Asthma Control

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Background
Asthma is a chronic inflammatory disorder of the airways characterized by an obstruction of airflow, which may be completely or partially reversed with or without specific therapy. Airway inflammation is the result of interactions between various cells, cellular elements, and cytokines. In susceptible individuals, airway inflammation may cause recurrent or persistent bronchospasm, which causes
symptoms that include wheezing, breathlessness, chest tightness, and cough, particularly at night (early morning hours) or after exercise. Airway inflammation is associated with airway hyperreactivity or bronchial hyperresponsiveness (BHR), which is defined as the inherent tendency of the airways to narrow in response to various stimuli (eg, environmental allergens and irritants).[1] Asthma affects an estimated 300 million individuals worldwide (see Epidemiology). The prevalence of asthma is increasing, especially in children. Annually, the World Health Organization (WHO) has estimated that 15 million disability-adjusted life-years are lost and 250,000 asthma deaths are reported worldwide.[2] Approximately 500,000 annual hospitalizations (34.6% in individuals aged 18 y or younger) are due to asthma. In the United States, asthma prevalence, having increased from 1980 to 1996, showed a plateau at 9.1% of children (6.7 million) in 2007.[3] The cost of illness related to asthma is around $6.2 billion. Each year, an estimated 1.81 million people (47.8% in individuals aged 18 y or younger) require treatment in the emergency department. Among children and adolescents aged 5-17 years, asthma accounts for a loss of 10 million school days and costs caretakers $726.1 million because of work absence.[4] Guidelines from the National Asthma Education and Prevention Program provide recommendations on the diagnosis and treatment of pediatric asthma (see Clinical Presentation, Workup, and Treatment and Management). For more information, see the Medscape Reference topic Asthma.
Pathophysiology
Interactions between environmental and genetic factors result in airway inflammation, which limits airflow and leads to functional and structural changes in the airways in the form of bronchospasm, mucosal edema, and mucus plugs. Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of breathing. Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intra-alveolar pressure due to hyperinflation all lead to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxia also contributes to this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion mismatch. In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the early stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes a decrease in PaCO2. An increase in alveolar ventilation in the early stages of an acute exacerbation prevents hypercarbia.
With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis.
Role of inflammation
Chronic inflammation of the airways is associated with increased BHR, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease. New insights in the pathogenesis of asthma suggest that lymphocytes play a role. Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of T helper (Th) lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2 and interferon- (IFN-), which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (interleukin-4 [IL-4], IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation.
The hygiene hypothesis

The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in Westernized countries.[5] This hypothesis is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation). Over time, environmental stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance. Evidence suggests that the prevalence of asthma is reduced in children who experience the following events:

Certain infections (Mycobacterium tuberculosis, measles, or hepatitis A) Rural living Exposure to other children (eg, presence of older siblings and early enrollment in childcare Less frequent use of antibiotics, including in the first week of life[6] Early introduction of fish in the diet[6]
Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern. Under these conditions, the genetic background of the child, with a cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-byenvironment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating IgE, and sensitization occurs. A reciprocal interaction is apparent between the two subpopulations, in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternatively, recent studies have suggested the possibility that the loss
of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished.[7] Results of two recently reported cross sectional studies of children growing up on farms in Central Europe who were exposed to greater variety of environmental microorganisms showed an inverse relationship between microbial exposure and the probability of asthma.[8]
Genetic factors
Some studies highlight the importance of genotypes in contributing to asthma susceptibility and allergic sensitization, as well as response to specific asthma treatments.[9, 10, 11, 12] Through the use of cluster analysis, the Severe Asthma Research Program of the National Heart, Lung, and Blood Institute identified 5 phenotypes of asthma.[13] Cluster 1 patients have early-onset atopic asthma with normal lung function treated with two or fewer controller medications and minimal health care utilization. Cluster 2 patients have early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 comprises mostly older obese women with late-onset nonatopic asthma, moderate reductions in pulmonary function, and frequent oral corticosteroid use to manage exacerbations. Cluster 4 and cluster 5 patients have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.[13] A recently reported meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations identified 5 susceptibility loci. Four were on previously reported loci on 17q21 and a new asthma susceptibility locus at PYHIN1, which is specific to the African American population.[14] An Australian study identified 2 new loci with genome-wide significant association with asthma risk: rs4129267 in IL6R and rs7130588 on band 11q13.5. The IL6R association supports the hypothesis that cytokine dysregulation affects asthma risk, hence a specific antagonist to IL6R may help. The results for the 11q13.5 locus suggest its association with allergic sensitization and subsequent development of asthma.[15]
Other factors
Lemanske et al reported that wheezing illnesses caused by rhinovirus infection during infancy were the strongest predictor of wheezing in the third year of life.[16] In a study of preschool children with asthma, Guilbert et al found that 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued.[17] In a study of children in the Cincinnati area, Reponen et al found that a high Environmental Relative Moldiness Index (ERMI)[18] at age 1 year made asthma at age 7 years more likely. The ERMI did not predict specific mold allergies at age 7 years. Air conditioning made asthma less likely. An elevated ERMI at age 7 years had no correlation with current asthma. Seeing or smelling mold in a home inspection at age 1 year did not correlate with the ERMI or with the development of asthma. They also
found that black race, having a parent with asthma, and house dust allergy was predictive of a greater likelihood of asthma.[19] A recent study from Australia reported that obesity is a determinant of asthma control independent of inflammation, lung function, and airway hyperresponsiveness.[20] A similar association between increased risk of worse asthma control and obesity was reported in a recent retrospective study of 32,321 children aged 5-17 years.[21] A significant inverse relationship between serum vitamin D levels and patient IgE levels, steroid requirements, and in vitro responsiveness to corticosteroids in children has been reported.[22]
Etiology
In most cases of asthma in children, multiple triggers or precipitants are recognized, and the patterns of reactivity may change with age. Treatment can also change the pattern. Certain viral infections, such as respiratory syncytial virus (RSV) bronchiolitis in infancy, predispose the child to asthma.
Respiratory infections
Most commonly, these are viral infections. In some patients, fungi (eg, allergic bronchopulmonary aspergillosis), bacteria (eg, Mycoplasma, pertussis), or parasites may be responsible. Most infants and young children who continue to have a persistent wheeze and asthma have high immunoglobulin E (IgE) production and eosinophilic immune responses (in the airways and in circulation) at the time of the first viral upper respiratory tract infection (URTI). They also have early IgE-mediated responses to local aeroallergens.
Allergens and irritants

In patients with asthma, 2 types of bronchoconstrictor responses to allergens are recognized: early and late. Early asthmatic responses occur via IgE-induced mediator release from mast cells within minutes of exposure and last for 20-30 minutes. Late asthmatic responses occur 4-12 hours after antigen exposure and result in more severe symptoms that can last for hours and contribute to the duration and severity of the disease. Inflammatory cell infiltration and inflammatory mediators play a role in the late asthmatic response. Allergens can be foods, household inhalants (eg, animal allergens, molds, fungi, roach allergens, dust mites), or seasonal outdoor allergens (eg, mold spores, pollens, grass, trees). Tobacco smoke, cold air, chemicals, perfumes, paint odors, hair sprays, air pollutants, and ozone can initiate BHR by inducing inflammation.
Other factors
Asthma attacks can be related to changes in atmospheric temperature, barometric pressure, and the quality of air (eg, humidity, allergen and irritant content). In some individuals, emotional upsets clearly aggravate asthma. Exercise can trigger an early asthmatic response. Mechanisms underlying exercise-induced asthmatic response remain somewhat uncertain. Heat and water loss from the airways can increase the osmolarity of the fluid lining the airways and result in mediator release. Cooling of the airways results
in congestion and dilatation of bronchial vessels. During the rewarming phase after exercise, the changes are magnified because the ambient air breathed during recovery is warm rather than cool. The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase airway resistance and airway reactivity. Inflammatory conditions of the upper airways (eg, allergic rhinitis, sinusitis, or chronic and persistent infections) must be treated before asthmatic symptoms can be completely controlled. Multiple factors have been proposed to explain nocturnal asthma. Circadian variation in lung function and inflammatory mediator release in the circulation and airways (including parenchyma) have been demonstrated. Other factors, such as allergen exposure and posture-related irritation of airways (eg, gastroesophageal reflux, sinusitis), can also play a role. In some cases, abnormalities in CNS control of the respiratory drive may be present, particularly in patients with a defective hypoxic drive and obstructive sleep apnea.
Epidemiology
Approximately 34.1 million people in the United States have been diagnosed with asthma in their lifetime. According to the most recent US Centers for Disease Control and Prevention (CDC) Asthma Surveillance Survey, the prevalence of current asthma during 2001-2003 prevalence is estimated at 6.7% in adults and 8.5% in children, and the burden of asthma increased more than 75% from 19801999.[23, 24] Asthma accounts for more school absences and more hospitalizations than any other chronic illness. In most children's hospitals in the United States, it is the most common diagnosis at admission. Worldwide, 130 million people have asthma. The prevalence is 8-10 times higher in developed countries (eg, United States, Great Britain, Australia, New Zealand) than in the developing countries. In developed countries, the prevalence is higher in low-income groups in urban areas and inner cities than in other groups.
Race-, sex-, and age-related demographics

The prevalence of asthma is higher in minority groups (eg, blacks, Hispanics) than in other groups; however, findings from one study suggest that much of the recent increase in the prevalence is attributed to asthma in white children. Approximately 5-8% of all black children have asthma at some time. The prevalence in Hispanic children is reported to be as high as 15%. In blacks, the death rate is consistently higher than in whites. Before puberty, the prevalence of asthma is 3 times higher in boys than in girls. During adolescence, the prevalence is equal among males and females. Adult-onset asthma is more common in women than in men. In most children, asthma develops before age 5 years, and, in more than half, asthma develops before age 3 years. Among infants, 20% have wheezing with only upper respiratory tract infections (URTIs), and 60% no longer have wheezing by age 6 years. As Martinez et al have pointed out, however, many of these children are "transient wheezers" whose symptoms subside during the preschool or early school years. [25, 26] They tend to have no allergies, although their lung function is often abnormal. These findings have led to the idea that they have small lungs.
Children in whom wheezing begins early in conjunction with allergies are more likely to have wheezing when they are aged 6-11 years. Similarly, children in whom wheezing begins after age 6 years often have allergies, and the wheezing is more likely to continue when they are aged 11 years.[16]
Prognosis
Of infants who wheeze with URTIs, 60% are asymptomatic by age 6 years. However, children who have asthma (recurrent symptoms continuing at age 6 y) have airway reactivity later in childhood. Some findings suggest a poor prognosis if asthma develops in children younger than 3 years, unless it occurs solely in association with viral infections. Individuals who have asthma during childhood have significantly lower forced expiratory volume in 1 second (FEV1), higher airway reactivity, and more persistent bronchospastic symptoms than those with infection-associated wheezing. Children with mild asthma who are asymptomatic between attacks are likely to improve and be symptom-free later in life. Children with asthma appear to have less severe symptoms as they enter adolescence, but half of these children continue to have asthma. Asthma has a tendency to remit during puberty, with a somewhat earlier remission in girls. However, compared with men, women have more BHR.
Mortality and morbidity associated with asthma

Globally, morbidity and mortality associated with asthma have increased over the last 2 decades. This increase is attributed to increasing urbanization. Despite advancements in the understanding of asthma and the development of new therapeutic strategies, the morbidity and mortality rates due to asthma definitely increased from 1980-1995. In the United States, the mortality rate due to asthma has increased in all age, race, and sex strata. In the United States, the mortality rate due to asthma is more than 17 deaths per 1 million population (ie, 5000 deaths per year). From 1975-1993, the number of deaths nearly doubled in people aged 5-14 years. In the northeastern and midwestern United States, the highest mortality rate has been among persons aged 5-34 years. According to the most recent report from the CDC and the National Center for Health Statistics, 187 children aged 0-17 years died from asthma, or 0.3 deaths per 100,000 children compared with 1.9 deaths per 100,000 adults aged 18 or older in the year 2002.[23] Non-Hispanic blacks were the most likely to die from asthma and had an asthma death rate more than 200% higher than non-Hispanic whites and 160% higher than Hispanics.
Patient Education
Patient and parent education should include instructions on how to use medications and devices (eg, spacers, nebulizers, metered-dose inhalers [MDIs]). The patient's MDI technique should be assessed on every visit. Discuss the management plan, which includes instructions about the use of medications, precautions with drug and/or device usage, monitoring symptoms and their severity (peak flow meter reading), and identifying potential adverse effects and necessary actions.
Write and discuss in detail a rescue plan for an acute episode. This plan should include instructions for identifying signs of an acute attack, using rescue medications, monitoring, and contacting the asthma care team. Parents should understand that asthma is a chronic disorder with acute exacerbations; hence, continuity of management with active participation by the patient and/or parents and interaction with asthma care medical personnel is important. Emphasize the importance of adherence to treatment. Incorporate the concept of expecting full control of symptoms, including nocturnal and exerciseinduced symptoms, in the management plans and goals (for all but the most severely affected patients). Avoid unnecessary restrictions in the lifestyle of the child or family. Expect the child to participate in recreational activities and sports and to attend school as usual. A systematic review by Coffman and colleagues suggested a benefit school-based asthma education. Their review included 25 studies in children aged 4-17 years.[27] In most of those studies, compared with usual care, school-based asthma education improved knowledge of asthma (7 of 10 studies), selfefficacy (6 of 8 studies), and self-management behaviors (7 of 8 studies). Fewer studies reported favorable effects on quality of life (4 of 8 studies), days of symptoms (5 of 11 studies), nights with symptoms (2 of 4 studies), and school absences (5 of 17 studies).[27] For patient education information, see the Asthma Center, as well as Asthma, Asthma FAQs, Understanding Asthma Medications, Asthma in Children, and Asthma in School Children: Educational Slides.
History
Guidelines from the National Asthma Education and Prevention Program, which were updated in 2007, highlight the importance of correctly diagnosing asthma.[28] To establish the diagnosis of asthma, the clinician must confirm the following:

Episodic symptoms of airflow obstruction are present Airflow obstruction or symptoms are at least partially reversible Alternative diagnoses are excluded
Thus, obtaining a good patient history is crucial when diagnosing asthma and excluding other causes. The clinician should establish whether the patient has any of the following symptoms:

Wheezing Cough Cough at night or with exercise Shortness of breath Chest tightness Sputum production
The clinician should determine the pattern of symptoms, as follows:

Perennial, seasonal, or both Continuous or intermittent Daytime or nighttime Onset and duration
The clinician should ask whether any of the following precipitate and/or aggravate symptoms:

Viral infections Environmental allergens Irritants (eg, smoke exposure, chemicals, vapors, dust) Exercise Emotions Home environment (eg, carpets, pets, mold) Stress Drugs (eg, aspirin, beta blockers) Foods Changes in weather
The presence of other conditions that may affect asthma should be determined. Such conditions may include the following:

Thyroid disease Pregnancy Menses Gastroesophageal reflux disease (GERD) Sinusitis Rhinitis
Questions about the development and treatment of the patients disease should touch on the following:

Age at onset and diagnosis Progression of symptoms (better or worse) Improvement with bronchodilators Use of oral corticosteroids
The family history should include any history of asthma, allergy, sinusitis, rhinitis, eczema, or nasal polyps in close relatives, and the social history should cover factors that may contribute to nonadherence of asthma medications, as well as any illicit drug use. The history of exacerbations should include the usual prodromal signs or symptoms, rapidity of onset, associated illnesses, number in the last year, and need for hospitalization. Symptoms of asthma may include wheezing, coughing, and chest tightness, among others. Patients with persistent asthmatic symptoms are more likely to experience severe asthma exacerbations.[29]
Wheezing
A musical, high-pitched, whistling sound produced by airflow turbulence is one of the most common symptoms. In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts throughout expiration. In a more severe asthmatic episode, wheezing is also present during inspiration. During the most severe episodes, wheezing may be absent because of the severe limitation of airflow associated with airway narrowing and respiratory muscle fatigue.
Asthma can occur without wheezing when obstruction involves predominantly the small airways. Thus, wheezing is not necessary for the diagnosis of asthma. Furthermore, wheezing can be associated with other causes of airway obstruction, such as cystic fibrosis and heart failure. Patients with vocal cord dysfunction have a predominantly inspiratory monophonic wheeze (different from the polyphonic wheeze in asthma), which is heard best over the laryngeal area in the neck. Patients with bronchomalacia and tracheomalacia also have a monophonic wheeze. In exercise-induced or nocturnal asthma, wheezing may be present after exercise or during the night, respectively.
Coughing and chest tightness

Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma. Usually, the cough is nonproductive and nonparoxysmal. In addition, coughing may be present with wheezing. Children with nocturnal asthma tend to cough after midnight, during the early hours of morning. A history of tightness or pain in the chest may be present with or without other symptoms of asthma, especially in exercise-induced or nocturnal asthma.
Other nonspecific symptoms

Infants or young children may have a history of recurrent bronchitis, bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most children with chronic or recurrent bronchitis have asthma. Asthma is the most common underlying diagnosis in children with recurrent pneumonia. Older children may have a history of chest tightness and/or recurrent chest congestion. In an acute episode, symptoms vary according to the severity of the episode. During a mild episode, patients may be breathless after physical activity such as walking. They can talk in sentences and lie down, and they may be agitated. During a moderate-to-severe episode, patients are breathless while talking. Infants have feeding difficulties and a softer, shorter cry. During a severe episode, patients are breathless during rest, are not interested in feeding, sit upright, talk in words (not sentences), and are usually agitated. With imminent respiratory arrest (in addition to the aforementioned symptoms), the child is drowsy and confused. However, adolescents may not have these symptoms until they are in frank respiratory failure.
Physical Examination
The clinical picture of pediatric asthma varies. Symptoms may be associated with upper respiratory infections (URTIs), nocturnal or exercise-induced asthmatic symptoms, and status asthmaticus. Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a medical emergency that requires aggressive inpatient management. This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure. Physical findings vary with the absence or presence of an acute episode and its severity.
Findings in the absence of an acute episode
The physical findings between acute episodes vary with the severity of the asthma. During an outpatient visit, a patient with mild asthma may have normal findings on physical examination. Patients with more severe asthma are likely to have signs of chronic respiratory distress and chronic hyperinflation. Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa due to allergic rhinitis, may be present. The anteroposterior diameter of the chest may be increased because of hyperinflation. Hyperinflation may also cause an abdominal breathing pattern. Lung examination may reveal prolongation of the expiratory phase, expiratory wheezing, coarse crackles, or unequal breath sounds. Clubbing of the fingers is not a feature of straightforward asthma and indicates a need for more extensive evaluation and work-up to exclude other conditions, such as cystic fibrosis.
Findings during an acute episode

Physical examination during an acute episode may reveal different findings in mild, moderately severe, and severe episodes and in status asthmaticus with imminent respiratory arrest. Findings during a mild episode include the following:

Increased respiratory rate Accessory muscles of respiration are not used The heart rate is less than 100 beats per minute Pulsus paradoxus is not present Auscultation of chest reveals moderate wheezing, which is often end expiratory Oxyhemoglobin saturation with room air is greater than 95%
Findings during a moderately severe episode include the following:

Increased respiratory rate Accessory muscles of respiration typically are used Suprasternal retractions are present The heart rate is 100-120 beats per minute Loud expiratory wheezing can be heard Pulsus paradoxus may be present (10-20 mm Hg) Oxyhemoglobin saturation with room air is 91-95%
Findings during a severe episode include the following:

The respiratory rate is often greater than 30 breaths per minute Accessory muscles of respiration are usually used Suprasternal retractions are commonly present The heart rate is greater than 120 beats per minute Loud biphasic (expiratory and inspiratory) wheezing can be heard Pulsus paradoxus is often present (20-40 mm Hg)
Oxyhemoglobin saturation with room air is less than 91%.
Findings in status asthmaticus with imminent respiratory arrest include the following:

Paradoxical thoracoabdominal movement Wheezing may be absent (in patients with the most severe airway obstruction) Severe hypoxemia may manifest as bradycardia Pulsus paradoxus may disappear; this finding suggests respiratory muscle fatigue
Diagnostic Considerations
Problems to be considered include the following:

Tracheobronchomalacia Hyperventilation syndrome Vocal cord dysfunction Pulmonary edema Collagen vascular disease Reactive airway disease
Differentials

Airway Foreign Body Allergic Rhinitis Aspergillosis Aspiration Syndromes Bronchiectasis Bronchiolitis Bronchopulmonary Dysplasia Cystic Fibrosis Gastroesophageal Reflux Primary Ciliary Dyskinesia
Approach Considerations
According to the National Asthma Education and Prevention Program guidelines, spirometry is an essential objective measure for establishing the diagnosis of asthma. Additional studies are not routinely necessary, but they may be useful when the clinician is considering alternative diagnoses.[28] Eosinophil counts and IgE levels may be useful when allergic factors are suspected. Bronchial provocation tests may be performed to diagnose bronchial hyperresponsiveness (BHR). These tests are performed in specialized laboratories by specially trained personnel to document airway hyperresponsiveness to substances (eg, methacholine, histamine). Increasing doses of provocation agents are given, and FEV1 is measured. The endpoint is a 20% decrease in FEV1 (PD20). For more information, see the Medscape Reference topic Peak Flow Rate Measurement.
Pulmonary Function Tests

Results of pulmonary function testing are not reliable in patients younger than 5 years. In young children (3-6 y) and older children who are unable to perform the conventional spirometry maneuver, newer techniques, such as measurement of airway resistance using impulse oscillometry system, are used. Measurement of airway resistance before and after a dose of inhaled bronchodilator may help to diagnose bronchodilator-responsive airway obstruction.
Spirometry
In a typical case, an obstructive defect is present in the form of normal forced vital capacity (FVC), reduced forced expiratory volume in 1 second (FEV1), and reduced forced expiratory flow more than 25-75% of the FVC (FEF 25-75). The flow-volume loop can be concave. Documentation of reversibility of airway obstruction after bronchodilator therapy is central to the definition of asthma. FEF 25-75 is a sensitive indicator of obstruction and may be the only abnormality in a child with mild disease. In an outpatient or office setting, measurement of the peak flow rate by using a peak flow meter can provide useful information about obstruction in the large airways. Take care to ensure maximum patient effort. However, a normal peak flow rate does not necessarily mean a lack of airway obstruction.
Plethysmography
Patients with chronic persistent asthma may have hyperinflation, as evidenced by an increased total lung capacity (TLC) at plethysmography. Increased residual volume (RV) and functional residual capacity (FRC) with normal TLC suggests air trapping. Airway resistance is increased when significant obstruction is present.
Exercise Challenge
In a patient with a history of exercise-induced symptoms (eg, cough, wheeze, chest tightness or pain), the diagnosis of asthma can be confirmed with the exercise challenge. In a patient of appropriate age (usually >6 y), the procedure involves baseline spirometry followed by exercise on a treadmill or bicycle to a heart rate greater than 60% of the predicted maximum, with monitoring of the electrocardiogram and oxyhemoglobin saturation. The patient should be breathing cold, dry air during the exercise to increase the yield of the study. Spirographic findings and the peak expiratory flow (PEF) rate (PEFR) are determined immediately after the exercise period and at 3 minutes, 5 minutes, 10 minutes, 15 minutes, and 20 minutes after the first measurement. The maximal decrease in lung function is calculated by using the lowest postexercise and highest pre-exercise values. The reversibility of airway obstruction can be assessed by administering aerosolized bronchodilators.
Fraction of Exhaled Nitric Oxide Testing

Measuring the fraction of exhaled nitric oxide (FeNO) has proved useful as a noninvasive marker of airway inflammation, in order to guide adjustment of the dose of inhaled corticosteroids. In one study
involving home monitoring of FeNO and symptom scores, the 2 correlated. Further, in some patients, the FeNO rose before significant exacerbations of the asthma[30] ; thus, although studies of FeNO in large groups have either shown it to be helpful or not, it may be a useful method of evaluating therapy in individual patients. Due to the high cost of equipment, FeNO measurement is used primarily as a research tool at present.
Radiography and CT Scan

Include chest radiography in the initial workup if the asthma does not respond to therapy as expected. In addition to typical findings of hyperinflation and increased bronchial markings, a chest radiograph may reveal evidence of parenchymal disease, atelectasis, pneumonia, congenital anomaly, or a foreign body. In a patient with an acute asthmatic episode that responds poorly to therapy, a chest radiograph helps in the diagnosis of complications such as pneumothorax or pneumomediastinum. Consider using sinus radiography and CT scanning to rule out sinusitis. For more information, see the Medscape Reference topic Imaging in Asthma.
Allergy Testing
Allergy testing can be used to identify allergic factors that may significantly contribute to the asthma. Once identified, environmental factors (eg, dust mites, cockroaches, molds, animal dander) and outdoor factors (eg, pollen, grass, trees, molds) may be controlled or avoided to reduce asthmatic symptoms. Allergens for skin testing are selected on the basis of suspected or known allergens identified from a detailed environmental history. Antihistamines can suppress the skin test results and should be discontinued for an appropriate period (according to the particular agents duration of action) before allergy testing. Topical or systemic corticosteroids do not affect the skin reaction.
Histologic Findings
Asthma is an inflammatory disease characterized by the recruitment of inflammatory cells, vascular congestion, increased vascular permeability, increased tissue volume, and the presence of an exudate. Eosinophilic infiltration, a universal finding, is considered a major marker of the inflammatory activity of the disease. Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs. Additionally, a patient with severe asthma may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth muscle hypertrophy or hyperplasia. Proceed to Treatment & Management
Table 1. Stepwise Approach to Asthma Medications
Intermittent Asthma Age Step 1 < 5 y Rapidacting beta2agonist prn
Persistent Asthma: Daily Medication Step 2 Low-dose inhaled corticosteroid (ICS) Alternate regimen: cromolyn or montelukast Low-dose ICS Step 3 Medium-dose ICS Step 4 Medium-dose ICS plus either long-acting beta2-agonist (LABA) or montelukast Step 5 High-dose ICS plus either LABA or montelukast Step 6 High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid
5-11 Rapidy acting beta2agonist prn Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline 12 y Rapid- Low-dose ICS or acting older beta2agonist as Alternate needed regimen: cromolyn, LTRA, or theophylline
Either low-dose ICS plus either LABA, LTRA, or theophylline OR Mediumdose
Medium-dose High-dose ICS High-dose ICS ICS plus LABA plus LABA plus LABA plus oral systemic corticosteroid Alternate Alternate Alternate regimen: regimen: regimen: high- high-dose ICS medium-dose dose ICS plus plus LRTA or ICS plus either either LABA or theophylline plus LTRA or theophylline systemic theophylline corticosteroid Medium-dose High-dose ICS High-dose ICS ICS plus LABA plus LABA plus either LABA (and consider plus oral omalizumab for corticosteroid (and patients with consider Alternate allergies) omalizumab for regimen: patients with medium-dose allergies) ICS plus either LTRA, theophylline, or zileuton
Low-dose ICS plus LABA OR Medium-dose ICS Alternate regimen: lowdose ICS plus either LTRA, theophylline, or zileuton
Approach Considerations
The National Asthma Education and Prevention Program guidelines highlight the importance of treating impairment and risk domains of asthma.[28] The goals for therapy are as follows:

Control asthma by reducing impairment through prevention of chronic and troublesome symptoms (eg, coughing or breathlessness in the daytime, in the night, or after exertion) Reduce the need for a short-acting beta2-agonist (SABA) for quick relief of symptoms (not including prevention of exercise-induced bronchospasm) Maintain near-normal pulmonary function
Maintain normal activity levels (including exercise and other physical activity and attendance at work or school) Satisfy patients' and families' expectations for asthma care
Reduction in risk can be achieved by preventing recurrent exacerbations of asthma and minimizing the need for emergency room visits and hospitalizations, and preventing progressive loss of lung function. For children, preventing reduced lung growth and providing optimal pharmacotherapy with minimal or no adverse effects is important. When a patient has major allergies to dietary products, avoidance of particular foods may help. In the absence of specific food allergies, dietary changes are not necessary. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided. The goal of long-term therapy is to prevent acute exacerbations. The patient should avoid exposure to environmental allergens and irritants that are identified during the evaluation.
Components of Asthma Care

The current guidelines emphasize 4 important components of asthma care, as follows[28] :

Assessment and monitoring Education Control of environmental factors and comorbid conditions Pharmacologic treatment
Assessment and monitoring

Once the patient's condition is classified and therapy has been initiated, continual assessment is important for disease control. Asthma control is defined as "the degree to which the manifestations of asthma are minimized by therapeutic intervention and the goals of therapy are met."[28] Asthma can be classified as well controlled, not well controlled, or very poorly controlled; classification criteria vary by patient age (view PDF). In order to assess asthma control and adjust therapy, impairment and risk must be assessed. Assessment of impairment focuses on the frequency and intensity of symptoms and the functional limitations associated with these symptoms. Risk assessment focuses on the likelihood of asthma exacerbations, adverse effects from medications, and the likelihood of the progression of lung function decline; spirometry should be measured every 1-2 years, or more frequently for uncontrolled asthma. Because asthma varies over time, follow-up every 2-6 weeks is initially necessary (when gaining control of the disease) and then every 1-6 months thereafter.
Education
Patient education continues to be important in all areas of medicine and is particularly important in asthma. Self-management education should focus on teaching patients the importance of recognizing their own their level of control and signs of progressively worsening asthma symptoms.
Both peak flow monitoring and symptom monitoring have been shown to be equally effective; however, peak flow monitoring may be more helpful in cases in which patients have a history of difficulty in perceiving symptoms, a history of severe exacerbations, or moderate-to-severe asthma. Educational strategies should also focus on environmental control and avoidance strategies and medication use and adherence (eg, correct inhaler techniques and use of other devices). Using a variety of methods to reinforce educational messages is crucial in patient understanding. Providing written asthma action plans in partnership with the patient (making sure to review the differences between long-term control and quick-relief medications), education through the involvement of other members of the healthcare team (eg, nurses, pharmacists, physicians), and education at all points of care (eg, clinics, hospitals, schools) are examples of various educational tools that are available and valuable for good patient adherence and understanding.
Control of environmental factors and comorbid conditions

As mentioned above, environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with asthma. Lastly, comorbid conditions that may affect asthma must be diagnosed and appropriately managed. These include the following:

Bronchopulmonary aspergillosis Gastroesophageal reflux disease (GERD) Obesity Obstructive sleep apnea Rhinitis Sinusitis Depression Stress Low vitamin D levels
Based upon reports of an inverse correlation between low vitamin D levels and asthma control, vitamin D supplementation in children might enhance corticosteroid responses, control atopy, and improve asthma control.[22] A recent clinical trial of lansoprazole in children with poorly controlled asthma without gastroesophageal symptoms showed no improvement in symptoms or lung function, but was associated with increased adverse effects.[31] Inactivated influenza vaccine may be helpful in those who are older than 6 months.
Pharmacologic treatment
Pharmacologic management includes the use of agents for control and agents for relief. Control agents include inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin
E (IgE) antibodies (omalizumab). Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium. For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child. A stepwise approach to pharmacologic therapy is recommended to gain and maintain control of asthma in both the impairment and risk domains. The type, amount, and scheduling of medication is dictated by asthma severity (for initiating therapy) and the level of asthma control (for adjusting therapy). Step-down therapy is essential to identify the minimum medication necessary to maintain control. See table below. For pharmacotherapy, children with asthma are divided into 3 groups based on age: 0-4 y, 5-11 y, 12 y and older. For all patients, quick-relief medications include rapid-acting beta2-agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid-acting beta2-agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta2-agonists for prevention of exercise induce symptoms), stepping up treatment may be considered. See the stepwise approach to asthma medications in Table 1, below. Table 1. Stepwise Approach to Asthma Medications (Open Table in a new window) Intermittent Asthma Age Step 1 < 5 y Rapidacting beta2agonist prn Persistent Asthma: Daily Medication Step 2 Low-dose inhaled corticosteroid (ICS) Alternate regimen: cromolyn or montelukast Low-dose ICS Step 3 Medium-dose ICS Step 4 Medium-dose ICS plus either long-acting beta2-agonist (LABA) or montelukast Step 5 High-dose ICS plus either LABA or montelukast Step 6 High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid
5-11 Rapidy acting beta2agonist prn Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline 12 y Rapid- Low-dose ICS or acting older beta2-
Either low-dose ICS plus either LABA, LTRA, or theophylline OR Mediumdose
Medium-dose High-dose ICS High-dose ICS ICS plus LABA plus LABA plus LABA plus oral systemic corticosteroid Alternate Alternate Alternate regimen: regimen: regimen: high- high-dose ICS medium-dose dose ICS plus plus LRTA or ICS plus either either LABA or theophylline plus LTRA or theophylline systemic theophylline corticosteroid
Low-dose ICS Medium-dose High-dose ICS High-dose ICS plus LABA OR ICS plus LABA plus LABA plus either LABA Medium-dose (and consider plus oral
omalizumab for corticosteroid (and patients with consider Alternate allergies) omalizumab for regimen: patients with medium-dose allergies) ICS plus either LTRA, theophylline, or zileuton In the Salmeterol Multicenter Asthma Research Trial (SMART), salmeterol use in asthma patients, particularly African Americans, was associated with a small but significantly increased risk of serious asthma-related events.[32] This trial was a large, double-blind, randomized, placebo-controlled, safety trial in which salmeterol 42 mcg twice daily or placebo was added to usual asthma therapy for 28 weeks. The study was halted following interim analysis of 26,355 participants because patients exposed to salmeterol (n = 13,176) were found to experience a higher rate of fatal asthma events compared with individuals receiving placebo (n = 13,179); the rates were 0.1% and 0.02%, respectively. This resulted in an estimated 8 excess deaths per 10,000 patients treated with salmeterol. In the post-hoc subgroup analysis, the relative risks of asthma-related deaths were similar among whites and blacks, although the corresponding estimated excess deaths per 10,000 patients exposed to salmeterol were higher among blacks than whites. A meta-analysis by Salpeter et al found that LABAs increased the risk for asthma-related intubations and deaths by 2-fold, even when used in a controlled fashion with concomitant inhaled corticosteroids. However, the absolute number of adverse events remained small.[33] The large pooled trial included 36,588 patients, most of them adults. The US Food and Drug Administration (FDA) has reviewed the data and the issues and has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when LABAs are used appropriately with an asthma controller medication in patients who need the addition of LABAs. The FDA recommends the following measures for improving the safe use of these drugs[34] :

agonist as Alternate needed regimen: cromolyn, LTRA, or theophylline
ICS Alternate regimen: lowdose ICS plus either LTRA, theophylline, or zileuton
LABAs should be used long-term only in patients whose asthma cannot be adequately controlled on inhaled steroids LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved; patients should then be switched to an asthma controller medication Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA to ensure compliance with both medications
Concerns about the safety of long-acting beta2-agonists and resultant drug safety communications create a question as to the course of treatment if asthma is not controlled by inhaled corticosteroids.[34] A study by Lemanske et al addressed this question and concluded that addition of long-acting beta2agonist was more likely to provide the best response than either inhaled corticosteroids or leukotrienereceptor antagonists.[35] Asthma therapy should be regularly monitored and adjusted accordingly.
A systematic review of 18 placebo-controlled clinical trials evaluating monotherapy with inhaled corticosteroids supports their safety and efficacy in children with asthma.[36] In addition, the data provide new evidence linking inhaled corticosteroids use in children with asthma to improved asthma control. A recent study to assess the effectiveness of an inhaled corticosteroid used as rescue treatment recommends that children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. This study suggests that inhaled corticosteroids as rescue medication with albuterol might be an effective step down strategy for children as it is more effective at reducing exacerbations than is use of rescue albuterol alone.[37] . A recent Cochrane review concluded that more research is needed to assess the effectiveness of increased inhaled corticosteroid doses at the onsetofasthmaexacerbation.[38] In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects, including growth failure. Recent data from the Childhood Asthma Management Program (CAMP) study and results of the long-term use of inhaled steroids (budesonide) suggest that the long-term use of inhaled steroids has no sustained adverse effect on growth in children.[39, 40] A review by Rodrigo et al looked at 8 studies of omalizumab in children with moderate-to-severe asthma and elevated IgE levels.[41] Children treated with omalizumab were more significantly able to reduce their use of rescue inhalers and their inhaled and/or oral steroid dose than patients in the placebo group. Although no significant differences in pulmonary function were observed, patients receiving omalizumab had fewer exacerbations than the children receiving placebo. These studies lasted a year or less and did not reveal any significant adverse effects of the omalizumab. A randomized trial of omalizumab for asthma in inner-city children showed improved asthma control, elimination of seasonal peaks in asthmatic exacerbations, and reduced need for other medications for asthma control.[42]
Delivery devices and best route of administration

In pediatric asthma, inhaled treatment is the cornerstone of asthma management. Inhaler devices currently used to deliver inhaled corticosteroids (ICSs) fall into the following 4 categories:

Pressurized metered dose inhaler (pMDI) - Propellant used to dispense steroid when canister is pressed manually Dry powder inhaler (DPI) - Does not require hand-breath coordination to operate Breath-actuated pMDI - Propellant used to dispense steroid when patient inhales Nebulized solution devices
Go to Use of Metered Dose Inhalers, Spacers, and Nebulizers for complete information on this topic. In pediatric patients, the inhaler device must be chosen on the basis of age, cost, safety, convenience, and efficacy of drug delivery.[2] Based on current research, the preferred device for children younger than 4 years is a pMDI with a valved holding chamber and age-appropriate mask. Children aged 4-6 years should use a pMDI plus a valved holding chamber. Lastly, children older than 6 years can use either a pMDI, a DPI, or a breathactuated pMDI. For all 3 groups, a nebulizer with a valved holding chamber (and mask in children younger than 4 y) is recommended as alternate therapy.[2] Valved holding chambers are important. The addition of a valved holding chamber can increase the amount of drug reaching the lungs to 20%. The use of a valved holding chamber helps reduce the
amount of drug particles deposited in the oropharynx, thereby helping to reduce systemic and local effects from oral and gastrointestinal absorption. A Cochrane review on the use of valved holding chambers versus nebulizers for inhaled steroids found no evidence that nebulizers are better than valved holding chamber.[43] Nebulizers are expensive, inconvenient to use, require longer time for administration, require maintenance, and have been shown to have imprecise dosing. Newer devices are showing greater efficacy. For MDIs, chlorofluorocarbon (CFC) propellants (implicated in ozone depletion) have been phased out in favor of the hydrofluoroalkane-134a (HFA) propellant. Surprisingly, the HFA component is more environmentally friendly and has proven to be more effective, due to its smaller aerosol particle size, which results in better drug delivery. MDIs with HFA propellant have better deposition of drug in the small airways and greater efficacy at equivalent doses compared with CFC-MDIs.
Treatment of Status Asthmaticus

Treatment goals for acute severe asthmatic episodes (status asthmaticus) are as follows:

Correction of significant hypoxemia with supplemental oxygen; in severe cases, alveolar hypoventilation requires mechanically assisted ventilation Rapid reversal of airflow obstruction with repeated or continuous administration of an inhaled beta2-agonist; early administration of systemic corticosteroids (eg, oral prednisone or intravenous methylprednisolone) is suggested in children with asthma that fails to respond promptly and completely to inhaled beta2-agonists Reduction in the likelihood of recurrence of severe airflow obstruction by intensifying therapy: Often, a short course of systemic corticosteroids is helpful
Achieving these goals requires close monitoring by means of serial clinical assessment and measurement of lung function (in patients of appropriate ages) to quantify the severity of airflow obstruction and its response to treatment. Improvement in FEV1 after 30 minutes of treatment is significantly correlated with a broad range of indices of the severity of asthmatic exacerbations, and repeated measurement of airflow in the emergency department can help reduce unnecessary admissions. The use of the peak flow rate or FEV1 values, patient's history, current symptoms, and physical findings to guide treatment decisions is helpful in achieving the aforementioned goals. When using the peak expiratory flow (PEF) expressed as a percentage of the patient's best value, the effect of irreversible airflow obstruction should be considered. For example, in a patient whose best peak flow rate is 160 L/min, a decrease of 40% represents severe and potentially life-threatening obstruction. An Australian study by Vuillermin et al found that asthma severity decreased in school-aged children when parents initiated a short course of prednisolone for acute asthma.[44] Children who received parent-initiated prednisolone for episodes of asthma had lower daytime and nighttime asthma scores, reduced risk of health resource use, and reduced school absenteeism compared with children who received placebo.
Consultations
Any patient with high-risk asthma should be referred to a specialist. The following may suggest high risk:

History of sudden severe exacerbations History of prior intubation for asthma Admission to an ICU because of asthma Two or more hospitalizations for asthma in the past year Three or more emergency department visits for asthma in the past year Hospitalization or an emergency department visit for asthma within the past month Use of 2 or more canisters of inhaled short-acting beta2-agonists per month Current use of systemic corticosteroids or recent withdrawal from systemic corticosteroids
Referral to an asthma specialist for consultation or comanagement of the patient is also recommended if additional education is needed to improve adherence or if the patient requires step 4 care or higher (step 3 care or higher for children aged 04 y). Consider referral if a patient requires step 3 care (step 2 care for children aged 04 y) or if additional testing for the role of allergy is indicated.[28] The choice between a pediatric pulmonologist and an allergist may depend on local availability and practices. A patient with frequent ICU admissions, previous intubation, and a history of complicating factors or comorbidity (eg, cystic fibrosis) should be referred to a pediatric pulmonologist. When allergies are thought to significantly contribute to the morbidity, an allergist may be helpful. Consider consultation with an ear, nose, and throat (ENT) specialist for help in managing chronic rhinosinusitis. Consider consultation with a gastroenterologist for help in excluding and/or treating gastroesophageal reflux.
Long-Term Monitoring
Regular follow-up visits are essential to ensure control and appropriate therapeutic adjustments. In general, patients should be assessed every 1-6 months. At every visit, adherence, environmental control, and comorbid conditions should be checked. If patients have good control of their asthma for at least 3 months, treatment can be stepped down. However, the patient should be reassessed in 2-4 weeks to make sure that control is maintained with the new regimen. If patients require step 2 asthma medications or higher, consultation with an asthma specialist should be considered. Outpatient visits should include the following:

Interval history of asthmatic complaints, including history of acute episodes (eg, severity, measures and treatment taken, response to therapy) History of nocturnal symptoms History of symptoms with exercise, and exercise tolerance Review of medications, including use of rescue medications Review of home-monitoring data (eg, symptom diary, peak flow meter readings, daily treatments)
Patient evaluation should include the following:
Assessment for signs of bronchospasm and complications
Evaluation of associated conditions (eg, allergic rhinitis) Pulmonary function testing (in appropriate age group)
Address issues of treatment adherence and avoidance of environmental triggers and irritants. Long-term asthma care pathways that incorporate the aforementioned factors can serve as roadmaps for ambulatory asthma care and help streamline outpatient care by different providers. In the author's asthma clinic, a member of the asthma care team sits with each patient to review the written asthma care plan and to write and discuss in detail a rescue plan for acute episodes, which includes instructions about identifying signs of an acute episode, using rescue medications, monitoring, and contacting the asthma care team. These items are reviewed at each visit. One study using directly observed administration of daily preventive asthma medications by a school nurse showed significantly improved symptoms among urban children with persistent asthma.[45]
Medication Summary
Pharmacologic management includes the use of control agents such as inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab). Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium
Bronchodilators, Beta2-Agonists
Class Summary
These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Several studies have suggested that short-acting beta2-agonists such as albuterol may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings are reported for long-acting beta2-agonists, such as salmeterol. View full drug information
Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MDI, PO solution). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor downregulation and receptor hyposensitivity. View full drug informationDosing Forms & Strengths aerosol
90mcg (base)/actuation (equivalent to 108mcg albuterol sulfate)
tablet

2mg 4mg
tablet, extended release

4mg 8mg
nebulizer solution

0.083% 0.21% 0.42% 0.5%
syrup
2mg/5mL
Bronchospasm
Treatment and prevention of bronchospasm associated with obstructive airwary disease Inhaler

>4 years old: As adult; 1-2 inhalations PO q4-6 hr Prevention of exercise-induced bronchospasm: 2 inhalations 15-30 minutes before exercise
Nebulizer

<2 years old (off-label): 0.2-0.6 mg/kg/day divided q4-6hr nebulized 2-12 years old, >15 kg: 0.63-2.5 mg TID/QID Adjust flow rate of albuterol delivery over period of 5-15 minutes
Tablets

<6 years old: 0.3 mg/kg/day divided q8hr PO; no more than 6 mg/day 6-12 years old: 2 mg PO TID/QID; may be increased gradually to no more than 24 mg/day in divided doses >12 years old: As adult
Oral solution

2-6 years old: Initiated at 0.1 mg/kg PO TID; not to exceed 2 mg (5 mL) TID; if needed, may increase to 0.2 mg/kg PO TID; not to exceed 4 mg (10 mL) TID 6-14 years old: 2 mg PO TID/QID; may be increased gradually to not to exceed 24 mg/day in divided doses
Other Information
Potential toxic dose <6 years old: 1 mg/kg
Pirbuterol (Maxair Autohaler)

Pirbuterol is available as a breath-actuated or ordinary inhaler. The ease of administration with the breath-actuated device makes it an attractive choice in the treatment of acute symptoms in younger children who otherwise cannot use an MDI. The Autohaler delivers 200 mcg per actuation.
Pediatric Dosing & Uses

Dosing Forms & Strengths
metered dose inhaler
200mcg/actuation (14g canister; ~400 actuations)
Asthma Maintenance Treatment

<12 years: Safety and efficacy not established 12 years or older: As adults; 1-2 actuations q4-6hr PRN, no more than 12 actuations/day Previous Next Section: Nonracemic Form of the Beta2-Agonist
Nonracemic Form of the Beta2-Agonist Albuterol

Class Summary
This nonracemic form of albuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia). View full drug information
Levalbuterol (Xopenex)
Nonracemic form of albuterol, levalbuterol (R isomer) is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or solution for nebulized inhalation.

neb solution

0.31mg/3mL 0.63mg/3mL 1.25mg/3mL 1.25mg/5mL
MDI
45mcg/inh
Bronchospasm
MDI

<4 yo: Safety & efficacy not established >4 yo: 2 puffs q4-6hr PRN
Nebulizer

< 4 yo: Safety & efficacy not established > 4yo: 6-12 yo: 0.31 mg neb TID; not to exceed 0.63 mg TID >12 yo: 0.63-1.25 mg q8hr PRN
Exacerbation of Asthma
MDI

< 4 yo: Safety & efficacy not established > 4 yo: 4-8 puffs q20min for 3 doses; THEN q1-4hr PRN
Nebulizer

<12 years: 0.075 mg/kg (1.25 mg minimum) q20min for 3 doses, THEN 0.075-0.15 mg/kg (5 mg maximum) q1-4hr PRN >12 years: 1.25-2.5 mg q20min for 3 doses, THEN 1.25-5mg q1-4hr PRN
Class Summary
Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example. Currently, 2 LABA are available in the United States: salmeterol (Serevent) and formoterol (Foradil). Salmeterol and formoterol are available as combination products with inhaled corticosteroids in the United States (Advair, Symbicort, Dulera).
LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma; they have also occurred in a few patients with less severe asthma. LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by a subspecialist (ie, pulmonologist, allergist). View full drug information
Salmeterol (Serevent Diskus)

This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exerciseinduced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to reduce the potential adverse effects of the steroids. The medication is delivered via a Diskus DPI.
View full drug information

powder
50mcg/inhalation
Children 4 years and older dose same as adult

Formoterol (Foradil Aerolizer)
Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma.

capsules for inhalation
12mcg
Asthma (Maintenance & Treatment)

<5 years: Safety and efficacy not established 5 years or older: As adult (Foradil Aerolizer); 12 mcg inhaled PO q12hr
Exercise-Induced Bronchospasm (EIB)

<5 years: Safety and efficacy not established 5 years or older: As adult (Foradil Aerolizer); 12 mcg inhaled PO 15 min before exercise PRN
Other Information
Perforomist: safety/efficacy not established in peds Previous Next

Methylxanthines
Class Summary
These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms. View full drug information
Theophylline (Theo-24, Theochron, Uniphyl)

Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency depend on the particular product selected.

capsule extended release, 24 hours

100mg 200mg 300mg 400mg
Bronchospasm
Load

No theophylline administered in previous 24 hours: 5-7 mg/kg IV/PO; infuse IV over 20-30 minutes 1 mg/kg result is approximately 2 mg/L increase in serum theophylline level
Maintenance

6 weeks-6 months: 0.5 mg/kg/hr IV OR 10 mg kg/day PO in divided doses 6 months-1 year: 0.6-0.7 mg//kg/hr IV OR 12-18 mg/kg/day PO in divided doses
1-9 years: 1 mg/kg/hr IV infusion OR 8 mg/kg PO with q8hr SR 9-12 years: 0.8-0.9 mg/kg/hr IV infusion OR 6.4 mg/kg PO with q8hr SR 12-16 years: 0.7 mg/kg/hr IV infusion OR 5.6 mg/kg PO with q8hr SR
Neonatal Apnea
Load: 4-5 mg/kg PO/IV x1 Maintenance: 3-6 mg/kg/day PO/IV divided q8hr
Other Information
If administering aminophylline, increase dose by 20-25% (aminophylline is approximately 79-86% theophylline; 100 mg aminophylline = 80 mg theophylline) Use ideal body weight to calculate dose

Inhaled Corticosteroids
Class Summary
Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. They are used for long-term control of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms reduce the need for systemic corticosteroids. Inhaled steroids block late asthmatic response to allergens; reduce airway hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use). View full drug information
Ciclesonide (Alvesco)
Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 y and older. Not indicated for relief of acute bronchospasm. Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation. Individual patients experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy. After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control.
MDI

80mcg/inhalation 160mcg/inhalation
Asthma Prophylaxis
<12 years: Safety and efficacy not established >12 years or older: As adults Receiving Bronchodilators or Inhaled Corticosteroids: 80 mcg inhaled BID initially; may increase to 160 mcg BID Receiving Oral Corticosteroids: 80 mcg inhaled BID initially; may increase to 320 mcg BID

Beclomethasone (QVAR)
Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. It is available as 40 mcg/actuation or 80 mcg/actuation.

MDI

40mcg/inhaler 80mcg/inhaler
Chronic Asthma
<5 years old: Safety and efficacy not established 5-12 years old: 40 mcg BID 80 mcg BID highest recommended dose >12 years old: As in adults; 1-2 nasal inhalations (42-84 mcg) in each nostril BID (total dose, 168-336 mcg/day)

Fluticasone (Flovent Diskus, Flovent HFA)

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as an MDI aerosolized product (HFA) or DPI (Diskus).

aerosol

44mcg/inh 110mcg/inh 220mcg/inh
Diskhaler

50mcg/inh 100mcg/inh 250mcg/inh
Asthma Maintenance
Flovent HFA inhaler

4-11 years: 88 mcg (2 puffs) inhaled PO BID 12 years or older: as adult; initial 88 mcg (2 puffs) inhaled PO BID; may incr to max 440 mcg inhaled PO BID
Flovent Diskus (formerly Flovent Rotadisk)

4-11 years: 50-100 mcg inhaled PO BID 12 years or older: same as adult dosing; initial 100 mcg inhaled PO BID; may incr to max 500 mcg BID
Eosinophilic Esophagitis (Orphan)

Treatment of pediatric and adult eosinophilic esophagitis Orphan indication sponsor

Eurand Pharmaceuticals, Inc; 790 Township Line Road, Suite 250; Yardley, PA 19067
Budesonide inhaled (Pulmicort Flexhaler or Respules)

Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as a DPI in 90 mcg/actuation (delivers about 80 mcg/actuation) or 180 mcg/actuation (delivers about 160 mcg/actuation). A nebulized susp (ie, Respules) is also available for young children.

suspension for nebulizer

0.25mg/2mL 0.5mg/2mL 1mg/2mL
powder for inhalation

80mcg/actuation 160mcg/actuation
spray
32mcg/spray
Budesonide Inhalation Suspension

Previous therapy with bronchodilators

< 1 years old: Safety & efficacy not established 1-8 years old: 0.5 mg qDay or divided BID; 0.5 mg/day maximum
Previous therapy with inhaled corticosteroids

< 1 years old: Safety & efficacy not established 1-8 years old: 0.5 mg qDay or BID; 1 mg/day maximum
Previous therapy with oral corticosteroids

< 1 year old: Safety & efficacy not established 1-8 years old: 1 mg/day administered as 0.5 mg BID or 1 mg qDay
Pulmicort Flexhaler
<6 years old: Safety and efficacy not established >6 years old: 180 mcg BID; in some patients, a starting dose of 360 mcg BID

Mometasone furoate inhalation powder (Asmanex Twisthaler)

Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic therapy.

metered dose inhaler

110mcg 220mcg
Asthma
4-11 years old: 110 mcg inhaled PO qEvening; not to exceed 110 mcg/day 12 years or older: Same as adults; 220 mcg inhaled PO qDay

Systemic Corticosteroids
Class Summary
These agents are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2-receptor subsensitivity and downregulation; these processes are reversed with corticosteroids. Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that GI transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours. View full drug information
Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred)

An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. View full drug information
Methylprednisolone (Solu-Medrol)
Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

oral solution
5mg/5mL (60mL)
5mg/5mL (120mL) 10mg/5mL 15mg/5mL (60mL)
tablet
5mg
tablet, dose pack

5mg (6 days [21 tabs]) 5mg (12 days [48 tabs])
Anti-inflammatory/Immunosuppressive
0.1-2 mg/kg PO qD or divided BID/QID; not to exceed 80 mg/day
Acute Asthma
1-2 mg/kg/day qD or divided BID for 3-5 days
Nephrotic Syndrome
Initial: 60 mg/sq.meter/day or 2 mg/kg/day not to exceed 80 mg/day divided TID PO for 4 weeks, THEN 40 mg/sq.meter or 1-1.5 mg/kg/dose PO qOD for 4 weeks Not to exceed 80 mg/day Treatment may need to be individualized

tablet

4mg 8mg 16mg 24mg 32mg
injectable suspension

20mg/mL 40mg/mL 80mg/mL
powder for injection

40mg 125mg 500mg 1g 2g
Methylprednisolone
0.117-1.66 mg/kg/day divided TID-QID PO
Methylprednisolone Sodium Succinate

0.03-0.2 mg/kg IM qDay-BID Pneumocystis carinii pneumonia in AIDS patients (Off-label): >13 years old: Same as adult Severe lupus nephritis (Off-label): 30 mg/kg IV qOD x6 doses
Anti-inflammatory/Immunosuppressive
0.5-1.7 mg/kg/day divided q12hr IV/PO/IM
Status Asthmaticus
Load: 2 mg/kg IV/IM x 1 dose Maintenance: 2 mg/kg/day divided q6hr IV/IM
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Leukotriene Modifiers
Class Summary
Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists. View full drug information
Zafirlukast (Accolate)
Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors. View full drug information

tablets

10mg 20mg
Asthma
<5 years: Safety and efficacy not established 5-11 years: 10 mg PO BID >12 years: 20 mg PO BID
Administration
Take at least 1 hour before or 2 hours after meals Take at regular intervals
Hepatic Impairment
Contraindicated

Montelukast (Singulair)
The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

tablet
10mg
tablet, chewable

4mg 5mg
oral granules
4mg/packet
Asthma Maintenance
Indicated for prophylaxis and chronic treatment of asthma in patients 12 months of age and older <12 months: Safety and efficacy not established 12-24 months: 4 mg (granules) PO qEvening 2-5 years: 4 mg (chewable tablet or granules) PO qEvening 6-14 years: 5 mg (chewable tablet) PO qEvening 15 years or older: 10 mg (conventional tablet) PO qEvening
Exercise-Induced Bronchospasm (EIB), Prophylaxis

<15 years: Safety and efficacy not established 15 years or older: 10 mg PO 2 hours before exercise; do not take additional dose within 24 hours If taking drug for another indication, do not take additional dose to prevent EIB
Perennial Allergic Rhinitis

<6 months: Safety and efficacy not established 6-24 months: 4 mg (granules) PO qDay
2-5 years: 4 mg (chewable tablet or granules) PO qDay 6-14 years: 5 mg (chewable tablet) PO qDay 15 years or older: 10 mg (conventional tablet) PO qDay
Seasonal Allergic Rhinitis

<2 years: Safety and efficacy not established 2-5 years: 4 mg (chewable tablet or granules) PO qDay 6-14 years: 5 mg (chewable tablet) PO qDay 15 years or older: 10 mg (conventional tablet) PO qDay
Administration
Patients >12 months with both asthma and allergic rhinitis: Take 1 tablet PO qEvening For allergic rhinitis dosing time may be individualized to patient needs Granules may be taken directly, mixed in applesauce, carrots, rice, or ice cream or dissolved in 5 mL breast milk or baby formula (administer within 15 minutes of opening)

Monoclonal Antibodies
Class Summary
These agents bind selectively to human IgE on the surface of mast cells and basophils. View full drug information
Omalizumab (Xolair)
Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. It reduces mediator release, which promotes allergic response. It is indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

>12 years old: Same as adult

Combination Inhaled Steroids/Long-Acting Beta2Agonists

Class Summary
These combinations may decrease asthma exacerbations when inhaled short-acting beta2agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study,
use of combination therapy using fluticasone propionate and salmeterol prolonged time to first severe asthma exacerbation.[46]
Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDI in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg. View full drug information
Budesonide/formoterol (Symbicort)
Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MDI in 2 strengths; each actuation delivers formoterol 4.5-mcg with either 80-mcg or 160-mcg of budesonide. View full drug information
Mometasone and formoterol (Dulera)

This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation. This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to mediumdose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.
Fluticasone and salmeterol (Advair)

This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg. Previous Next Section: Anticholinergic

budesonide/formoterol inhaler

(80mcg/4.5mcg)/puff (160mcg/4.5mcg)/puff
Asthma
<12 years old: Safety & efficacy not established >12 years old: As in adults

mometasone/formoterol metered dose inhaler

100mcg/5mcg/actuation 200mcg/5mcg/actuation
Asthma
<12 years: Safety and efficacy not established 12 years or older: As adults; 2 inhalations PO BID Starting dose

Based on prior asthma therapy Inhaled medium dose corticosteroids: 100 mcg/5 mcg 2 inhalations PO BID; not to exceed daily dose of 400 mcg/20 mcg Inhaled high dose corticosteroids: 200 mcg/5 mcg 2 inhalations PO BID; not to exceed daily dose of 800 mcg/20 mcg
Anticholinergic Agents
Class Summary
These agents may be added to beta2-agonist therapy for treatment of acute exacerbations. View full drug information
Ipratropium (Atrovent)
Chemically related to atropine, protropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The
MDI delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02% solution for nebulization).

aerosol
17 mcg/puff
neb solution
0.02%
Acute Asthma Exacerbation

Inhaler

<12 yo: 4-8 inhalation q20 min PRN for up to 3 hr >12 yo: 8 inhalations q20 min PRN for up to 3 hr
Nebulizer

<12 yo: 150-500 mcg q20 min for 3 doses then PRN >12 yo: 500 mcg q20 min for 3 doses; then PRN
Pediatric Status Asthmaticus
Author: Adam J Schwarz, MD; Chief Editor: Michael R Bye, MD more...
Overview Presentation DDx Workup Treatment Medication Follow-up
Updated: Oct 26, 2011
Background Pathophysiology Epidemiology
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Multimedia Library References
Background
Asthma is the most common chronic disease of childhood, affecting 5-10% of children and resulting in approximately 400,000 hospitalizations annually. In 1997, the National Heart, Lung, and Blood Institute defined asthma as a chronic inflammatory disorder of the airways that involves many different cells, including mast cells, eosinophils, and T lymphocytes. This inflammation causes recurrent episodes of wheezing, dyspnea, and cough. Episodes are associated with obstruction that occurs in predominantly small-to-medium airways and that reverses partially or completely, either spontaneously or with treatment. Asthma is also associated with increased airway hyperresponsiveness to various stimuli. Status asthmaticus is an acute exacerbation of asthma that remains unresponsive to initial treatment with bronchodilators. Status asthmaticus can vary from a mild form to a severe form with bronchospasm, airway inflammation, and mucus plugging that can cause difficulty breathing; carbon dioxide retention; hypoxemia; and respiratory failure. The typical clinical presentation involves persistent wheezing with retractions. However, not all children with severe asthma wheeze; some may present with cough, dyspnea, or emesis. Alternatively, not all patients who present with wheezing have asthma; some may have one of various other causes of obstructed airways.
Pathophysiology
Exposure to an allergen or trigger causes a characteristic form of airway inflammation in susceptible individuals, exemplified by mast cell degranulation, release of inflammatory mediators, infiltration by eosinophils, and activated T lymphocytes. Multiple inflammatory mediators may be involved, including interleukin (IL)3, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-13; leukotrienes; and granulocytemacrophage colony-stimulating factors (GM-CSFs). These, in turn, incite involvement of mast cells, neutrophils, and eosinophils.
Figure depicting antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma symptoms.
Physiologically, acute asthma has 2 components: an early acute bronchospastic aspect marked by smooth muscle bronchoconstriction and a later inflammatory component resulting in airway swelling and edema.
Early bronchospastic response

Within minutes of exposure to an allergen, mast cell degranulation is observed along with the release of inflammatory mediators, including histamine, prostaglandin D2, and leukotriene C4. These substances cause airway smooth muscle contraction, increased capillary permeability, mucus secretion, and activation of neuronal reflexes. Early asthmatic response is characterized by bronchoconstriction that is generally responsive to bronchodilators, such as beta2-agonist agents.
Later inflammatory response

Release of inflammatory mediators prime adhesion molecules in the airway epithelium and capillary endothelium, which then allows inflammatory cells, such as eosinophils, neutrophils, and basophils, to attach to the epithelium and endothelium and subsequently migrate into the tissues of the airway. Eosinophils release eosinophilic cationic protein (ECP) and major basic protein (MBP). Both ECP and MBP induce desquamation of the airway epithelium and expose nerve endings. This interaction promotes further airway hyperresponsiveness in asthma. This inflammatory component may even occur in individuals with mild asthma exacerbation. Bronchospasm, mucus plugging, and edema in the peripheral airways result in increased airway resistance and obstruction. Air trapping results in lung hyperinflation, ventilation/perfusion (V/Q) mismatch, and increased dead space ventilation. The lung becomes inflated near the end-inspiratory end of the pulmonary compliance curve, with decreased compliance and increased work of breathing. The increased pleural and intra-alveolar pressures that result from obstruction and hyperinflation, together with the mechanical forces of the distended alveoli, eventually lead to a decrease in alveolar perfusion. The combination of atelectasis and decreased perfusion leads to V/Q mismatch within lung units. The V/Q mismatch and resultant hypoxemia trigger an increase in minute ventilation. In the early stages of acute asthma, hyperventilation may result in respiratory alkalosis. This is because obstructed lung units (slow compartment) are relatively less numerous than unobstructed lung units (fast compartment). Hyperventilation allows carbon dioxide removal via the fast compartment. However, as the disease progresses and more lung units become obstructed, an increase in the slow compartments occurs with decreased ability for carbon dioxide removal, eventually resulting in hypercarbia.
Epidemiology
Frequency
United States
Asthma affects up to 10% of the US population. Prevalence has increased by 60% in all ages in the past 2 decades, with an approximate 40% increase in children. A significant rise in hospitalization and asthma mortality rates, especially in children aged 0-4 and 9-16 years, has accompanied the increased incidence. Asthma, including status asthmaticus that requires hospitalization,[1] is the leading cause of school absenteeism among children with chronic illness. Factors associated with the increase in
asthma include indoor pollution, overcrowding, increased incidence of viral infections, allergens, cockroach allergy, and, possibly, a decrease in breastfeeding. In addition, some researchers have described the hygiene hypothesis, which suggests that the public health success in reducing early childhood infections through vaccination and hygiene reduces early autoimmunization and increases the likelihood of allergies and asthma. This hypothesis remains controversial.
International
Worldwide incidence is unclear but is estimated to be about 20 million cases, 15% of which occur in children. The dramatic rise in the worldwide incidence of asthma has been attributed, in part, to pollution and industrialization. Under the hygiene hypothesis, improved immunization and public health measures would contribute to the increase in asthma.
Mortality/Morbidity
The mortality rate from asthma has increased at an alarming rate. From 1993-1995, the overall annual age-adjusted death rate for asthma increased 40%. The rise in the mortality rate is even higher among blacks, among people living in poverty, and among children aged 0-4 and 9-16 years.
Race
Although asthma affects people of all races, in the United States, Hispanic children seem to have a higher incidence. The mortality rate in the United States is highest among blacks.
Sex
In infants, males generally have more severe disease than females. In older children, males and females are equally affected. Asthma has a higher incidence among adult females.
Age
Asthma is well distributed among people of all age groups. Children who have asthma in the first year of life and those aged 9-16 years tend to have much more severe disease.
History
When obtaining the history from a child presenting with an acute exacerbation of asthma, the following should be determined:
Presence of current illness, such as upper respiratory tract infection or pneumonia o History of chronic respiratory diseases (eg, bronchopulmonary dysplasia, chronic lung disease of infancy) o Severe previous respiratory syncytial virus (RSV) disease o History of atopy o History of allergies o Family history of asthma o Presence of pets or smokers in the home
Known triggering factors Home medications (Obtain a detailed list of medications being taken at home and, if possible, the timing and dosage of medications) Risk factors for developing severe or persistent status asthmaticus o History of increased use of home bronchodilator treatment without improvement or effect o History of previous ICU admissions, with or without intubation o Asthma exacerbation despite recent or current use of corticosteroids o Frequent emergency department (ED) visits and/or hospitalization (implies poor control) o Less than 10% improvement in peak expiratory flow rate (PEFR) from baseline despite treatment o History of syncope or seizures during acute exacerbation o Oxygen saturation below 92% despite supplemental oxygen o Whether the patient has a severe asthma exacerbation without wheezing (ie, the silent chest): Such patients may have such severe airway obstruction or be fatigued so that he or she is unable to generate enough airflow to wheeze. This is an ominous sign of impending respiratory failure.
o o
Physical
Immediately determine patient's condition and risk for respiratory failure at initial assessment. The acute episode of asthma may begin with mild symptoms of dyspnea. As the degree of airway obstruction worsens, respiratory distress, including retractions, use of abdominal muscles in exhalation, and inability to speak more than one or two words at a time, may all be observed. V/Q mismatch results in decreased oxygen saturation and hypoxia. Vital signs may show tachycardia and hypertension. The peak flow rate should be included in the vital signs in children who are able to cooperate and who are able to tolerate the peak flow maneuver without significant distress. Level of consciousness may progress from lethargy to agitation from air hunger and even syncope and seizures. If untreated, prolonged airway obstruction and marked increase in work of breathing may eventually lead to bradycardia, hypoventilation, and even cardiorespiratory arrest.
General examination o In the early stage of acute asthma exacerbation, slight tachycardia and tachypnea may be observed. As the episode progresses, tachycardia and tachypnea may worsen. Blood pressure may be elevated. The peak flow rate is a standard measure of airflow obstruction and is relatively simple to perform. Most patients with more than a mild exacerbation of asthma have hypoxia and decreased oxygen saturation due to V/Q mismatch. Some patients prefer to remain seated and leaning forward, rather than assuming a supine position. Use of accessory muscles has been shown to correlate with severity of airflow obstruction. An abnormally prolonged expiratory phase with audible wheezing can be observed. o Children with status asthmaticus may appear dehydrated as a result of poor intake, vomiting, and increased work of breathing. o Retractions (ie, intercostal, subcostal, use of abdominal muscles) may be observed. o The use of accessory muscles correlates to severity of disease. o Patients with moderate-to-severe asthma are often unable to speak in full sentences.
Cardiovascular symptoms may include tachycardia or hypertension in mild-tomoderate asthma. With worsening hypoxemia, hypercarbia, marked air trapping, and hyperinflation, stroke volume is compromised and hypotension and bradycardia may be observed. o CNS status ranges from wide-awake to lethargic, agitated to comatose. As hypoxemia progresses, lethargy progresses to agitation caused by air hunger. As more lung units become obstructed, hypoxemia worsens and hypercarbia develops. Both hypoxemia and hypercarbia can lead to seizures and coma and are late signs of respiratory compromise. Examination of the respiratory system o Wheezing occurs from air moving through narrowed obstructed airways. This exhalation results in turbulent airflow and produces wheezes. Although asthma is the most common cause of wheezing, anything that causes airway obstruction and narrowing that results in turbulent airflow may generate wheezes. Therefore, not all wheezing is asthma. Other causes of wheezing may include the following: Viral infections/bronchiolitis: Common respiratory viral infections, such as RSV, may cause airway swelling and narrowing in infants and children, causing inflammation and swelling of the bronchioles and resulting in bronchiolitis. Although viral infections may clearly trigger asthma, typical bronchiolitis results from airway swelling and edema, not from bronchospasm, and is generally unresponsive to treatment with bronchodilators. Foreign body: Aspiration of a foreign body is a particularly important consideration in toddlers. These episodes are generally unwitnessed. When the foreign body lodges in the right or left mainstem bronchus or beyond, the child may present with a cough and wheezing, often unilaterally. When suspected, a chest radiograph should be obtained. Cystic fibrosis: Airways are obstructed with thick inspissated secretions. Extrinsic compression: Airways can be compressed from vascular structures, such as vascular rings, lymphadenopathy, or tumors. Congestive heart failure (CHF): Airway edema may cause wheezing in CHF. In addition, vascular compression may compress the airways during systole with cardiac ejection, resulting in a pulsatile wheeze that corresponds to the heart rate. This is sometimes erroneously referred to as cardiac asthma. Tracheomalacia: Although the airway sounds are slightly different from those of asthma, they are often referred to as wheezes. o Auscultation often reveals bilateral expiratory and possibly inspiratory wheezes and crackles; air entry may or may not be diminished or absent, depending on severity. Remember, the silent chest may herald impending respiratory failure in a patient too obstructed or fatigued to generate wheezing. o If tension pneumothorax develops, signs of tracheal deviation to the opposite side, decreased or absent air entry on the affected side, shift of the location of heart sounds, and hypotension may be evident. Air leaks may also include pneumomediastinum and subcutaneous emphysema. o In moderate-to-severe status asthmaticus, abdominal muscle use can cause symptoms of abdominal pain. o Pulsus paradoxus is a decrease in the systolic blood pressure during inspiration. It results from a decrease in cardiac stroke volume with inspiration due to greatly increased left-ventricular afterload generated by the dramatic increase in negative
o
intrapleural and transmural pressure in a patient struggling to breathe against significant airways obstruction. Pulsus paradoxus greater than 20 mm Hg correlates well with the presence of severe airways obstruction (ie, forced expiratory volume in 1 second [FEV 1 ] < 60% predicted).
Causes
Asthma results from a number of factors, including genetic predisposition and environmental factors.
Inhaled allergens o Patients often have a history of atopy. o The severity of asthma has been correlated with the number of positive skin test results. Viral infections Air pollutants (eg, dust, cigarette smoke, industrial pollutants) Medications, such as beta-blockers, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) Gastroesophageal reflux disease o Studies indicate that reflux of gastric contents with or without aspiration can trigger asthma in susceptible children and adults. o Animal studies have shown that the instillation of even minute amounts of acid into the distal esophagus can result in marked increases in intrathoracic pressure and airway resistance. This response is thought to be due to vagal and sympathetic neural responses. Cold temperature Exercise
Differentials

Airway Foreign Body Aspiration Syndromes Bronchiectasis Bronchiolitis Cystic Fibrosis Gastroesophageal Reflux Heart Failure, Congestive Inhalation Injury Lymphadenopathy Pulmonary Artery Sling Respiratory Syncytial Virus Infection Tracheomalacia Vascular Ring, Double Aortic Arch
Laboratory Studies
Selection of laboratory studies depends on historical data and patient condition.
Pulse oximetry provides a continuous evaluation of oxygen saturation, which is vitally important because the primary cause of death in status asthmaticus is hypoxia. o The advantages of pulse oximetry are that pulse oximetry is readily available, it is noninvasive, it provides continuous monitoring, and it is a good indicator of hypoxemia resulting from V/Q mismatch. o The disadvantages of pulse oximetry are that movement artifact can be significant and pulse oximetry may provide an erroneous reading when pulsatile flow is inadequate (ie, shock with poor perfusion) or in the presence of anemia. The use of blood gas determination is controversial. The information generated by a blood gas measurement may be helpful in making a determination of whether to intubate a patient with asthma. However, such decisions are usually made on the basis of clinical grounds in a patient who is either in respiratory arrest or impending respiratory arrest. If a patient with acute asthma has adequate peripheral oxygen saturation, is receiving further therapy, and does not warrant immediate intubation, then the use of the blood gas information should be considered against the potential pain and agitation that it may cause in the child. Improvement or deterioration in acute asthma can generally be followed clinically. Indwelling arterial catheters reduce the pain issue and generate highly reliable and reproducible information. Serum electrolyte measurement is important, particularly to monitor serum potassium levels. Medications used to treat status asthmaticus may cause hypokalemia. A low pH may result in a transient elevation of potassium. Serum glucose levels may become elevated from stress, use of beta-agonist agents, such as epinephrine, and from the use of corticosteroids. However, because of poor stores, hypoglycemia may develop in younger children in response to stress. A CBC count and differential may demonstrate an elevated white blood cell count, with or without a shift to the left. CBC count may also indicate a bacterial infection; however, betaagonists and corticosteroids may result in demargination of white cells with an increase in the peripheral white cell count. Blood theophylline levels provide an important monitoring component in patients taking theophylline (either at home or while hospitalized) and especially in those who have received a bolus infusion of theophylline followed by continuous intravenous infusion. The volume of distribution of theophylline is 0.56 mg/L in children and adults. A dose of 1 mg/kg of theophylline raises the serum level by approximately 2 mg/dL. If theophylline is used in the management of asthma, monitor serum levels. If the patient has been receiving theophylline at home, obtain a serum theophylline level before therapy. Following a loading dose (if needed), obtain a serum level 30 minutes after the end of the infusion. For serum theophylline steady-state levels, obtain a serum sample at 24-36 hours in children younger than 6 months, at 12-24 hours for those aged 6 months to 12 years, and at 24 hours for children aged 12 years and older. o Factors that decrease theophylline clearance (increase levels) include cimetidine, erythromycin and other macrolide antibiotics, viral infections, cirrhosis, fever, propranolol, and ciprofloxacin. o Factors that increase theophylline clearance (decrease levels) are intravenous isoproterenol, phenobarbital, smoking, phenytoin, and rifampin. Peak flow monitoring provides an objective measure of airflow obstruction in children old enough and able to tolerate this maneuver without exacerbating their reactive airways disease.
Imaging Studies
Chest radiography is indicated in children who have an atypical presentation or in those who do not respond to therapy. In children with a known diagnosis of asthma, chest radiography is indicated when pneumonia, pneumothorax, pneumomediastinum, or significant atelectasis is suspected.
Other Tests
Pulmonary function testing can be useful to quantify the severity of disease and response to therapy; it should be performed in children who are old enough and who are capable of cooperating.

FEV 1 is used to monitor the degree of airway obstruction. In patients who are acutely ill, peak flow monitoring is more commonly performed. Findings may be diminished in other pulmonary function tests (eg, maximum expiratory flow rate, mid-maximum expiratory flow rate, forced vital capacity). Functional residual capacity and residual volume increase because of air trapping; however, these tests require the child being in a body plethysmograph, which is impractical in the severely ill child.
Procedures
Tracheal intubation and mechanical ventilation are indicated for respiratory failure. Noninvasive ventilation may be tried to reduce the work of breathing and fatigue in order to avoid intubation. Placement of an indwelling arterial catheter is indicated for blood gas sampling and continuous blood pressure measurement in patients with mechanical ventilation. The arterial waveform can also be used for measurement of pulsus paradoxus. Chest tube placement may be necessary in the management of pneumothorax
Medical Care
According to the most recent guidelines available from the National Asthma Education and Prevention Program (NAEPP) Expert Panel, overall care for a child with asthma includes intensive outpatient treatment with medications and alteration of the environment.[2] Admission to the hospital represents a failure of outpatient management. This discussion is limited to inpatient treatment for status asthmaticus.
Oxygen o Supplemental oxygen generally must be provided in any patient who presents with status asthmaticus. Oxygen helps to correct V/Q mismatch. Oxygen can be provided via nasal cannula or face masks. o In the event of significant hypoxemia, nonrebreathing masks may be used to deliver as much as 98% oxygen. The goal of supplemental oxygen therapy is an oxygen saturation above 90%. Inhaled beta-agonists o Beta-agonist agents, typically albuterol or salbutamol, and terbutaline, are the mainstays of acute therapy in asthma. Levalbuterol is also used (see Medscape Viewpoints for a discussion on the use of levalbuterol). They act via stimulation of cyclic adenosine monophosphate (AMP)mediated bronchodilation. The airway is rich
in beta-receptors; the stimulation of these receptors relaxes airway smooth muscles, increases mucociliary clearance, and decreases mucous production. o Andrews et al conducted a randomized, double-blind trial to compare equipotent doses of racemic albuterol (RAC) with levalbuterol in children with severe asthma exacerbation who failed initial therapy in the emergency department with RAC and steroids.[3] Patients received continuous nebulized RAC at 20 mg/h (n = 40) or levalbuterol (n = 41). Results did not significantly vary between the groups for median time for continuous therapy (RAC for 18.3 h vs levalbuterol for 16 h), asthma severity scores, individual clinical measures, or time to discharge (RAC for 45 h vs levalbuterol for 46 h). o The nebulized inhaled route of administration is generally the most effective route of delivery, though some patients with severe refractory status asthmaticus may benefit by the addition of beta-agonists delivered intravenously. Beta-agonists are generally most effective in the early asthma reaction phase. However, patients who present with status asthmaticus despite frequent use of beta-agonists at home may have tachyphylaxis and resistance to these agents. Similar issues may be seen in patients on chronic long acting beta agonists. Therefore, these patients may not respond as well when these agents are given in the hospital. Inhaled beta-agonists can be administered intermittently or as continuous nebulized aerosol in a monitored setting. Corticosteroids o Corticosteroids, such as methylprednisolone prednisolone or prednisone, are critical in the therapy of status asthmaticus and are used to decrease the intense airway inflammation and swelling in asthma.[4] In addition, corticosteroids potentiate the effects of beta-agonist agents and improve capillary leak. Therefore, corticosteroids affect the late asthma reaction phase. o Corticosteroids may be administered intravenously or orally. Although most practitioners administer corticosteroids intravenously during status asthmaticus, some studies indicate that early administration of oral corticosteroids may be just as effective. Anticholinergics o Anticholinergic agents act via inhibition of cyclic guanosine monophosphate (GMP) mediated bronchoconstriction. They may also decrease mucus production and improve mucociliary clearance o Ipratropium bromide (Atrovent), a quaternary amine that does not cross the blood-brain barrier, is the recommended sympathomimetic agent of choice. Atropine, a tertiary amine, may also be used and nebulized but may cause CNS effects because it may enter the CNS. In patients with severe airflow obstruction, the combination of ipratropium and albuterol can provide better bronchodilatation than albuterol alone. Further therapy: Although not as well investigated in large-scale, randomized, controlled trials, other therapies may be helpful when the standard combination of oxygen and intermittent or continuous beta-agonists (ie, albuterol), intermittent inhaled anticholinergics (ie, ipratropium bromide), and corticosteroids are insufficient in relieving significant respiratory distress in severe acute asthma. These include the following: o Magnesium sulfate Magnesium can relax smooth muscle and hence cause bronchodilation by competing with calcium at calcium-mediated smooth muscle binding sites. The published doses used range from 25-75 mg/kg infused over 20 minutes or less, with a maximum of 2-2.5 g/dose.
One double-blind placebo-controlled study reported a significant increase in peak expiratory flow, FEV1, and forced vital capacity in children who had asthma and were treated with a single 40-mg/kg dose of magnesium sulfate (MgSO4) infused over 20 minutes, along with steroids and inhaled bronchodilators, compared with control subjects who received saline placebo.[5] In addition, patients who received intravenous magnesium (8 of 16 patients) were significantly more likely to be discharged home from the presenting ED than control subjects (0 of 14 patients; P = .002). No data regarding duration of effect or efficacy with repeated doses are available, and no guidelines describe the monitoring of serum magnesium levels if more than an initial magnesium dose is administered. In one small study of 4 children who received 40-50 mg/kg MgSO4, serum magnesium levels were all less than 4 mg/dL, whereas ECG changes are generally not seen until levels exceed greater than 4-7 mg/dL. Adverse effects may include facial warmth, flushing, tingling, nausea, and hypotension. Intravenous beta-agonists Some patients with refractory status asthmaticus may respond to intravenous administration of beta-agonists. Intravenous albuterol and salbutamol may be administered where available but are not available in the United States. Intravenous terbutaline is most commonly used in the United States.[6] Historically, isoproterenol has been used, but its potent beta1 stimulation may lead to significant tachycardia and inotropy, which has caused myocardial infarction in adults. Reported doses for intravenous terbutaline have ranged from 0.4-10 mcg/kg/min in children. The dose administered should be titrated to effect and adverse cardiac effects (tachycardia, arrhythmias, ECG changes). Some practitioners advocate monitoring cardiac enzyme levels in patients who receive prolonged significant infusions of intravenous beta-agonists. Small studies in children have shown that enzymes such as troponin I may be elevated during terbutaline infusion, although these levels normalize as terbutaline is discontinued. The clinical significance of such enzyme elevation remains unclear.[7, 8] Ketamine Ketamine is a short-acting pentachlorophenol (PCP) derivative that exerts bronchodilatory effects because it leads to an increase in endogenous catecholamine levels, which may bind to beta-receptors and cause smooth muscle relaxation and bronchodilation. Case reports have also described the use of ketamine as a sedative to reduce anxiety and agitation that can exacerbate tachypnea and work of breathing and potentially obviate further respiratory failure in small children with status asthmaticus. Methylxanthines The role of methylxanthines, such as theophylline or aminophylline, in the treatment of severe acute asthma has been diminished since the advent of potent selective beta-agonists and their use at higher doses.[9] At therapeutic doses, methylxanthines are weaker bronchodilators than beta-agonists and have many undesirable adverse effects, such as frequent induction of nausea and vomiting. Furthermore, most studies have failed to show additional benefit when methylxanthines are administered to patients who are already receiving frequent beta-agonists and steroids.
Nevertheless, several recent prospective, randomized, controlled studies in children with refractory status asthmaticus have reexamined the role of the methylxanthines theophylline and aminophylline and demonstrated improvement in the clinical asthma scores when compared with placebo control. One study compared intravenous theophylline with intravenous terbutaline in critically ill children with refractory asthma and demonstrated equal therapeutic efficacy but significantly lower costs associated with theophylline use.[10] Among the theophylline effects that are important in managing asthma are bronchodilatation, increased diaphragmatic function, and central stimulation of breathing. Other potential therapies o Helium Helium is an inert gas that is less dense than nitrogen. The administration of a helium-oxygen mixture (heliox) reduces turbulent airflow across narrowed airways, which can help to reduce and, thus, relieve the work of breathing. This, in turn, can result in improved gas exchange and improve pH and clinical symptoms.[11, 12] It does not improve the caliber of the narrowed airways. Some data suggest that nebulized-size particles may be more uniformly distributed in the distal airways when nebulization treatments are administered via heliox than with a standard oxygen-nitrogen mixture.[13] Heliox can be administered via a well-fitting face mask at flows high enough to prevent entrainment of room air. The effectiveness of heliox in reducing the density of administered gas and improving laminar airflow depends on the helium concentration of the gas; the higher the helium concentration, the more effective the result. Therefore, an 80:20 mixture of helium-oxygen is most effective, and heliox loses most of its clinical utility when the FiO2 is greater than 40%, reducing the percentage of helium to less than 60%. Therefore, the limitation to the use of heliox is the amount of supplemental oxygen the patient requires to maintain an adequate oxygen saturation. Heliox has also been used to drive mechanical ventilation with lower dynamic peak inspiratory pressures. o Inhaled anesthetic agents: Inhaled anesthetic agents, such as halothane, isoflurane, and enflurane, have been used with varying degrees of success in refractory intubated patients with severe asthma. The mechanism of action is unclear but they may have direct relaxant effects on airway smooth muscle. o Extracorporeal membrane oxygenation (ECMO): Some case reports describe instances of ECMO being successfully used in extreme cases of refractory status asthmaticus in which maximum standard pharmacotherapy and mechanical ventilation was unsuccessful, often involving significant pneumothoraces and hypoxia.[14]
Surgical Care
Status asthmaticus is generally managed by means of medical therapy, with some exceptions.

Thoracentesis or thoracostomy is indicated in pneumothoraces. Some children may have asthma that is primarily exacerbated by gastroesophageal reflux disease (GERD). Some can be treated with a combination of antireflux and histamine 2 (H2) receptor antagonist agents; however, surgery, such as Nissen fundoplication, is occasionally required.
Anesthesia support is needed if inhaled anesthetic agents are considered for refractory severe intubated status asthmaticus. If all other support modalities fail and ECMO is required, surgical support for cannula placement at an established pediatric ECMO center should be performed as a life-saving therapy.
Consultations
Consult allergists or pulmonologists because these specialists can provide comprehensive follow-up care with the appropriate therapy; allergy testing, if indicated; control of environmental factors; and consistent follow-up testing and manipulation of medications as required. Admission to hospital for asthma should be considered a failure of outpatient management. Better outpatient therapy is necessary to prevent subsequent admissions. Consultation with a surgeon may be required if the child can benefit from fundoplication. Consultation with a member of social services can provide support in the complex management of a chronic illness. Adolescents who have severe uncontrolled asthma and are nonadherent or have depression or significant behavioral issues may require the services of a psychiatrist or psychologist.
Diet
Some children with asthma may have episodes triggered by food allergies. Consultation with a nutritionist may be necessary to provide appropriate dietary management. Proceed to Medication
Medication Summary
Management goals for status asthmaticus are (1) to reverse airway obstruction rapidly through aggressive use of beta2-agonist agents and early use of corticosteroids, (2) to correct hypoxemia by monitoring and administering supplemental oxygen, and (3) to prevent or treat complications such as pneumothorax or respiratory arrest.
Beta2-agonist agents
Class Summary
These agents relax airway smooth muscle, thus causing bronchodilation in patients with reversible airway obstruction such as asthma. View full drug information
Albuterol (Proventil, Ventolin, ProAire)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Administer continuous nebulization through pump-driven aerosol or via small-particle aerosol generator

aerosol
90mcg (base)/actuation (equivalent to 108mcg albuterol sulfate)
tablet

2mg 4mg
tablet, extended release

4mg 8mg
nebulizer solution

0.083% 0.21% 0.42% 0.5%
syrup
2mg/5mL
Bronchospasm
Treatment and prevention of bronchospasm associated with obstructive airwary disease Inhaler

>4 years old: As adult; 1-2 inhalations PO q4-6 hr Prevention of exercise-induced bronchospasm: 2 inhalations 15-30 minutes before exercise
Nebulizer

<2 years old (off-label): 0.2-0.6 mg/kg/day divided q4-6hr nebulized 2-12 years old, >15 kg: 0.63-2.5 mg TID/QID Adjust flow rate of albuterol delivery over period of 5-15 minutes
Tablets
<6 years old: 0.3 mg/kg/day divided q8hr PO; no more than 6 mg/day
6-12 years old: 2 mg PO TID/QID; may be increased gradually to no more than 24 mg/day in divided doses >12 years old: As adult
Oral solution

2-6 years old: Initiated at 0.1 mg/kg PO TID; not to exceed 2 mg (5 mL) TID; if needed, may increase to 0.2 mg/kg PO TID; not to exceed 4 mg (10 mL) TID 6-14 years old: 2 mg PO TID/QID; may be increased gradually to not to exceed 24 mg/day in divided doses
Other Information
Potential toxic dose <6 years old: 1 mg/kg

Levalbuterol (Xopenex)
A selective beta2-agonist. Albuterol is a racemic mixture, while levalbuterol contains only the levo isomer of albuterol. Safety and efficacy have not been determined in children < 12 y; multicenter trials in children 0-12 y are ongoing.
View full drug informationPediatric
Dosing & Uses

neb solution

0.31mg/3mL 0.63mg/3mL 1.25mg/3mL 1.25mg/5mL
MDI
45mcg/inh
Bronchospasm
MDI

<4 yo: Safety & efficacy not established >4 yo: 2 puffs q4-6hr PRN
Nebulizer

< 4 yo: Safety & efficacy not established > 4yo: 6-12 yo: 0.31 mg neb TID; not to exceed 0.63 mg TID
>12 yo: 0.63-1.25 mg q8hr PRN
Exacerbation of Asthma
MDI

< 4 yo: Safety & efficacy not established > 4 yo: 4-8 puffs q20min for 3 doses; THEN q1-4hr PRN
Nebulizer

<12 years: 0.075 mg/kg (1.25 mg minimum) q20min for 3 doses, THEN 0.075-0.15 mg/kg (5 mg maximum) q1-4hr PRN >12 years: 1.25-2.5 mg q20min for 3 doses, THEN 1.25-5mg q1-4hr PRN
Terbutaline (Brethine)
Selective beta2-adrenergic agent produces relaxation of airway smooth muscle, resulting in bronchodilation in patients with asthma.

tablet

2.5mg 5mg
injectable solution
1mg/mL
inhaler
0.2mg/puff
nebulizer suspension
1mg/mL
Bronchospasm
PO

<12 years old: initial 0.05 mg/kg TID, increase PRN, no more than 5 mg/day >12 years old: as adult; <15 years old no more than 7.5 mg/day
Nebulizer

<2 years old: 0.5 mg/2.5 mL NS q4-6hour PRN 2-9 years old: 1 mg/2.5 mL NS q4-6hour PRN >9 years old: 1.5-2.5 mg/2.5 mL NS q4-6hour PRN
SC (in lateral deltoid)

<12 years old: 0.005-0.01 mg/kg (no more than 0.4 mg) q15-20min x3; THEN q2-6hour PRN >12 years old: as adult
IV

load 2-10 mcg/kg , THEN 0.1-0.4 mcg/kg/min
Anticholinergic agents
Class Summary
These agents are used for bronchodilation in patients with bronchospasm associated with asthma or chronic obstructive pulmonary disease (COPD). View full drug information
Ipratropium bromide (Atrovent)

Chemically related to atropine. Has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Inhibits acetylcholine at parasympathetic sites in bronchial smooth muscle, resulting in bronchodilation.

aerosol
17 mcg/puff
neb solution
0.02%
Acute Asthma Exacerbation

Inhaler

<12 yo: 4-8 inhalation q20 min PRN for up to 3 hr >12 yo: 8 inhalations q20 min PRN for up to 3 hr
Nebulizer
<12 yo: 150-500 mcg q20 min for 3 doses then PRN >12 yo: 500 mcg q20 min for 3 doses; then PRN
Corticosteroids
Class Summary
These agents decrease inflammatory response observed in asthma. They also decrease capillary leak and augment beta-receptor response to beta-adrenergic agents.
Methylprednisolone (Solu-Medrol, Medrol); Prednisone

Interferes with arachidonic acid metabolism and production of leukotrienes, reduces microvascular leakage, reduces cytokine production, and prevents migration of inflammatory cells.
Other bronchodilator therapy

Class Summary
These agents are used as additional therapy for patients who remain in refractory status asthmaticus despite maximal inhalational therapy and the use of corticosteroids. These medications may be administered intravenously. View full drug information
Theophylline
Bronchodilator in patients with reversible bronchospasm associated with asthma or COPD. Mechanism of action of theophylline is unclear, but its beneficial effects in asthma are thought to result from bronchodilation partly caused by phosphodiesterase inhibition, improved diaphragmatic inotropicity, CNS stimulation of the respiratory drive, and possible antiinflammatory effects. Start PO (eg, Slo-bid, Slo-Phyllin, Theolair, Theo-24, Uni-Dur, Theobid) dosing when patient is stable on continuous IV dose. Theophylline is administered PO. Aminophylline can be administered PO or IV. However, IV aminophylline is generally used for refractory status asthmaticus because of the severity of the patient's asthma, which results in the decision to add methylxanthines to the treatment regimen. Aminophylline IV is 79% theophylline.

capsule extended release, 24 hours

100mg 200mg 300mg 400mg
Bronchospasm
Load

No theophylline administered in previous 24 hours: 5-7 mg/kg IV/PO; infuse IV over 20-30 minutes 1 mg/kg result is approximately 2 mg/L increase in serum theophylline level
Maintenance

6 weeks-6 months: 0.5 mg/kg/hr IV OR 10 mg kg/day PO in divided doses 6 months-1 year: 0.6-0.7 mg//kg/hr IV OR 12-18 mg/kg/day PO in divided doses 1-9 years: 1 mg/kg/hr IV infusion OR 8 mg/kg PO with q8hr SR 9-12 years: 0.8-0.9 mg/kg/hr IV infusion OR 6.4 mg/kg PO with q8hr SR 12-16 years: 0.7 mg/kg/hr IV infusion OR 5.6 mg/kg PO with q8hr SR
Neonatal Apnea
Load: 4-5 mg/kg PO/IV x1 Maintenance: 3-6 mg/kg/day PO/IV divided q8hr
Other Information
If administering aminophylline, increase dose by 20-25% (aminophylline is approximately 79-86% theophylline; 100 mg aminophylline = 80 mg theophylline) Use ideal body weight to calculate dose

Magnesium sulfate
Relaxes smooth muscle and may lead to adjunctive bronchodilation. Mechanism of action unknown, but may compete with calcium for smooth muscle binding sites leading to relaxation.

injectable solution
100mg/mL, 50%
infusion solution

1g/100mL 2g/100mL
Acute Nephritis
100 mg/kg IM q4-6hr PRN OR 20-40 mg/kg PRN Severe: 100-200 mg/kg IV infusion as a 1-3% solution Administer total dose within 1 hour, with one-half administered in the first 15-20 minutes Monitor: BP
Hypomagnesemia
25-50 mg/kg IV/IM q4-6hr for 3-4 doses PRN 100-200 mg/kg PO q6hr
Bronchospasm (Off-label)
25-50 mg/kg IV infusion over 10-20 minutes x1 Monitor: HR, BP
Further Inpatient Care
Indications for ICU admission o Altered sensorium o Use of continuous inhaled beta-agonist therapy o Exhaustion o Markedly decreased air entry o Rising PCO2 despite treatment o Presence of high-risk factors o Failure to improve despite adequate therapy Indications for intubation and mechanical ventilation o Apnea or respiratory arrest o Diminishing level of consciousness o Impending respiratory failure marked by significantly rising PCO2 with fatigue, decreased air movement, and altered level of consciousness o Significant hypoxemia that is poorly responsive or unresponsive to supplemental oxygen therapy alone Considerations in mechanical ventilation o The decision to intubate a patient with asthma is taken with extreme caution. Positive pressure ventilation in a patient with asthma is complicated by severe airway obstruction and air trapping, which results in hyperinflated lungs that may resist further inflation and places the patient at high risk of barotrauma. Therefore, mechanical ventilation should be undertaken only in the face of continued deterioration despite maximal bronchodilatory therapy. Asthma is a disease of airway obstruction (ie, increased airway resistance), resulting in prolongation of the time constant (the time needed for lung units to fill and empty). Slow ventilator rates are usually needed.
In the face of high peak airway pressures, the principle of mechanical ventilation of status asthmaticus is controlled hypoventilation, tolerating higher levels of PCO2 in order to minimize tidal volume and peak inspiratory pressures. Permissive hypercapnia can be tolerated as long as the patient remains adequately oxygenated. A longer I:E ratio, often greater than 1:3-4, helps allow time for optimal exhalation, facilitating ventilation and avoiding excessive further air-trapping (auto-PEEP). The use of positive end-expiratory pressure (PEEP) is controversial. A patient with status asthmaticus in respiratory failure on mechanical ventilation usually has a significant amount of air trapping that results in intrinsic PEEP, which may be worsened by maintaining PEEP during exhalation. However, some patients may benefit by the addition of PEEP, perhaps by maintaining airway patency during exhalation. Thus, in a patient who remains refractory to the initial ventilatory settings with no or very low PEEP, cautiously increasing the PEEP may prove beneficial. Traditionally, slow controlled ventilation with heavy sedation, often with muscle relaxation, is used to ventilate patients with status asthmaticus. Caution is warranted, however, as use of muscle relaxants together with high-dose steroids has been associated with the development of prolonged paralysis. Alternatively, some practitioners report ventilating children with status asthmaticus with pressure support alone. This strategy may allow the patient to set his or her own respiratory rate as determined by the physiologic time constant, while assisting ventilation and relieving the fatigue due to significantly increased work of breathing. Noninvasive positive pressure ventilation (NPPV), such as continuous positive airway pressure (CPAP) or bimodal positive airway pressure (BiPAP) delivered through a face mask, has been used for support of status asthmaticus. NPPV has been shown to "splint" the airways, allowing for better exhalation and emptying. Patients require supportive measures and monitoring during mechanical ventilation. Patients may be uncomfortable and air hungry while ventilated with low respiratory rates, prolonged exhalation times, and hypercapnia due to a strategy of controlled hypoventilation. Ideally, monitor flow-volume loops to ascertain if adequate time is provided for exhalation to avoid breath stacking, which occurs if the next breath is delivered before exhalation is completed. Monitoring exhaled tidal volume and auto positive end-expiratory pressure (auto-PEEP) is also important. Fluids and electrolytes should be monitored. Before arrival in the hospital, children with status asthmaticus have often had diminished oral intake and may have been vomiting because of respiratory difficulty or adverse effects from their medications. This leads to decreased intravascular volume status that may be potentiated by the effects of positive pressure ventilation. In addition, cardiac output may be decreased because of decreased preload that results from air trapping and auto-PEEP. This decreased cardiac output and intravascular volume may be accompanied by metabolic acidosis. Intravascular fluid expansion is needed to treat hypoperfusion, hypotension, or metabolic acidosis. In addition, diastolic hypotension may occasionally result from high doses of beta-agonists. A vasoconstrictor (ie, norepinephrine, phenylephrine) may be considered if significant diastolic hypotension in the face of adequate intravascular volume persists. Monitor serum electrolyte levels, as medications used to treat asthma can result in significant kaliuresis.
Indwelling arterial catheters: Placement of indwelling arterial catheters provides continuous blood pressure monitoring, as well as arterial blood gas sampling, in mechanically ventilated patients. Blood gases should be monitored to assess response to mechanical ventilation support.
Further Inpatient Care
Indications for ICU admission o Altered sensorium o Use of continuous inhaled beta-agonist therapy o Exhaustion o Markedly decreased air entry o Rising PCO2 despite treatment o Presence of high-risk factors o Failure to improve despite adequate therapy Indications for intubation and mechanical ventilation o Apnea or respiratory arrest o Diminishing level of consciousness o Impending respiratory failure marked by significantly rising PCO2 with fatigue, decreased air movement, and altered level of consciousness o Significant hypoxemia that is poorly responsive or unresponsive to supplemental oxygen therapy alone Considerations in mechanical ventilation o The decision to intubate a patient with asthma is taken with extreme caution. Positive pressure ventilation in a patient with asthma is complicated by severe airway obstruction and air trapping, which results in hyperinflated lungs that may resist further inflation and places the patient at high risk of barotrauma. Therefore, mechanical ventilation should be undertaken only in the face of continued deterioration despite maximal bronchodilatory therapy. Asthma is a disease of airway obstruction (ie, increased airway resistance), resulting in prolongation of the time constant (the time needed for lung units to fill and empty). Slow ventilator rates are usually needed. In the face of high peak airway pressures, the principle of mechanical ventilation of status asthmaticus is controlled hypoventilation, tolerating higher levels of PCO2 in order to minimize tidal volume and peak inspiratory pressures. Permissive hypercapnia can be tolerated as long as the patient remains adequately oxygenated. A longer I:E ratio, often greater than 1:3-4, helps allow time for optimal exhalation, facilitating ventilation and avoiding excessive further air-trapping (auto-PEEP). o The use of positive end-expiratory pressure (PEEP) is controversial. A patient with status asthmaticus in respiratory failure on mechanical ventilation usually has a significant amount of air trapping that results in intrinsic PEEP, which may be worsened by maintaining PEEP during exhalation. However, some patients may benefit by the addition of PEEP, perhaps by maintaining airway patency during exhalation. Thus, in a patient who remains refractory to the initial ventilatory settings with no or very low PEEP, cautiously increasing the PEEP may prove beneficial. o Traditionally, slow controlled ventilation with heavy sedation, often with muscle relaxation, is used to ventilate patients with status asthmaticus. Caution is warranted,
however, as use of muscle relaxants together with high-dose steroids has been associated with the development of prolonged paralysis. o Alternatively, some practitioners report ventilating children with status asthmaticus with pressure support alone. This strategy may allow the patient to set his or her own respiratory rate as determined by the physiologic time constant, while assisting ventilation and relieving the fatigue due to significantly increased work of breathing. o Noninvasive positive pressure ventilation (NPPV), such as continuous positive airway pressure (CPAP) or bimodal positive airway pressure (BiPAP) delivered through a face mask, has been used for support of status asthmaticus. NPPV has been shown to "splint" the airways, allowing for better exhalation and emptying. o Patients require supportive measures and monitoring during mechanical ventilation. Patients may be uncomfortable and air hungry while ventilated with low respiratory rates, prolonged exhalation times, and hypercapnia due to a strategy of controlled hypoventilation. Ideally, monitor flow-volume loops to ascertain if adequate time is provided for exhalation to avoid breath stacking, which occurs if the next breath is delivered before exhalation is completed. Monitoring exhaled tidal volume and auto positive end-expiratory pressure (auto-PEEP) is also important. Fluids and electrolytes should be monitored. Before arrival in the hospital, children with status asthmaticus have often had diminished oral intake and may have been vomiting because of respiratory difficulty or adverse effects from their medications. This leads to decreased intravascular volume status that may be potentiated by the effects of positive pressure ventilation. In addition, cardiac output may be decreased because of decreased preload that results from air trapping and auto-PEEP. This decreased cardiac output and intravascular volume may be accompanied by metabolic acidosis. Intravascular fluid expansion is needed to treat hypoperfusion, hypotension, or metabolic acidosis. In addition, diastolic hypotension may occasionally result from high doses of beta-agonists. A vasoconstrictor (ie, norepinephrine, phenylephrine) may be considered if significant diastolic hypotension in the face of adequate intravascular volume persists. Monitor serum electrolyte levels, as medications used to treat asthma can result in significant kaliuresis. Indwelling arterial catheters: Placement of indwelling arterial catheters provides continuous blood pressure monitoring, as well as arterial blood gas sampling, in mechanically ventilated patients. Blood gases should be monitored to assess response to mechanical ventilation support.
Further Outpatient Care
Outpatient follow-up and continued care of a patient who is hospitalized in the pediatric ICU because of severe status asthmaticus is important in optimizing long-term outcome and quality of life and minimizing recurrent episodes of severe asthma exacerbation. Follow-up is best provided by a specialist in the treatment of asthma. Among the important considerations are home medications, such as anti-inflammatory agents. Corticosteroids are now considered the mainstays of asthma maintenance therapy. Studies indicate that the underuse of anti-inflammatory agents is related to more severe asthma. This is thought to be due to airway remodeling and the persistence of inflammatory changes. Bronchodilators are recommended for acute exacerbations.
Environmental management is also necessary in those children with environmental allergies.
Inpatient & Outpatient Medications

Medications include bronchodilators for inhalation such as albuterol, inhaled steroids, oral agents such as leukotriene antagonists, and/or theophylline. Corticosteroid therapy, if indicated, should include written instructions on corticosteroid use.
Transfer
A child admitted to the ICU with severe status asthmaticus may be considered for transfer to an inpatient ward once the patient meets the following criteria:

The child has been successfully extubated. The child has been weaned off continuous intravenous beta-agonists (ie, terbutaline, aminophylline, if used) and is stable on intermittent beta-agonist aerosol therapy. The child can tolerate cessation of continuous albuterol and is converted to intermittent albuterol nebulization at a frequency that can be delivered on the general pediatric floor. The child has a stable hemodynamic status.
Deterrence/Prevention
The goal of chronic asthma therapy is the prevention of admission. This article, however, addresses severe acute exacerbation of asthma (status asthmaticus).
Complications
Complications may include the following:

Cardiac arrest Respiratory failure or arrest Hypoxemia with hypoxic ischemic CNS injury Pneumothorax or pneumomediastinum Toxicity from medications
Patient Education
Asthma is a chronic illness. Patients and their families must be provided with a team that can offer education and follow-up care. Prior to discharge, the team that provides asthma education should meet with the family and the patient to impart information regarding maintenance and monitoring and environmental control. For patient education resources, see the Asthma Center, as well as Asthma, Asthma FAQs, Understanding Asthma Medications, and Asthma in School Children: Educational Slides.
Asthma Outcome Measures
Joannie Shen; Michael Johnston; Ron D Hays Authors and Disclosures Posted: 10/06/2011; Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(4):447-453. 2011 Expert Reviews Ltd. Rate This Article:
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Abstract and Introduction Asthma Exacerbation Asthma Control Survey Measurement Instruments Asthma Severity Asthma Symptoms Diaries Health-related Quality of Life Lung Function Tests Airway Hyper-responsiveness Biomarkers Asthma Self-management Therapeutic Adherence Expert Commentary & Five-year View
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Abstract and Introduction

Abstract
Asthma is a common chronic disease with underlying inflammation of the airway. Advances in science have led to increased understanding of the heterogeneous nature of asthma and its complex mechanisms. Traditionally, asthma-practice guidelines have focused on optimizing lung function and the US FDA has required increases in lung function and reduction of exacerbation as primary outcomes in clinical trials of new asthma therapeutics. Improved lung function is a critical indicator of bronchodilator therapy, but the importance of long-term asthma control while maintained on controller medication is increasingly emphasized. The NIH asthma guidelines suggest the use of patient-reported outcomes, including healthrelated quality-of-life measures, to assess asthma control. Clinical practices and research studies concerning asthma can benefit from harmonizing the major outcome measures so that comparisons across studies can be made. In this article, we review common asthma outcome measures with a focus on recent efforts to harmonize outcomes for therapeutic clinical trials in asthma.
Introduction
Asthma is a common chronic disease with underlying inflammation of the airway that affects more than 300 million people worldwide and 25 million people in the USA. [101] Advances in science have increased understanding of the heterogeneous nature of asthma and its complex mechanisms. Asthma comprises asthma symptoms, variable airflow obstruction, airway hyper-responsiveness (AHR) and underlying inflammation.[1,102] The goals of asthma treatment are not only controlling the patient's current symptoms, but also preventing recurrent asthma exacerbations (AEs). As noted by the US FDA, bronchodilators may control symptoms and lung function in the short term, but use of long-acting bronchodilators without the
concurrent use of an inhaled corticosteroid is dangerous because bronchodilators do not reduce airway inflammation or AHR. Asthma management needs to optimize the patient's current clinical state and prevent adverse outcomes, including AEs and side effects of the therapeutics. Identifying relevant short-term and long-term outcome measures is critical for the management of asthma and evaluating the efficacy and effectiveness of therapeutic interventions. The criteria used to assess asthma outcomes have varied widely from study to study. When asthma is poorly controlled, the patient's activities tend to be restricted, their role function is limited and their work productivity is reduced. In addition, they may require unscheduled, urgent use of healthcare. Hence, patient-reported outcomes, including health-related quality of life (HRQOL), are important indicators of asthma control. Clinical practices and research studies in asthma can benefit from harmonizing the major outcomes so that comparison across studies can be made and meta-analyses performed, thereby contributing to comparative effectiveness research. In this article, we review asthma outcome measures with a focus on recent efforts to standardize outcomes for therapeutic clinical trials in asthma and with attention to HRQOL.
Asthma Exacerbation
Leading international asthma guidelines have consistently described the goals of asthma treatment as not only controlling current symptoms, but also preventing recurrent AEs. These guidelines include the Global Initiative for Asthma and the National Heart, Lung and Blood Institute/National Asthma Education and Prevention Program: Expert Panel Report 3.[1,102] Experts have argued that AEs may be the most important clinical outcome because they constitute a great risk, cause distress to patients and their families and generate substantial healthcare system costs. AE episodes vary considerably in speed of onset and time to resolution, ranging from a few minutes to several weeks. While severe AEs are more common in patients with poorly controlled asthma, they may also occur in patients with well-controlled asthma. For example, an airway infection can overwhelm the asthma control achieved previously by use of combination therapeutics. AEs are defined by use of healthcare, systemic corticosteroids and rescue medicine. The recently published American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Asthma Control and Exacerbations (joint ATS/ERS statement), provides a comprehensive review of the definitions of AE, asthma control and severity. [2] The joint ATS/ERS statement defined AEs as events characterized by a change from the patient's previous status and it stratified AEs by severity. In the clinical setting, the severity of AEs varies considerably. AEs can be identified by changes in symptoms, rescue medication use or lung function that differ from the patient's usual day-to-day variation. Severe AEs are events that include at least one of the following: requirement for systemic corticosteroids; an increase from a maintenance dose of daily medicine for at least 3 days; or a hospitalization or emergency department (ED) visit requiring systemic corticosteroids. Moderate asthma exacerbations are defined by temporary changes in treatment and include one or more of the following: deterioration in symptoms; deterioration in lung function; or increased rescue bronchodilator use lasting for 2 days or more, but requiring neither a hospitalization or ED visit, nor systemic corticosteroids. Other recommendations proposed by expert workgroups and researchers differed in part from the joint ATS/ERS statement. However, there may be difficulty in distinguishing moderate AEs from worsening of symptom control. Defining AEs by systemic corticosteroid use, ED use or hospitalizations is consistent with the joint ARS/ERS statement's definition of severe AE, without including the less severe moderate AE category. Measures of asthma-specific healthcare use are often applied as indirect indicators of intervention efficacy and asthma control. These measures, whether made prospectively or retrospectively, may include outpatient care, pharmacy-dispensing data, ED visits and hospitalization. Measures of asthma-specific events can be obtained from survey data, administrative claims or health services encounter data.
Each type of data source has limitations. Administrative data are rich in details on duration, diagnosis and treatment, but errors and bias may occur owing to coding and billing issues. Survey data collection relies on self-reports and is affected by recall bias. [3] Unscheduled outpatient visits could indicate AEs or worsening of asthma control. Asthma-specific systemic corticosteroid use for at least 3 days (higher than maintenance dose) or ED visits or hospitalization or both, indicate loss of asthma-symptom control and severe AE. Consistent methods and reporting of these outcomes allow comparability across studies. When measuring counts of asthma healthcare events, study duration is an important consideration; adverse outcomes such as hospitalizations are relatively rare events may fluctuate owing to seasonal factors and may be under- or over-represented in studies of less than 12 months duration.
Asthma Control
With the growing recognition of the importance of the patient's perspective, [46] current leading asthma guidelines, including the Global Initiative for Asthma and Expert Panel Report 3, have consistently identified asthma control as the focal concept for asthma. Asthma-practice guidelines traditionally focused on optimizing lung function, minimizing symptoms and preventing exacerbations. Lung function was regarded as the primary end point in earlier guidelines, [7,8] until recent findings on the poor correlation between lung function, inflammation and symptoms.[9,10] Both clinical practices and clinical trials have focused increasingly on assessing asthma control. Asthma control incorporates the global assessment of symptoms, use of rescue or reliever medicine or both, lung function and patient-reported functioning and activity limitations. Asthma control can be defined as the extent to which manifestations of asthma are reduced by treatment. The concept that asthma control ought to encompass not only a patient's current or recent clinical state, but also future risk of exacerbation and side effects from therapeutic interventions, is increasingly recognized. Because asthma control is a multidimensional construct without universally recognized criterion standards, the criteria used to assess asthma control have varied widely from study to study. Therefore, harmonizing the measures of asthma control is important for assessing the efficacy of therapeutic interventions in patients with asthma.
Survey Measurement Instruments

The Asthma Control Questionnaire includes lung function tests and has been extensively evaluated. [11] The Asthma Control Test consists of five survey items and does not include lung function tests: shortness of breath, night-time symptoms, use of rescue medications, daily functioning and overall perceptions of asthma control. A simple sum of the items is used to create a score that indicates 'poor' to 'complete' asthma control.
Asthma Severity
Asthma severity is a key concept in asthma control. Previously, severity was defined before treatment began. More recently, severity has been measured based on the intensity of treatment required to achieve good asthma control.[6] Asthma severity is influenced by the underlying disease activity as well as by the patient's phenotype and responsiveness to treatment. Patients' pathological and physiological markers may help characterize asthma severity and act as surrogate measures of future risk.
Asthma Symptoms
In primary care settings, where most asthma is managed, the diagnosis of asthma is often based on symptoms (wheezing, coughing, shortness of breath and chest tightness) despite the fact that these symptoms are often nonspecific to asthma. Revicki et al. recommended the Asthma Symptom Utility Index as a core measure for asthma therapeutic studies. [12]
As asthma symptoms vary over time, retrospective surveys are limited by patient recall. In addition, it has been noted that self-reports of symptoms may underestimate severity compared with measures of airway obstruction from a medical exam.[13] Thus, some have argued that clinical measures more accurately assess the level of asthma control achieved. [14] Patients can also use daily symptom diaries, as summarized in the following section.
Diaries
Diaries can be useful for minimizing recall bias and documenting symptoms while patients are using medications in their day-to-day life.[15,16] 'Symptom-free days' is a useful diary variable, but it is not responsive to change among those at the extremes with either very frequent or infrequent symptoms. In addition to symptoms, ambulatory peak expiratory flow (PEF) measurements can be recorded in dairies. PEF provides an objective measure of airway obstruction and is one of the most commonly reported asthma outcomes. However, PEF is inferior to the forced expiratory volume (FEV) in 1 s (FEV1) as a measure of airways obstruction because PEF underestimates airway obstruction in patients with airway remodeling. Diaries can also be used to record inhaler use for prophylactic or rescue use.
Health-related Quality of Life

The National Asthma Education and Prevention Program recommends using patient-reported outcomes such as HRQOL measures to assess asthma control. HRQOL includes physical functioning, role limitations, emotional wellbeing, social functioning and a variety of symptoms such as pain and energy or fatigue levels, along with disease-targeted symptoms.[17] HRQOL measures provide an important indication of the effects of asthma on daily functioning and wellbeing. [18] Generic HRQOL instruments such as the Short Form (SF)-36 provide a means to compare the effects of asthma with those of other conditions such as cancer.[19] Role functioning and work-related productivity are among the most important aspects of HRQOL for asthma. Health-related work productivity losses may occur through either absenteeism (time missed from the workplace) or presenteeism (reduced productivity while at the workplace). [20] Mattke et al. conducted a systematic review of methods to measure and monetize health-related work productivity loss.[21] Support for the reliability and validity of several of these methods has been published. [22,23] The Work Limitations Questionnaire[24] and the nonproprietary WHO Health and Work Performance Questionnaire[25,26] are perhaps the two most highly regarded measures of health-related work productivity loss.[27] However, the survey instrument most often used in research is the nonproprietary Work Productivity Assessment Instrument. [28] Using these tools to measure health-related work productivity losses provides information on the ways in which asthma impacts on the ability of adults to work and participate fully when at work. Asthma-targeted instruments such as the Asthma Quality of Life Questionnaire[15] and Asthma Quality of Life Questionnaire (Marks') [29,30] provide in-depth information about the effects of asthma on functioning and wellbeing. Meads et al. developed the Asthma Life Impact Scale to go beyond the earlier focus on symptoms, functioning and environmental triggers.[31] For example, the Asthma Life Impact Scale includes items to assess emotional issues not represented in other instruments. Turner-Bowker et al. developed an online computerized adapting test (ASTHMA-CAT) that assesses HRQOL with minimal respondent burden.
[32]
Preference-based measures integrate across domains to produce a single summary score for each health state anchored relative to 'dead' (score of 0) and 'perfect' or 'full' health (score of 1). Some of the most widely used preference-based measures include the Quality of Wellbeing scale,[33] the Health Utilities Indexes Mark 2 and Mark 3,[34] the EuroQol-5D[35] and the SF-6D.[36] However, these measures are not interchangeable. For example, Kaplan et al. administered the five preference-based measures to a sample of 457 cataract patients before and after surgery and found statistically significant improvements in HRQOL 1 month after surgery for all indexes except the SF-6D.[37] The mean differences in HRQOL ranged from 0.00 (for the SF-6D) to 0.06 (for the Health Utilities Indexes Mark 3).
Preference-based measures are especially important for costeffectiveness analyses used to evaluate different interventions. Quality-adjusted life years (QALYs) combine preference-based measures and life expectancy to yield a single measure of the morbidity and mortality effects. QALYs were recommended by the Institute of Medicine's Committee to Evaluate Measures of Health Benefits for Environmental, Health and Safety regulation.[38] Two alternatives similar to QALYs for measuring disease burden are healthy-year equivalents and disability-adjusted life years. Healthy-year equivalents measure the number of years in optimal health that yield the same level of utility as a particular lifetime health profile that reflects all health states experienced over one's lifetime. Disability-adjusted life years represent the number of healthy years of life lost owing to death or disability and are estimated by assigning disability scores to diseases.
Lung Function Tests

Symptoms and lung function tests are not strongly correlated with one another. Both symptoms and lung function should be monitored by clinicians who assess asthma control in clinical practice and analyzed separately in clinical trials. For example, improvement in symptoms can be achieved by using long-acting -agonist therapy, which may occur without any change in FEV1 before bronchodilator (BD) use (pre-BD FEV1).[39] Spirometry is one of the fundamental measures of asthma control; it provides an objective measure of airflow limitation caused by smooth-muscle contraction or structural changes. The measures relevant to asthma are: FEV1, forced vital capacity (as vital capacity or FEV6), FEV1 to forced vital capacity ratio, BD responsiveness (change in FEV1 after inhaled BD) and post-BD spirometric results. Pre-BD FEV1 has been used as the primary end point of lung function in most of the asthma clinical trials over the last three decades, based on the early focus on airway obstruction as the primary characteristic of asthma. Low FEV1 measures (pre-BD, on treatment or random) are independent predictors of subsequent AEs. [4042] BD reversibility is also an independent predictor of death due to asthma. [41] BD responsiveness is only weakly associated with measures of AHR and airway inflammation, but is an independent predictor of response to inhaled corticosteroid therapy.[43] Studies have found that pre-BD FEV1 is associated with most other measures of asthma control [4446] but it correlates weakly with symptoms [47] and with disease-targeted HRQOL. [48,49] Changes in FEV1 over time are associated with changes in most other asthma outcome measures, [50] but such associations are generally poor (including airway inflammation indexes).[51] Taken together, these findings indicate that lung-function measurements provide complementary information to that provided by other measures. [52
Airway Hyper-responsiveness
Airway hyper-responsiveness is a measure of variable airflow limitation and is one of the defining features of asthma. AHR reflects the increased sensitivity of the airways to inhaled stimuli, even when spirometric results are normal. AHR is commonly measured by using direct or indirect challenge tests (referring to the mode of action of the agents in relation to smooth-muscle contraction; methacholine is commonly used as a direct smooth-muscle stimuli). AHR is a crucial outcome measure in studies focusing on modifying underlying disease activity. Direct challenge agents can be considered for assessing mid- and long-term disease modification, while indirect challenge agents are relatively more responsive when investigating short-term responses to anti-inflammatory interventions. Airway hyper-responsiveness is only weakly associated with symptoms, lung function and markers of airway inflammation,[53] but provides independent and complementary information. [54] Studies performed with direct-challenge agents have demonstrated that AHR is strongly related to the clinical course of asthma. Increased AHR is an important risk factor: it predicts loss of control of asthma [55,56] and development of irreversible loss of lung function. [57,58] Increased AHR is a significant risk factor for the subsequent development of physician-diagnosed asthma and chronic obstructive pulmonary disorder in the general population. [59]
Airway hyper-responsiveness is considered an integrative disease marker reflecting multiple pathophysiological mechanisms and should be included in asthma therapeutic trials. In treatment, AHRguided therapy has shown promise in preventing lung-function decline[60,61] by targeting bronchial hyperresponsiveness.[62]
Biomarkers
Phenotypical or pathophysiological biomarkers can be useful in providing relevant information in guiding treatment decisions. Several pathological and physiological biomarkers have been shown to predict risk of exacerbations.[63] However, no single biomarker has been recommended to assess asthma among all patients for all medications. Biomarkers of airway inflammation are becoming more widely available in clinical settings and can be considered when the differential diagnosis of asthma is difficult. They also provide objective measurements for asthma clinical trials. Characterization of patients' phenotype will probably become increasingly important in developing targeted therapies. For example, in treatments based on sputum eosinophils, measurements of exhaled nitric oxide have shown benefit in terms of fewer exacerbations or reduced medication requirements. [64,65] Clinical studies may collect biomarkers such as IgE, cortisol, urinary leukotrienes, exhaled nitric oxide and sputum esoinophils for supplementary information.
Asthma Self-management
Leading asthma treatment guidelines emphasize that asthma self-management education should be integrated into all aspects of asthma care and reinforced over time.[1,66,102] Asthma self-management refers to the problem-solving behaviors that patients use to manage asthma over time and involves several tasks in multiple areas. Patients must learn to implement behaviors that enable them to understand their illness and take action to avoid known triggers, monitor their symptoms over time, detect declining physiological function, communicate accurately with healthcare providers, access appropriate treatments and take medications properly. The goal of self-management is to optimize physiological status, improve symptoms and improve functioning and wellbeing. Asthma self-management practices, including therapeutic adherence and use of an asthma action plan, are associated with asthma outcomes. Appropriate consideration of patients' asthma self-management practices can further characterize patient risk and factors that mediate treatment effectiveness. A Cochrane review indicates that self-adjustment with the aid of a written action plan is equally as beneficial as regular review by a physician. [67] Several measurement tools have been developed for patient asthma self-management. Notably, the Asthma SelfManagement Questionnaire, includes items that focus specifically on self-management activities. [68] These activities include knowledge of proper use of preventive strategies, proper use of inhalers, understanding the differences between rescue and maintenance medications and use of peak flow meters. Therapeutic adherence is discussed in more detail in the next section
Therapeutic Adherence
Adherence with controller therapy is the cornerstone of long-term asthma treatment. Multiple studies have reported that nonadherence is common not only in clinical practice but also in clinical trials. Because patient adherence to therapeutics is a fundamental factor in determining asthma outcomes, patient adherence measures are essential to differentiate poor asthma control owing to nonadherence from treatment-resistant asthma. In clinical studies, accurate measures of patient adherence demonstrate the degree to which nonadherence contributes to therapeutic failure. Asthma adherence is most commonly measured in clinical research by a self report survey or diary, medication measurement (dose or pill counting), electronic medication monitors or pharmacy refill data. In clinical trials, self-reports should be used in combination with more valid measures of adherence. Electronic pharmacy records can yield a wealth of data on asthma patients' patterns of adherence based on refill data and can be useful in characterizing patients individually or as a group.
Expert Commentary & Five-year View

Traditionally, asthma-practice guidelines have focused on optimizing lung function and the FDA requires increases in lung function to be the primary outcome in clinical trials of new asthma therapy. Improved lung function has been an important measure of BD therapy, but long-term asthma control when maintained on controller therapy has been increasingly emphasized and is arguably an even more important outcome. Asthma guidelines have consistently described the goals of asthma treatment as encompassing not only the control of the patients' short-term symptoms, but also risk prevention preventing recurrent AEs. Protection from side effects of therapeutic interventions and long-term protection from adverse outcomes such as airway remodeling and fixed-airway obstruction should also be considered in the guidelines.
The clinical usefulness of these asthma outcome measures is also affected by the rapidity of symptom changes over time in response to treatment. Symptoms and lung function may change quickly from day to day or even hour to hour and can respond rapidly to initiation of treatment, whereas airway responsiveness tends to change slowly with therapeutic interventions. How patients with asthma should be assessed and how therapeutic outcomes should be evaluated are important and challenging issues. Outcome measures to evaluate therapeutic asthma interventions are now increasingly available. Harmonizing major clinical outcomes to allow comparison across studies can benefit asthma treatment in clinical practices and research. This article highlights the major issues in measuring asthma outcomes. Comprehensive understanding of the effects of therapeutic agents on asthma requires assessment of standard clinical indicators of lung function and AHR, multidimensional indicators of asthma control such as symptoms and their severity and the effect on day-to-day functioning and wellbeing. Finally, evaluating asthma self-management and adherence to therapeutic recommendations is critical
From Medscape Pediatrics > Viewpoints
A Better Measure of Childhood Asthma Control

William T. Basco, Jr., MD Authors and Disclosures Posted: 08/19/2011 Rate This Article:
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The Relationship of the Bronchodilator Response Phenotype to Poor Asthma Control in Children With Normal Spirometry
Galant SP, Morphew T, Newcomb RL, Hioe K, Guijon O, Liao O J Pediatr. 2011;158:953-959. Epub 2011 Jan 13
Study Summary
Evidence on clinical variation in patients with asthma is increasing, further advancing the concept of asthma phenotypes. For example, different biomarkers including eosinophils in sputum and the degree of exhaled nitric oxide have been shown to be markers of the "inflammatory" phenotype. However, biomarkers are not readily available to clinicians as they make an initial diagnosis of asthma or classify a patient's asthma severity. Spirometry is currently considered critical to the proper diagnosis of asthma, and use of spirometry is emphasized for all clinicians treating patients with asthma, not just subspecialists. However, office spirometry can be misleading in that many young children will have normal prebronchodilator spirometry results regardless of the severity of their asthma. Therefore, response to bronchodilators, as measured by changes in spirometry pre- and postbronchodilator use, may represent another way to determine a patient's asthma phenotype and risk of experiencing asthma exacerbations. The data for this study were collected from school children participating in a program provided by a mobile health van from 2004 to 2008. All children had an appropriate clinical diagnosis of asthma. Investigators also collected data on the number of exacerbations experienced by the children and use of short-acting beta2-agonists, inhaled steroids, or oral steroid bursts. Children who had not used a controller medication for 6-8 weeks before their mobile van visit were considered naive to controllers. The investigators identified children who had normal prebronchodilator spirometry results as the analysis cohort for this study. Participants were children who were 5 years of age and who could complete spirometry. At least 3 spirometry attempts were completed for each child, and the best attempt was used. The children were then given 2 puffs of albuterol inhaler with a spacer, and spirometry was repeated 10 minutes later. To calculate bronchodilator response (BDR), the investigators used measurements of before-and-after forced expiratory volume in 1 second (FEV1). Children also had screening skin tests for common inhaled allergens. The investigators collected demographic information and measures of impairment, such as daytime and nocturnal frequency of symptoms, and limitation of activities due to symptoms. Data on school absenteeism were also collected. Commonly accepted asthma cutpoints were used as the threshold for whether a child's asthma was poorly controlled. These included experiencing daytime symptoms > 2 times per week, nocturnal awakening for symptoms > 2 nights per month, limitations of exercise, use of beta2-agonists > 2 times per week, or 5 days of school absence per year. One of the main goals of the project was to identify a threshold of BDR that would correlate with or predict poor asthma control. Therefore, the investigators tested different levels of BDR ( 8% change, 10% change, and 12% change) to determine the best predictor of poor asthma control. Of almost 900 enrolled children, 679 had normal prebronchodilator spirometry and comprised the cohort of interest. Of those children, 510 (75%) were controller naive. In controller-naive children, daytime symptoms were present > 2 times per week in approximately 49%, and a similar percentage had nocturnal awakenings for symptoms > 2 nights per month. Daytime exercise limitations affected at least 30% of the children; a beta2-agonist was used more than twice per week by 29%; and school absenteeism of 5 days was documented in 29%. When looking at the bronchodilator-naive children, 36% experienced 8% improvement in BDR after bronchodilators; 27% experienced 10% improvement; and 19% demonstrated 12% improvement. After adjustment for all confounding factors, children who were 5-6 years of age were more likely to have a positive BDR compared with older children (odds ratio, 2.0; 95% confidence interval, 1.1-3.3). Other groups with a higher likelihood of a positive BDR included children with atopic disease, those with increased beta2-agonist use, and those with activity limitations. Sex, weight status, family history, and environmental tobacco smoke exposure did not correlate with a positive BDR. When evaluating impairment factors, a positive BDR was associated with increased odds of nocturnal symptoms, exercise limitations, and use of beta2-agonist > 2 times per week. The investigators concluded that in controller-naive children, the BDR phenotype is associated with clinical markers of asthma control even in children with normal prebronchodilator spirometry testing. BDR response was not predictive of clinical markers of control in children already on controllers, a finding that
may actually be the result of the positive, long-term effects of using inhaled corticosteroids on bronchodilator responsiveness.
Viewpoint
Galant and colleagues remark in their discussion that almost 50% of the children had at least 1 measure of poor asthma control! This suggests that this cohort of patients had many unaddressed asthma symptoms, which is not surprising, given that these children were from an urban setting where the asthma mobile clinic was used to improve healthcare access for children who might otherwise have poor access. The findings of this study correlate well with the findings of the study by Britto and colleagues [1] that I reviewed last month. Both studies demonstrate that multiple methods are needed to both appropriately classify the severity of a patient's asthma and make a decision about beginning a controller medication. The study by Britto and colleagues revealed that adolescents' reported qualitative assessments of their symptom control were very poor compared with more objective measures of asthma control such as symptom frequencies. Galant and colleagues suggest that even children with normal prebronchodilator spirometry should be considered candidates for controller medication if they have a BDR 10%. The rationale for this approach is that the degree of response to bronchodilator correlates with widely accepted clinical measures of asthma control, such as frequency of daytime symptoms, nighttime symptoms, and bronchodilator use. A BDR 10% appears to be a good practical cutoff to use in children, although testing this cutoff in a prospective study with a more varied patient population is needed. Still, this study emphasizes the overarching concept that BDR may be a more appropriate measure than spirometry results.
In order to prevent health complications that arise due to asthma, patient must go through allergy tests. These tests are usually combined with personal history of reactivity to specific allergen in order to diagnose and track growth of asthma. Doctor can also opt out of allergy tests if he can figures out the triggering medium from history itself. Allergy skin tests are reliable and fast ways for determining condition and growth of asthma. Testing for asthma is usually suggested if there are fair chances of asthma being caused by specific allergen or group of allergens. In the tests, allergens are injected under the skin for identification of immunoglobulin E (IgE) mediated responses. The chemical compound found in people with allergies is responsible for activation of mast cells of skin. Thereafter, these cells release chemicals and causing swelling, or redness, or itching, if a certain level of IgE is found. Skin Prick Test In this test, few drops of allergens are dropped on the back skin. Thereafter, a needle is pricked through the skin. Within the space of 15 minutes, a hive will become evident at the portion having IgE antibodies. Intradermal Test One of the common asthma allergy testing methods, intradermal allergy tests are usually used on a negative skin prick testing. In this test, allergen extract is injected into the skin. These are often used with environmental allergens or drugs, but are not done with food allergens or latex. Owing to more risk of inducing a systemic allergic reaction and accuracy aspect, these are not preferred by all. Patch Test In an allergy patch test, a specific allergen is applied to the patch and is then placed on your skin. The patch will take 48 hours to take an effect. The result is positive in case skin turns red and itches, the chances are great that you are allergic to the specific allergen. Radioallergosorbent Test (RAST) Radioallergosorbent test (RAST) measures IgE reactions to specific triggers causing asthma. Carried out in a test tube, the test
is quite effective for individuals who cannot take skin test due to some complications. One of the advantages of choosing RAST over other tests is its non-sensitivity to medications. Quantitative Immunoglobulin Determination Test Quantitative immunoglobulin determination test is another comprehensive technique of blood testing for asthma by measuring immunoglobulin or antibody proteins from blood. This helps in figuring out symptom of asthma, which is either an allergy or an infection.

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54

The hygiene hypothesis

Allergens and irritants

Race-, sex-, and age-related demographics

Mortality and morbidity associated with asthma

The clinician should determine the pattern of symptoms, as follows:

Coughing and chest tightness

Other nonspecific symptoms

Findings in the absence of an acute episode

Findings during an acute episode

Findings during a moderately severe episode include the following:

Findings during a severe episode include the following:

Oxyhemoglobin saturation with room air is less than 91%.

Pulmonary Function Tests

Fraction of Exhaled Nitric Oxide Testing

Radiography and CT Scan

Table 1. Stepwise Approach to Asthma Medications

Intermittent Asthma Age Step 1 < 5 y Rapidacting beta2agonist prn

Either low-dose ICS plus either LABA, LTRA, or theophylline OR Mediumdose

Components of Asthma Care

Assessment and monitoring

Control of environmental factors and comorbid conditions

Either low-dose ICS plus either LABA, LTRA, or theophylline OR Mediumdose

agonist as Alternate needed regimen: cromolyn, LTRA, or theophylline

Delivery devices and best route of administration

Treatment of Status Asthmaticus

Patient evaluation should include the following:

Assessment for signs of bronchospasm and complications

Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)

90mcg (base)/actuation (equivalent to 108mcg albuterol sulfate)

tablet, extended release

0.083% 0.21% 0.42% 0.5%

Pirbuterol (Maxair Autohaler)

Pediatric Dosing & Uses

200mcg/actuation (14g canister; ~400 actuations)

Asthma Maintenance Treatment

Nonracemic Form of the Beta2-Agonist Albuterol

Pediatric Dosing & Uses

0.31mg/3mL 0.63mg/3mL 1.25mg/3mL 1.25mg/5mL

Salmeterol (Serevent Diskus)

View full drug information

Pediatric Dosing & Uses

Dosing Forms & Strengths

Children 4 years and older dose same as adult

Formoterol (Foradil Aerolizer)

Pediatric Dosing & Uses

Dosing Forms & Strengths

Asthma (Maintenance & Treatment)

Exercise-Induced Bronchospasm (EIB)

Theophylline (Theo-24, Theochron, Uniphyl)

Pediatric Dosing & Uses

100mg 200mg 300mg 400mg

View full drug information

Pediatric Dosing & Uses

Dosing Forms & Strengths

View full drug information

Pediatric Dosing & Uses

Dosing Forms & Strengths

Fluticasone (Flovent Diskus, Flovent HFA)

View full drug information

Pediatric Dosing & Uses

Dosing Forms & Strengths

44mcg/inh 110mcg/inh 220mcg/inh

50mcg/inh 100mcg/inh 250mcg/inh