec.com. You can also visit our home page at http://www.ahcpub.com. We look forward to hearing from you.