asthma-nelson n harrison.docx

8/14/2019 asthma-nelson n harrison.docx

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Asthma is a leading cause of chronic illness in childhood, responsible for a significant proportion of school days lost

because of chronic illness. Asthma is the most frequent admitting diagnosis in children's hospitals and results

nationally in 5{endash}7 lost school days/yr/child. As many as 10{endash}15% of boys and 7{endash}10% of

girls may have asthma at some time during childhood. Before puberty approximately twice as many boys as girls

are affected; thereafter, the sex incidence is equal. Asthma can lead to severe psychosocial disturbances in the

family. With proper treatment, however, satisfactory control of symptoms is almost always possible. There is no

universally accepted definition of asthma; it may be regarded as a diffuse, obstructive lung disease with (1) hyper-reactivity of the airways to a variety of stimuli and (2) a high degree of reversibility of the obstructive process,

which may occur either spontaneously or as a result of treatment. Also known as reactive airway disease, the

asthma complex probably includes wheezy bronchitis, viral-associated wheezing, and atopic related asthma. In

addition to bronchoconstriction, inflammation is an important pathophysiologic factor; it involves eosinophils,

monocytes, and immune mediators and has resulted in the alternative designation of chronic desquamating

eosinophilic bronchitis.

Both large (>2 mm) and small (


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hyperirritability of their airways ever disappears is unknown; abnormal responsiveness to methacholine inhalation

in formerly asthmatic patients has been found as long as 20 yr after symptoms have abated.

Both prevalence and mortality from asthma have increased during the last 2 decades. The causes of the increased

prevalence are unknown, but some of the factors associated with both onset of asthma and increased mortality

have been identified. Risk factors for the occurrence of asthma include poverty, black race, maternal age less than

20 yr at the time of birth, birthweight less than 2,500 gm, maternal smoking (more than one-half pack per day),small home size (


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However, it cannot compensate for hypoxemia while breathing room air because of the patient's inability to

increase the partial pressure of oxygen and oxyhemoglobulin saturation. Further progression of airway obstruction

causes more alveolar hypoventilation, and hypercapnia may occur suddenly. Hypoxia interferes with conversion o f

lactic acid to carbon dioxide and water, causing metabolic acidosis. Hypercapnia increases carbonic acid, which

dissociates into hydrogen ions and bicarbonate ions, causing respiratory acidosis.

Hypoxia and acidosis can cause pulmonary vasoconstriction, but cor pulmonale resulting from sustainedpulmonary hypertension is not a common complication of asthma. Hypoxia and vasoconstriction may damage type

II alveolar cells, diminishing production of surfactant, which normally stabilizes alveoli. Thus, this process may

aggravate the tendency toward atelectasis.

ETIOLOGY. Asthma is a complex disorder involving autonomic, immunologic, infectious, endocrine, and psychologic

factors in varying degrees in different individuals. The control of the diameter of the airways may be considered a

balance of neural and humoral forces. Neural bronchoconstrictor activity is mediated through the cholinergic

portion of the autonomic nervous system. Vagal sensory endings in airway epithelium, termed cough or irritant

receptors, depending upon their location, initiate the afferent limb of a reflex arc, which at the efferent end

stimulates bronchial smooth muscle contraction. Vasoactive intestinal peptide (VIP) neurotransmission initiates

bronchial smooth muscle relaxation. VIP may be a dominant neuropeptide involved in maintaining airway patency.

Humoral factors favoring bronchodilation include the endogenous catecholamines that act on b{beta}-adrenergic

receptors to produce relaxation in bronchial smooth muscle. When local humoral substances such as histamineand leukotrienes are released through immunologically mediated reactions, they produce bronchoconstriction,

either by direct action on smooth muscle or by stimulation of the vagal sensory receptors. Locally produced

adenosine, which binds to a specific receptor, may contribute to bronchoconstriction. Methylxanthines are

competitive antagonists of adenosine.

Asthma may be due to abnormal b{beta}-adrenergic receptor-adenylate cyclase function, with decreased

adrenergic responsiveness. Reports of decreased numbers of b{beta}-adrenergic receptors on leukocytes of

asthmatic patients may provide a structural basis for hyporesponsiveness to b{beta}-agonists. Alternatively,

increased cholinergic activity in the airway has been proposed as a defect in asthma, perhaps due to some intrinsic

or acquired abnormality in irritant receptors, which seem in asthmatic patients to have lower than normal

thresholds for response to stimulation. Neither theory reconciles all the data. In individual patients a number of

factors generally contribute in varying degrees to the activity of the asthmatic process.

Immunologic Factors. In some patients with so-called extrinsic or allergic asthma, exacerbations follow exposure to

environmental factors such as dust, pollens, and danders. Often but not always, such patients have increased

concentrations both of total IgE and of specific IgE against the allergen implicated. In other patients with clinically

similar asthma, there is no evidence of IgE involvement; skin tests are negative and IgE concentrations low. This

form of asthma, which is seen most often in the first 2 yr of life and in older adults (late-onset asthma), has been

called intrinsic. The distinction between intrinsic and extrinsic asthma may be artificial because the basic immune

mediator-induced mucosal injury is similar in both groups. Extrinsic asthma may be associated with more easily

identified stimuli of mediator release than intrinsic asthma. Patients of all ages with asthma usually have elevated

serum IgE levels, suggesting an allergic-extrinsic component in most patients. Although increased IgE levels may be

due to atopy, chronic nonspecific stimulation of the mast cell allergen-induced late-phase immune reactions

creates a prolonged nonspecific airway hyper-reactivity, which can produce bronchospasm in the absence of

identifiable extrinsic factors.

Viral agents are the most important infectious triggers of asthma. Early in life respiratory syncytial virus (RSV) and

parainfluenza virus are most often involved; in older children rhinoviruses have also been implicated. Influenza

virus infection assumes importance with increasing age. Viral agents may act to initiate asthma through

stimulation of afferent vagal receptors of the cholinergic system in the airways. An IgE response to RSV can occur

in infants and children with RSV-associated wheezing but not in those whose RSV respiratory disease is without

associated wheezing. Wheezing with RSV infection may unmask a predisposition to asthma.


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Endocrine Factors. Asthma may worsen in relation to pregnancy and menses, especially premenstrually, or may

have its onset in women at the menopause. It improves in some children at puberty. Little else is known about the

role of endocrine factors in the etiology or pathogenesis of asthma. Thyrotoxicosis increases the severity of

asthma; the mechanism is unknown.

Psychologic Factors. Emotional factors can trigger symptoms in many asthmatic children and adults, but "deviant"

emotional or behavioral characteristics are not more common among asthmatic children than among children withother chronic disabling illnesses. On the other hand, the effects of severe chronic illness such as asthma on

children's views of themselves, their parents' views of them, or their lives in general can be devastating. Emotional

or behavioral disturbances are related more closely to poor control of asthma than to the severity of the attack

itself; accordingly, skillful medical intervention can have an important impact.

CLINICAL MANIFESTATIONS. The onset of an asthma exacerbation may be acute or insidious. Acute episodes are

most often caused by exposure to irritants such as cold air and noxious fumes (smoke, wet paint) or exposure to

allergens or simple chemicals, for example, aspirin or sulfites. When airway obstruction develops rapidly in a few

minutes, it is most likely due to smooth muscle spasm in large airways. Exacerbations precipitated by viral

respiratory infections are slower in onset, with gradual increases in frequency and severity of cough and wheezing

over a few days. Because airway patency decreases at night, many children have acute asthma at this time. The

signs and symptoms of asthma include cough, which sounds tight and is nonproductive early in the course of an

attack; wheezing, tachypnea, and dyspnea with prolonged expiration and use of accessory muscles of respiration;cyanosis; hyperinflation of the chest; tachycardia and pulsus paradoxus, which may be present to varying degrees

depending upon the stage and severity of the attack. Cough may be present without wheezing, or wheezing may

be present without cough; tachypnea also may be present without wheezing. Manifestations will vary depending

on the severity of the exacerbation (Table 137{endash}1 Table 137{endash}1).

When the patient is in extreme respiratory distress, the cardinal sign of asthma, wheezing, may be strikingly

absent; in such patients, only after bronchodilator treatment gives partial relief of the airway obstruction can

enough movement of air occur to evoke wheezing. Shortness of breath may be so severe that the child has

difficulty walking or even talking. The patient with severe obstruction may assume a hunched-over, tripod-like

sitting position that makes it easier to breathe. Expiration is typically more difficult because of premature

expiratory closure of the airway, but many children complain of inspiratory difficulty as well. Abdominal pain is

common, particularly in younger children, and is due presumably to the strenuous use of abdominal muscles and

the diaphragm. The liver and spleen may be palpable because of hyperinflation of the lungs. Vomiting is common

and may be followed by temporary relief of symptoms.

During severe airway obstruction respiratory effort may be great, and the child may sweat profusely; a low-grade

fever may develop simply from the enormous work of breathing; fatigue may become severe. Between

exacerbations the child may be entirely free of symptoms and have no evidence of pulmonary disease on physical

examination. A barrel chest deformity is a sign of the chronic, unremitting airway obstruction of severe asthma.

Harrison sulci, an anterolateral depression of the thorax at the insertion of the diaphragm, may be present in

children with recurrent severe retractions. Clubbing of the fingers is rarely observed in uncomplicated asthma,

even in severe asthma. Clubbing suggests other causes of chronic obstructive lung disease such as cystic fibrosis.

DIAGNOSIS. Recurrent episodes of coughing and wheezing, especially if aggravated or triggered by exercise, viral

infection, or inhaled allergens, are highly suggestive of asthma. However, asthma can also cause persistent

coughing in children with no history of wheezing because flow rates are insufficient to generate wheezing, airway

obstruction is relatively mild, or caretakers are unable to recognize wheezing. Symptoms may have been ascribed

erroneously to "allergic cough," "allergic bronchitis," "wheezy bronchitis," or "chronic bronchitis." Pulmonary

function testing before and after administration of methacholine or a bronchodilator or before and after exercise

may help establish the diagnosis of asthma. Examination during an episode of severe symptoms may also be

helpful if improvement occurs following bronchodilator therapy. Furthermore, when treated by measures that are

specific for asthma, affected children show remarkable improvement, strongly suggesting that the cough is a sign

of asthma.


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Laboratory Evaluation. Eosinophilia of the blood and sputum occurs with asthma. Blood eosinophilia of more than

250{endash}400 cells/mm3 is usual. Asthmatic sputum is grossly tenacious, rubbery, and whitish. An eosin-

methylene blue stain usually discloses numerous eosinophils and the granules from disrupted cells. Few diseases in

children other than asthma are likely to cause eosinophilia in sputum. Sputum cultures are generally not helpful in

asthmatic children because bacterial superinfection is rare and cultures are frequently contaminated with

oropharyngeal organisms. Serum protein and immunoglobulin concentrations are generally normal in asthma

except that IgE levels may be increased.

Allergy skin testing and rast (radioallergosorbent test) or other in vitro determinations of specific IgE are useful in

identifying potentially important environmental allergens (Chapter 134).

Inhalation bronchial challenge testing is only rarely done to explore the clinical significance of allergens implicated

by skin testing, because the allergenic challenge can provoke a late-phase asthmatic response, the procedure is

time consuming, and only a single allergen can be tested at a time. When the diagnosis of asthma is uncertain,

testing for hyper-responsiveness to the bronchoconstrictive effect of methacholine or histamine may be helpful in

children old enough to cooperate in pulmonary function testing. Methacholine provocative testing should not be

performed when baseline pulmonary function is abnormal; the response to bronchodilator therapy is more

appropriate.

The response of the asthmatic patient to exercise testing is quite characteristic (Chapter 321). Running for1{endash}2 min often causes bronchodilation in patients with asthma, but prolonged strenuous exercise causes

bronchoconstriction in virtually all asthmatic subjects when breathing dry, relatively cold air. Demonstration of this

abnormal response to exercise is diagnostically helpful and helps to convince patients and parents of the

importance of preventive treatment. Treadmill running at 3{endash}4 miles/hr up a 15% grade while breathing

through the mouth for at least 6 min elicits airway obstruction in most patients with asthma, especially if the

exercise has caused an increase in pulse rate to at least 180 beats/min. Measurement of pulmonary function

immediately before exercise, immediately after exercise, and 5 and 10 min later usually discloses decreases in peak

expiratory flow rate (PFR) or forced expiratory volume in 1 sec (FEV1) of at least 15% without premedication. If

exercise causes no airway obstruction, repeat testing on other days when relative humidity is low usually elicits a

positive response in patients with asthma. Exercise testing should be deferred whenever significant airway

obstruction is already present. If possible, bronchodilators and cromolyn should be withheld for at least 8 hr

before testing; slow-release theophylline should not be administered 12{endash}24 hr prior to testing.

Every child suspected of having asthma does not require roentgenograms of the chest, but these are often

appropriate to exclude other possible diagnoses or complications, such as atelectasis or pneumonia. Lung markings

are commonly increased in asthma. Hyperinflation occurs during acute attacks and may become chronic when

airway obstruction is persistent. Atelectasis may occur in as many as 6% of children during acute exacerbations and

is especially likely to involve the right middle lobe, where it may persist for months. Repeated chest

roentgenograms during exacerbations usually are not indicated in the absence of fever, unless there is suspicion of

a pneumothorax, or tachypnea greater than 60 beats/min, tachycardia of more than 160 beats/min, localized rales

or wheezing, or decreased breath sounds.

Pulmonary function testing (Chapters 321 and 324.8) is valuable in the evaluation of children in whom asthma is

suspected. In those known to have asthma, such tests are useful in assessing the degree of airway obstruction and

the disturbance in gas exchange, in measuring response of the airways to inhaled allergens and chemicals or

exercise (bronchial provocation testing), in assessing the response to therapeutic agents, and in evaluating the

long-term course of the disease. Assessments of pulmonary function in asthma are most valuable when made

before and after administration of an aerosol bronchodilator, a procedure that indicates the degree of reversibility

of the airway obstruction at the time of the testing (Chapters 321 and 324.8). An increase of at least 10% in PFR or

FEV1 after aerosol therapy is strongly suggestive of asthma. Failure to respond does not exclude asthma and may

be due to status asthmaticus or to near-maximal pulmonary function.

In mild cases of asthma in remission, no abnormalities may be detected. In others a variety of abnormalities may

be found (see Table 137{endash}1 Table 137{endash}1). Total lung capacity, functional residual capacity, and


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residual volume are increased. Vital capacity is usually decreased. Dynamic tests of air flow, forced vital capacity

(FVC), FEV1, PFR, and maximum expiratory flow between 25 and 75% of the vital capacity (FEF25{endash}75%)

may also show reduced values, which return toward normal after administration of aerosolized bronchodilators.

With the availability of small, relatively inexpensive instruments that measure peak expiratory flow rate (Mini-

Wright Peak Flow Meter, Healthscan Assess Plus peak flow meter), it is feasible to monitor expiratory flow rate at

home two to three times each day. This provides objective measurements of the degree of airway obstruction

between office visits. A fall in peak expiratory flow predicts the onset of an exacerbation and encourages earlyintervention with additional drug therapy.

Determination of arterial blood gases and pH is important in evaluation of the patient with asthma during an

exacerbation requiring hospitalization. During remission, partial pressure of oxygen (PO2), partial pressure of

carbon dioxide (PCO2), and pH may be normal. In symptomatic periods, low PO2 is regularly found and may persist

days to weeks after an acute episode is over. Determination of oxygen saturation by pulse oximetry is helpful in

determining the severity of an acute exacerbation. PCO2 is generally low during the early stages of acute asthma.

As the obstruction worsens, PCO2 rises; this is an ominous sign. Blood pH remains normal (or sometimes slightly

alkalotic owing to hyperventilation) until the buffering capacity of the blood is exhausted, and then acidosis

develops. As airway obstruction and hypoxia become more severe, a mixed respiratory and metabolic acidosis

develops owing to hypercarbia and lactic acidosis, respectively.

DIFFERENTIAL DIAGNOSIS. Most children who have recurrent episodes of coughing and wheezing have asthma.Other causes of airway obstruction include congenital malformations (of the respiratory, cardiovascular, or

gastrointestinal systems), foreign bodies in the airway or esophagus, infectious bronchiolitis, cystic fibrosis,

immunologic deficiency disease, hypersensitivity pneumonitis, allergic bronchopulmonary aspergillosis, and a

variety of rarer conditions that compromise the airway, including endobronchial tuberculosis, fungal diseases, and

bronchial adenoma (Table 137{endash}2 Table 137{endash}2). Very rarely in the United States, tropical

eosinophilia and other parasitic infections may involve the lung and mimic asthma.

ASTHMA IN EARLY LIFE. Wheezing in the infant merits special mention because it is common and presents

substantial diagnostic and therapeutic problems. A significant number of children subsequently shown to have

asthma have had symptoms of obstructive airway disease early in life (30% younger than 1 yr and 50{endash}55%

younger than 2 yr).

A number of anatomic and physiologic peculiarities of early life predispose to obstructive airway disease: (1) adecreased amount of smooth muscle in the peripheral airways compared to adults may result in less support; (2)

mucous gland hyperplasia in the major bronchi compared to adults favors increased intraluminal mucus

production; (3) disproportionately narrow peripheral airways up to 5 yr of age result in decreased conductance

relative to adults and render the infant and young child vulnerable to disease affecting the small airways; (4)

decreased static elastic recoil of the young lung prediposes to early airway closure during tidal breathing and

results in mismatching of ventilation and perfusion and hypoxemia; (5) highly compliant rib cage and mechanically

disadvantageous angle of insertion of diaphragm to rib cage (horizontal vs. oblique in the adult) increase

diaphragmatic work of breathing; (6) decreased number of fatigue-resistant skeletal muscle fibers in the

diaphragm leave the diaphragm poorly equipped to maintain high work output; and (7) deficient collateral

ventilation with the pores of Kohn and the Lambert canals deficient in number and size. The infant and young child

are therefore predisposed to the development of atelectasis distal to obstructed airways. The combination of

these factors with the normal susceptibility of infants and children to viral respiratory infections renders this agegroup particularly vulnerable to lower respiratory tract obstructive disease.

The clinical, roentgenographic, and blood gas findings in asthma and bronchiolitis are quite similar. It is helpful to

remember that the incidence of bronchiolitis caused by RSV peaks during the first 6 mo of life, principally during

the cold weather months, and that second and third attacks are uncommon. Some clinicians have proposed using

the response to epinephrine or albuterol aerosols to help decide whether an episode is asthma or bronchiolitis,

with a favorable response favoring asthma. The validity of this test has not been established; the degree of


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response may be related more to the severity of the obstructive process than to its underlying nature. Trials of

epinephrine or other bronchodilators are worthwhile, however, as discussed later.

The onset of symptoms is rather typical. Previously well infants or young children develop what may seem to be a

cold with rhinorrhea, rapidly followed by irritability, cough, tachypnea, and wheezing. The symptoms may progress

rapidly and often require hospitalization.

During infancy, respiratory tract infections with viruses or Chlamydia may cause symptoms of airway obstruction

that can be confused with asthma. Bacterial infections of the lower airway are rare, and the concept that allergic

reactions to bacteria cause asthma is unproved. A child with recurrent episodes of coughing and wheezing

associated with bacterial infections should be investigated for cystic fibrosis or immunologic deficiency. Chronic

aspiration caused by swallowing dysfunction (usually in developmentally delayed children) or gastroesophageal

reflux also may cause recurrent cough and wheezing in early life. Symptoms of respiratory distress often occur with

or shortly after feeding, and a chest roentgenogram is commonly abnormal. Rarer causes of obstructive airway

disease in early life include obliterative bronchiolitis (usually a sequela of a severe viral insult, most often

adenovirus) and bronchopulmonary dysplasia (see Table 137{endash}2 Table 137{endash}2).

The role of food allergy as a major cause of obstructive airway symptoms during early life is controversial. Positive

skin tests for IgE-mediated sensitivity to foods are very unusual in asthmatic infants, but when present, they

indicate the need for temporary elimination of the suspected food, usually milk, wheat, or egg from the diet of theasthmatic patient. After elimination from the diet for 3 wk, challenge with the implicated food may be appropriate

to confirm the clinical relevance of the positive skin test. Challenge may be necessary two or three times after

temporary dietary elimination to ensure clinical relevance. Challenge is contraindicated in patients with a history

of anaphylaxis after ingestion of the food. Confirmed food allergy indicates a need for dietary elimination for at

least 6 mo (Chapters 135 and 145).

For an infant who has had several episodes of obstructive airway disease, a history of asthma, hay fever, or atopic

dermatitis in mother, father, or siblings is an important predictor of subsequent obstructive airway problems.

Eczema is also frequently associated with the subsequent appearance of asthma. Eosinophilia >400 cells/mm3

(and especially >700 cells/mm3) and high serum IgE concentrations predict continuing respiratory tract problems.

TREATMENT. Asthma therapy includes basic concepts of avoiding allergens, improving bronchodilation, and

reducing mediator-induced inflammation. Systemic or topical inhaled medications are used, depending upon theseverity of the episode. The principles of avoidance of allergens outlined under treatment of allergic rhinitis also

serve the child with asthma. The hyper-reactivity of the asthmatic airway as an additional factor is dealt with by

minimizing exposure to nonspecific irritants such as tobacco smoke, smoke from wood-burning stoves, and fumes

from kerosene heaters and to strong odors such as wet paint and disinfectants, and by avoiding ice-cold drinks and

rapid changes in temperature and humidity. Maintenance of humidified air is important in dry, cold climates in the

winter, but relative humidity should not exceed 50% because house dust mites thrive at higher humidity. If the

clinical history suggests IgE-mediated sensitivity to inhalant allergens that cannot be avoided or can be only

partially avoided, immunotherapy should be considered; its indications and evidence for its efficacy in asthma are

discussed in Chapter 135.

Treatment of acute asthma based on severity and location (home, emergency department, in-patient hospital) is

summarized in Figures 137{endash}2 to 137{endash}4 Figures 137{endash}2 to 137{endash}4.

Pharmacologic therapy is the mainstay of treatment of asthma. Oxygen administered by mask or nasal prongs at

2{endash}3 L/min is indicated in most children during acute asthma. Not only is the PO2 reduced during an acute

episode, but drugs used in therapy (b{beta}-adrenergic agonists or intravenous aminophylline) may cause a

transient fall in PO2 secondary to worsening of ventilation-perfusion mismatching, which occurs because these

agents cause pulmonary vasodilatation and increased cardiac output. Injection of epinephrine had been the

treatment of choice for acute asthma for many years, but bronchodilator aerosols are now preferable.


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When epinephrine is used, a dose of 0.01 mL/kg of the 1:1,000 (1.0 mg/mL) concentration of the aqueous

preparation may be given. It may be necessary to repeat the same dose once or twice at intervals of 20 min to

obtain optimal relief. In infants and small children a dose of 0.05 mL is often effective. The unpleasant side effects

of epinephrine (pallor, tremor, anxiety, palpitations, and headache) can frequently be minimized if doses of no

more than 0.3 mL are given at any age. Terbutaline, a more selective b{beta}2-agonist (Chapter 135), is available in

an injectable form and is an alternative to epinephrine. The usual dose of 0.01 mL/kg of the 1:1,000 (1 mg/mL)

concentration does not cause peripheral vasoconstriction and has a longer duration of activity, up to 4 hr. Themaximum dose of terbutaline by subcutaneous injection is 0.25 mL; this dose may be repeated once if necessary

after 20 min.

Inhalation of bronchodilator aerosols is rapidly effective in relieving the signs and symptoms of asthma. Aerosols

have the advantage that substantially less drug is given than would be required by the subcutaneous route; the

unpleasant side effects of injected drugs such as epinephrine are avoided. Furthermore, despite airway

obstruction, which may limit aerosol delivery to peripheral airways, aerosol therapy is probably more effective

than epinephrine in reversing bronchoconstriction. Albuterol (Proventil, Ventolin) solution is safe and effective at a

dose of 0.15 mg/kg (maximum 5 mg) followed by 0.05{endash}0.15 mg/kg at intervals of 20{endash}30 min until

response is adequate. Albuterol is available as a 0.5% solution (5 mg/mL) to be diluted with 2{endash}3 mL

normal saline and as a prediluted 2.5-mg unit dose, 0.083% (0.83 mg/mL). Nebulization with oxygen at 6 L/min

prevents hypoxemia that might be related to the treatment. Edetate disodium and benzalkonium chloride, found

in some solutions of albuterol and metaproterenol for nebulization, can cause bronchoconstriction in occasionalasthmatic patients; Ventolin Nebules contain neither.

If the response to epinephrine or bronchodilator aerosol is not satisfactory, aminophylline may be given

intravenously in a dose of 5 mg/kg for 5{endash}15 min at a rate no greater than 25 mg/min. This dose (which will

increase the serum theophylline concentration by no more than 10 m{mu}g/mL at the peak) is safe in the patient

who has had no theophylline in the past few hours. If there is reason to believe that the patient may already have

a significant serum theophylline concentration, the intravenous dose should be held until the theophylline level is

known. Thereafter, a theophylline dose of 1 mg/kg should increase the serum level by about 2 m{mu}g/mL. There

is little additional benefit to be gained from adding theophylline to optimal b{beta}2 aerosol therapy, but this

combination may be helpful in patients with very severe airway obstruction or those receiving less than maximal

treatment with inhaled b{beta}2-adrenergic agonists. Addition of theophylline increases the likelihood of adverse

side effects.

Most acute exacerbations of asthma respond to this treatment regimen. Unless the patient either is corticosteroid

dependent or has had corticosteroids in the recent past, administration of steroids as part of the emergency room

treatment program may be unnecessary. In borderline cases, however, when the decision is made to send the

child home rather than to hospitalize him or her, a prescription of prednisone in decreasing doses over 5{endash}

7 days may hasten resolution of the exacerbation and causes no harm. The patient should be discharged from the

emergency room with sufficient oral medication to continue therapy at home, and appropriate arrangements

should be made for follow-up. Good ambulatory management will almost always reduce the need for emergency

room visits for acute asthma. Overall, 70% of children treated in the emergency room remain well at home;

however, 10{endash}20% experience relapse within 10 days, and 15{endash}20% are hospitalized. Steroid

therapy reduces the relapse and hospitalization rates.

Status Asthmaticus

If a patient continues to have significant respiratory distress despite administration of sympathomimetic drugs

with or without theophylline, the diagnosis of status asthmaticus should be considered. Status asthmaticus is a

clinical diagnosis defined by increasingly severe asthma that is not responsive to drugs that are usually effective.

High-risk factors for severe status asthmaticus and for death from asthma are listed in Table 137{endash}3 Table

137{endash}3. A patient in whom the diagnosis is made should be admitted to a hospital, preferably to an

intensive care unit, where the condition can be carefully monitored. The severity should be determined initially

(see Table 137{endash}1 Table 137{endash}1) and monitored at regular intervals. An indwelling arterial catheter


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may be indicated. Baseline complete blood count and serum electrolytes should be measured. Because hypoxemia

and acid-base disturbances may predispose to cardiac arrhythmias and potentially cardiotoxic drugs (theophylline,

adrenergics) will be used, cardiac monitoring is almost always indicated. Analysis of arterial blood for PO2, PCO2,

and pH is also indicated. For these determinations well-arterialized capillary blood is adequate but less desirable

than arterial blood, particularly if the patient has received epinephrine, which constricts the peripheral vascular

bed.

Patients in status asthmaticus are hypoxemic. Oxygen in carefully controlled concentrations is therefore always

indicated to maintain tissue oxygenation. It may be administered very effectively by nasal prongs or mask at a flow

rate of 2{endash}3 L/min. A concentration of oxygen sufficient to maintain a partial pressure of arterial oxygen of

70{endash}90 mm Hg or oxygen saturation greater than 92% is optimal. A mist tent should not be used; the water

does not reach the lower airway to any significant extent, and mists have an irritant effect on the airways of many

asthmatic patients, leading to coughing and worsening of the wheezing. Furthermore, it is not possible to observe

a patient who is enveloped in a dense fog.

Dehydration may be present, owing to inadequate fluid intake, greatly increased insensible water loss as a result of

tachypnea, and the diuretic effect of theophylline. Care should be taken not to overhydrate the patient because

increased secretion of antidiuretic hormone occurs during status asthmaticus, promoting fluid retention, and

because the large negative peak-inspiratory pleural pressures that occur in children favor accumulation of fluid in

the interstitial spaces around the small airways. No more than 1{endash}

1.5 times maintenance levels of fluidshould be given usually. Sodium bicarbonate, 1.5{endash}2 mEq/kg, may be administered if the arterial pH is less

than 7.3, there is a metabolic acidosis, and serum sodium is less than 145 mEq/L. Because b{beta}2-adrenergic

agents may produce hypokalemia, potassium should be added to the intravenous solution after the patient voids.

Bronchodilator sympathomimetic aerosol therapy initiated in the emergency room should be continued.

Aminophylline, 4{endash}5 mg/kg, may be given intravenously over 20 min every 6 hr. Alternatively, a 5-mg/kg

loading dose followed by constant infusion in a dose of 0.75{endash}1.25 mg/kg/hr may be administered. If the

patient has received aminophylline intravenously in the emergency room, the loading dose should be omitted. It is

essential to adjust the aminophylline dose by monitoring serum theophylline concentrations because there are

many physiologic derangements that occur during the course of status asthmaticus that may affect the disposition

of theophylline. If the every 6-hr regimen is used, serum samples should be obtained 1 hr after the intravenous

injection and just before the next dose. During constant infusion, theophylline concentration should be monitored

at least at 1, 6, 12, and 24 hr as a basis for dose adjustments and 6 and 12 hr after any change in dosage or every

24 hr while receiving intravenous theophylline. A steady-state serum concentration of approximately 12{endash}

15 m{mu}g/mL should be sought. Because age affects theophylline kinetics, the starting dose for a continuous

infusion of aminophylline varies as follows: 0.5 mg/kg/hr at 1{endash}6 mo, 1.0 mg/kg/hr at 6{endash}11 mo,

1.2{endash}1.5 mg/kg/hr at 1{endash}9 yr, and 0.9 mg/kg/hr over 10 yr of age. Adrenergic drugs are best

administered by aerosol as previously described. Administration of b{beta}-agonists by inhalation at intervals of 20

min or continually is safer than administration by intravenous infusion and is probably equally effective.

Nonetheless, some authorities recommend terbutaline by subcutaneous (0.01 mg/kg; 0.3 mg maximum) or by

intravenous (10 m{mu}g/kg bolus; 0.4{endash}0.6 m{mu}g/kg/min continuous infusion increasing by 0.2

m{mu}g/kg/min to 3{endash}6 m{mu}g/kg/min) administration for severe status asthmaticus.

Treatment with an antimuscarinic such as atropine sulfate given in combination with a nebulized b{beta}-agonist

can be more effective than treatment with either alone, although the peak bronchodilation from atropine isreached more slowly than that of the b{beta}-agonist. Nebulization of atropine sulfate at doses of 0.05{endash}

0.1 mg/kg is safe for most children, but maximal doses of 0.025 mg/kg may be more appropriate for adolescents

and adults because of the possible side effects, including tachycardia and mental confusion. Inhalation of

nebulized atropine is usually safe at intervals of 4 hr.

Ipratropium bromide causes fewer side effects than atropine. Nebulization at doses of 0.25 mg every 6 hr is safe

for children at least 6 yr old, and 0.5 mg every 6 hr is safe for children older than 12 yr.


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Corticosteroids, such as methylprednisolone (Solu-Medrol), 1{endash}2 mg/kg every 6 hr, should be

administered. Because it has less effect on mineral metabolism when given in high doses and a lower cost for an

equivalent anti-inflammatory dose, methylprednisolone is preferable to hydrocortisone. Corticosteroids can

sometimes reverse tolerance to b{beta}-agonists within 1 hr, but maximal effects of steroids are usually delayed

for 6 hr. Steroids improve oxygenation, decrease airway obstruction, and shorten the time needed for recovery.

Treatment is guided by serial measurement of blood gases and pH every few hours, or more often if indicated. Ifgas and pH analysis both indicate that respiratory failure is impending, an anesthesiologist should be alerted, and

facilities and equipment should be available for tracheal intubation and respiratory support.

Mechanical ventilation should be anticipated; elective tracheal intubation with diazepam (Valium), vecuronium,

and atropine premedication is safer than emergency intubation. Respiratory care should include patient paralysis

on a volume-cycled ventilator with short inspiratory and long expiratory times, a 10- to 15-mL/kg tidal volume,

8{endash}15 breaths/min, and peak pressures of less than 60 cm H2O. The goals are to improve oxygenation,

maintain PCO2 between 40 and 60 mm Hg, and avoid barotrauma. Positive end-expiratory pressure is added in the

recovery phase to prevent atelectasis. Sedation during mechanical ventilation may be accomplished with Valium,

midazolam (Versed), or ketamine (which at doses of 1{endash}2.5 mg/kg/hr is a sedative-analgesic-anesthetic

with bronchodilator activity). Halothane anesthesia produces prompt bronchodilation but is difficult to administer

in an intensive care unit. It should be reserved for the most severe cases of status asthmaticus.

Sedation of nonventilated patients with status asthmaticus is hazardous. Tranquilizers, morphine, and other

opiates are also contraindicated because of their depressant effects on the respiratory center. The best sedative

for the patient is the presence of a competent, compassionate physician and nurse at the bedside and decreased

airway obstruction with relief of hypoxia and hypercarbia. Chest roentgenograms should be obtained in all severe

cases and repeated as indicated to detect complications such as mediastinal emphysema or pneumothorax.

Routine administration of antibiotics has not been shown to alter the course of status asthmaticus in children or to

reduce the incidence of infectious complications.

Daily Management of the Asthmatic Child

On the basis of the history, physical examination, laboratory data, pulmonary function testing, and need for

medication, patients may be classified as having mild, moderate, or severe asthma. The daily management of these

different degrees of illness varies (see Chapter 135; Figs. 137{endash}

2 to 137{endash}

4 Figs. 137{endash}

2 to137{endash}4).

MILD ASTHMA. Children with mild asthma have exacerbations of varying frequency, up to twice each week, with

decreases in peak expiratory flow rate of not more than 20% and respond to bronchodilator treatment within

24{endash}48 hr. Generally, medication is not required between exacerbations for very mild asthma with

symptoms less than every 2 wk, when the child is essentially free of symptoms of airway obstruction. Children with

mild asthma have good school attendance, good exercise tolerance, and little or no interruption of sleep by

asthma. They have no hyperinflation of the chest; their chest roentgenograms are essentially normal. Pulmonary

function testing may show mild, reversible airway obstruction, with little or no increase in lung volume.

MODERATE ASTHMA. Children with moderate asthma have symptoms more frequently than those with mild

disease and often have cough and mild wheezing between more severe exacerbations. School attendance may be

impaired, exercise tolerance will be diminished because of coughing and wheezing, and the child may lose sleep atnight, particularly during exacerbations. Such children will generally require continuous rather than intermittent

bronchodilator therapy to achieve satisfactory control of symptoms or continuous treatment with cromolyn,

nedocromil, or an inhaled corticosteroid to reverse bronchial hyper-responsiveness. Hyperinflation may be evident

clinically and roentgenographically. Signs of airway obstruction on physiologic testing are more marked than in the

mild group; lung volumes may be increased.

SEVERE ASTHMA. Children with severe asthma have virtually daily wheezing and more frequent and more severe

exacerbations; they require recurrent hospitalization, which is rarely required for mild or moderate asthma.


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Severely affected children may miss significant amounts of school, have their sleep interrupted often by asthma,

and have poor exercise tolerance. They have chest deformities as a result of chronic hyperinflation, which is

evident on roentgenograms. Bronchodilator medication will be required continuously, and regimens may include

the regular systemic or aerosol administration of corticosteroids. Physiologic testing will show more severe airway

obstruction than in mild or moderate asthma, less reversibility in response to aerosol bronchodilators, and more

severe disturbances of lung volumes.

Table 137{endash}2 Table 137{endash}2, Table 137{endash}3 Table 137{endash}3, and Table 137{endash}4

Table 137{endash}4 summarize treatment of acute asthma. Children with mild asthma should receive

bronchodilator medication only when symptomatic, and most exacerbations may be satisfactorily treated with

adrenergic agents, preferably by aerosol (albuterol, metaproterenol, terbutaline, pirbuterol, or bitolterol) or,

rarely, by injection (aqueous epinephrine, terbutaline). Use of a chamber such as an AeroChamber or InspirEase

enhances delivery of drug to the lower airways when a metered-dose inhaler is used by younger children who are

unable to coordinate actuation of the inhaler with inhalation. Such chambers permit effective administration of

b{beta}-agonists from metered-dose inhalers to children as young as 3 yr of age. Slow inhalation also increases

delivery to the lungs because a rapid inhalation causes impaction of drug particles in the pharynx. Breath holding

for up to 10 sec after inhalation of the drug also favors deposition in the lungs. When moderate or severe airway

obstruction is present, nebulization with an air compressor such as the Proneb with part LC jet or the DeVilbiss No.

561 Pulmo-Aide is often more effective than use of a metered-dose inhaler with a chamber. The apparent

advantage of nebulization over metered-dose inhaler is largely due to the different doses administered.Nebulization with such a compressor permits effective delivery of aerosols even to infants. b{beta}-Agonist liquids

for oral administration are also available for treatment of infants and young children. Theophylline may be added

to an oral regimen when indicated. Drug therapy usually can be discontinued after a few days. Exercise-induced

asthma is most effectively prevented by inhalation of an adrenergic drug immediately before exercise. Inhaled

albuterol usually affords protection for 4 hr; inhaled salmeterol (not labeled for patients younger than 12 yr by the

U.S. Food and Drug Administration [FDA]), for 12 hr. Salmeterol should be administered at least 30 min before

exercise. Inhalation of cromolyn or nedocromil shortly before exercise is also effective in preventing exercise-

induced asthma.

For children with moderate asthma who require round-the-clock therapy, two inhalations of an adrenergic aerosol

every 4{endash}6 hr, or two inhalations of salmeterol every 12 hr, often suffices. Theophylline may be added.

Dose and dosing regimen should be individualized. Some experienced allergists reserve monitoring of serum

theophylline concentrations for those patients who fail to show a favorable bronchodilator response or who have

symptoms of toxicity (gastrointestinal or central nervous system) with average dosages. When slow-release (S-R)

formulations of theophylline are used, the peak plasma concentration (assuming that a constant fraction of drug is

absorbed, which may not be the case) occurs 4{endash}8 hr after the dose, at which time a blood sample for

monitoring should be obtained. Peak concentration may not occur until 12 hr after a bedtime dose of an S-R

preparation because of delayed nocturnal absorption. Blood sampling should be delayed until after a day or so of

therapy with S-R drugs to ensure that a steady state has been achieved. Some children can be treated successfully

on an every-12-hr schedule, but others metabolize theophylline particularly rapidly and experience marked

fluctuations in serum concentration. These peaks and troughs of concentration are minimized by dividing the 24-hr

dose into equal 8-hr doses.

Younger children (aged 1{endash}9 yr) generally eliminate theophylline more rapidly than older children and

adolescents and hence require a higher daily dose on a mg/kg basis. Nonetheless, it is safest to begin with a doseof 14{endash}16 mg/kg/24 hr in most children. If this dose is well tolerated, one may increase by 25% increments

at 3- to 4-day intervals to average doses for age as necessary to control symptoms (see Table 135{endash}2 Table

135{endash}2, 137{endash}4 137{endash}4). If adequate control of symptoms is not achieved at the maximum

doses or if adverse effects become evident, adjustment in the dosing regimen must be guided by determination of

the serum theophylline concentration.

Rapidly absorbed liquids and uncoated tablets, while suitable for children with mild asthma who require a few days

of therapy for an exacerbation, have no place in the therapeutic regimen of children who require round-the-clock


12/14

theophylline therapy because wide fluctuations in serum theophylline concentrations are observed when rapidly

absorbed products are used. Which of the S-R products to use depends upon the dosage form (tablet vs capsule)

and the amount of drug needed (see Table 137{endash}4 Table 137{endash}4). Capsule formulations that can be

opened are virtually tasteless, should not be chewed, may be mixed with moist food, and are particularly suitable

for young children. Crushing an S-R tablet destroys its constant-release properties. Exacerbations of asthma in

patients receiving round-the-clock theophylline medication should be treated with adrenergic drugs, as described

earlier for children with mild asthma (see Fig. 137

{endash}2 Fig. 137

{endash}2).

Cromolyn powder inhaled four times a day from a Spinhaler or cromolyn aerosol delivered by a metered-dose

inhaler or nedocromil (not FDA labeled for patients younger than 12 yr) is useful in children with mild to moderate

asthma. A solution of cromolyn is available for home nebulization regimens for young children subject to recurrent

attacks of asthma. Cromolyn and albuterol or metaproterenol solutions may be mixed together in the nebulizer for

ease of administration if concurrent administration of a bronchodilator is necessary.

In certain children with moderate asthma, significant flare-ups occur from time to time that may require the use of

corticosteroids for a few days. Early use of steroids in the child who is known to become severely ill may reduce

the need for hospitalization. Early intervention with bronchodilator drugs (with or without steroids, depending

upon the clinical setting) is important in the management of all asthmatic children, regardless of the severity of

their conditions. Steroids should be given in adequate doses (1{endash}2 mg/kg/24 hr of prednisone or

prednisolone in two to three doses) and should be discontinued as quickly as possible, for example, within5{endash}7 days; a long "weaning" period following acute asthma is unnecessary. In patients who only rarely

require steroid administration, return of normal hypothalamic-pituitary-adrenal function is hastened by the

prompt discontinuation of the drug when the acute episode is over. Inhaled topical steroid preparations are also

effective for children with moderately severe asthma.

In a minority of children who have severe asthma despite the management guidelines outlined here, unacceptable

degrees of coughing and wheezing persist, severely limiting the child's play activities and school attendance. In

such children the judicious administration of oral corticosteroids on an alternate-day basis and as an inhaled

aerosol frequently results in significant amelioration of symptoms and allows the child to lead a normal life without

suffering the adverse effects of corticosteroids. If alternate-day therapy is indicated because of either chronic

disability or the severity or frequency of attacks of status asthmaticus, the patient is given 5{endash} 7 days of

intensive daily therapy and then switched to an alternate-day regimen with a short-acting steroid (prednisone,

prednisolone, or methylprednisolone). A 12-yr-old child might be given 60 mg, 40 mg, 30 mg, 20 mg, and 10 mg of

prednisone/24 hr over a 5-day period for an exacerbation of asthma, to be followed by alternate-day therapy at a

dose of 20 mg/24 hr given as a single dose at 7.00{endash}8.00 A.M. every 48 hr. If the patient responds well to

this regimen, the prednisone may be reduced by 5 mg per dose at 10- to 14-day intervals until the lowest dose

compatible with acceptable control of symptoms is reached, usually 5{endash}10 mg on alternate days.

Concurrent therapy with aerosol adrenergic drugs, theophylline, or cromolyn should be continued because this

reduces the dose of steroid required. Low-dose alternate-day therapy is associated with minimal adverse effects

and thus may be justified in a disease that can be life threatening and capable of causing chronic invalidism. Use of

steroid therapy should not, however, substitute for or delay comprehensive management of the disease.

Inhalational corticosteroids, such as beclomethasone dipropionate (Vanceril, Beclovent), flunisolide (AeroBid), and

triamcinolone (Azmacort), may provide an alternative to the use of every-other-day oral corticosteroid medication.

Inhalational corticosteroids may be more effective than oral steroids in reversing bronchial hyper-responsivenessand may therefore be indicated even in patients who also require continual treatment with oral steroids.

Beclomethasone, which is effective in microgram doses, is rapidly inactivated in the liver into metabolites devoid

of glucocorticoid activity. Accordingly, systemic effects in children given less than 14 m{mu}g/kg/24 hr (usual dose

is two inhalations or 84 m{mu}g four times a day) are minimal. Oropharyngeal candidiasis rarely occurs. Its

frequency and that of other adverse effects are diminished by rinsing the mouth and expectorating after inhaling

the aerosol and inhaling the aerosol through a chamber or spacer. Effective use of inhaled steroid requires a

degree of compliance by the patient not often found in children younger than 6{endash}7 yr. Studies of adults

who have received beclomethasone for up to 7 yr have shown no evidence of epithelial atrophy or thinning of


13/14

underlying connective tissue, and there have been no long-term adverse effects of the drug on the pharynx and

airways.

Continual treatment with an inhaled corticosteroid or with cromolyn is indicated for any child with symptoms of

asthma occurring as frequently as weekly except for exercise-induced asthma preventable by pretreatment with a

b{beta}-agonist, cromolyn or nedocromil.

Home monitoring of peak expiratory flow rate two to three times a day facilitates early detection of airway

obstruction in patients with severe asthma and in patients with infrequent symptoms that may progress to severe

airway obstruction. Graphing the results of monitoring will establish the child's diurnal variation and permit the

physician to suggest treatment guidelines that anticipate decreases in peak expiratory flow rate. Daily changes in

flow rate may also indicate a need for changes in continual treatment regimens. Whatever the degree of severity

of the asthma, a personalized, written crisis plan is helpful (Fig. 137{endash}5 Fig. 137{endash}5). This can

remind patients and parents about what to do in an emergency.

Emotional tensions surrounding asthma are best handled by unhurried discussion with the parents of the child's

difficulty, by avoidance of overdramatization of the child's illness, and by careful examinations with the parents of

those areas in which parent and child seem to be in conflict. The use of tranquilizers or sedatives as a substitute for

more direct attempts to solve emotional problems should be avoided. As the asthma is brought under control, the

emotional climate is often improved.

Various factors may exacerbate asthma or make the disease difficult to treat: gastroesophageal reflux, allergic

bronchopulmonary aspergillosis, nonsteroidal anti-inflammatory agents, pregnancy, and sinusitis. Chronic sinusitis

may be due to noninfectious immune-mediated inflammation or to bacterial infection. Treatment of sinusitis with

antibiotics, intranasal steroids, and oral or topical (3{endash}5 days) decongestants for 3 wk may improve

bronchoconstriction as well as sinusitis.

Asthma education programs, for example, ACT (Asthma Care Training) and Superstuff, are being used in

comprehensive asthma management. Their goal is to increase knowledge of asthma and its treatment on the part

of both the child and parent, to improve communication within the family and with the physician and nurse, to

improve compliance with the treatment plan, and to decrease the need for use of emergency room or hospital.

Prevention of Deaths from Asthma

Death from childhood asthma is rare, but asthma mortality rates have been increasing. In the United States

asthma mortality rates increased from 1.2/100,000 general population in 1979 to 2.0 in 1991. Among children

10{endash}14 yr old the asthma mortality rate increased from 0.1 in 1979 to 0.5/100,000 in 1987, the greatest

proportional increase for any age group. Rates have been three to nine times as high in black children as in whites.

Increases have also occurred in many other countries.

Reasons for these increases in mortality are unknown. Possible causes include increased prevalence of asthma;

increased indoor air pollution as a result of tighter construction of homes with emphasis on energy conservation;

excessive exposure to allergen; psychosocial dysfunction that may interfere with perception of airway obstruction

and with compliance with recommended management; delays in implementation of appropriate treatment for

acute asthma; lack of access or utilization of medical care, including preventive care; over-reliance on

bronchodilator inhalers leading to delayed treatment with steroids or other therapy until patients are in extremis;unavailability of epinephrine for patients unable to use inhalers effectively; inappropriate use of the metered-dose

inhaler; and failure to provide continuity of care or education about what to do for an unusually severe episode of

asthma.

Most but not all deaths from asthma are preventable with appropriate care. It is possible to identify many of those

at greatest risk for death from their histories, for example, respiratory failure with hypercapnia, loss of

consciousness caused by asthma, or psychosocial dysfunction in the patient or family. These patients require

especially close monitoring and psychotherapy when indicated. Each should carry a written emergency protocol


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indicating current medications and recommended emergency treatment as guidance for emergency personnel

who may be unfamiliar with the patient. They should also have a written crisis plan indicating what they should do

in an emergency. This should include which medications to use, which doses to use at what intervals, how to reach

their physicians, and where to get further assistance. A Medic-Alert emblem can be helpful if such a patient is

found unconscious or unable to indicate the nature of the illness. Such patients should be provided with injectable

epinephrine in a convenient preparation (e.g., EpiPen or EpiPen Jr.) for use in an emergency when inhalation

therapy is ineffective or inappropriate, but use of the EpiPen should not delay transport to an emergency facility.

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