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With antibiotic resistance on the rise and emergence of superbugs, should antibiotics such as carbapenems and colistin be used by general pediatricians_?
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ASTHMA IN CHILDREN
Dr C.T.Deshmukh
Professor of Pediatrics, K.E.M Hospital
Introduction Of Asthma

  • Asthma is the most common chronic condition of childhood.
  • The prevalence and severity of childhood asthma have increased substantially in recent years.
  • Despite continued research and the development of new pharmacological agents, it is one of the leading causes for emergency care requirements; one of the leading causes for missed school, and a cause for considerable morbidity, disability, and occasional mortality at all ages.
Definition Of Asthma:

Asthma is a diffuse obstructive lung disease due to inflammation of the airways, increased mucus production, contraction of the bronchial smooth muscles, with hyperactivity of the airways to a variety of stimuli, a high degree of reversibility of the obstructive process which may occur either spontaneously or as a result of treatment. (Reversible obstructive airway disease).

Current thinking is that regardless of severity, asthma is a chronic inflammatory disorder of the airways.

Epidemiology and Determinants of Pediatric Asthma
  • Despite the fact that pediatric asthma has become an important public health problem, the major determinants of childhood asthma are still unknown. Familial / genetic role for etiology is the most important factor.
  • Atopy is the strongest predisposing factor for development of asthma.
  • More than fifty percent of all children who wheeze with viral infection of the lungs during the first years of life have a transient condition that rapidly subsides sometime after the preschool years.
  • Those who persist to have wheezing at 6 years, who have history or tests suggestive of asthma-related allergies or atopy or have a positive family history of asthma, are more likely to have persistent symptoms until late childhood or even adult life.
  • Environmental factors are also important and the most preventable predisposing factors. The common environmental triggers are cigarette smoke, animal proteins, pet related biological matter and dust mite. Environmental agents work in synergy with viral infections to alter reactivity of the airways.
  • The prevalence of asthma varies from 5 -20 %.
  • Severe asthma leading to death is seen in about 1 %. Hypoxia or air leaks are the main cause of deaths.


    • Main reasons for increased mortality are:
    1. Faulty assessment of severity of illness either by doctor or patient.
    2. Late or sub optimal hospital treatment.
    3. Lack of medical care.
    4. Lack of knowledge of disease.
    5. Delayed use of steroids
    6. Over dependence on inhaled b agents.
Pathophysiology

Classical triad:
  1. Eosinophilia of the mucosa i.e. inflammation and thickening of airway,
  2. Increased mucus secretion and
  3. Contraction of smooth muscle of airways.

  • Hyperresponsiveness or hyperreactivity is the characteristic feature in asthma. This refers to the ease with which airways narrow in response to various nonallergic and nonsensitizing stimuli, including inhaled chemical mediators (e.g., histamine, methacholine) and natural physical stimuli (e.g. exercise, hyperventilation of cold air). It is likely that airway insult from chronic hyperresponsiveness early in life may lead to chronic changes in both lung structure and function.
  • Airway inflammation is a major contributor to the pathology of asthma. The inflammatory process includes infiltration of airways by eosinophils, activation of T cells and production of cytokines as well as other mediators involved in inflammation, an increase in mast cell numbers, and desquamation of airway epithelium. Chronic inflammatory process causes remodeling of the airways with mucosal thickening and smooth muscle hypertrophy even in mild asthmatics. Inflammation causes an associated increase in the existing airway hyperresponsiveness to a variety of stimuli.
  • Airway obstruction is due to narrowing of bronchioles and causes increased airway resistance, resulting in low forced expiratory volumes and flow rates. Obstruction causes premature closure of airways and air trapping. The blockage of airways from secretions and wall thickening causes atelectasis which leads V/ Q mismatch and the various changes in blood gases. Air trapping leads to hyperinflation and raised intrathoracic pressure, which in turn causes increase in work of breathing and may cause airleaks (pneumothorax, pneumomediastinum, subcutaneous emphysema). Increased intrathoracic pressure may cause hypotension by reducing venous return. Hypotension can cause hypoxia and decreased tissue perfusion and also affect the compliance.

  • Precipitating factors:
    1. Allergens – food, animal, mold, spores, pollens, insects, infective agents and drugs.
    2. Irritants – paint odors, sprays, perfumes, chemicals, smoke, cold air, cold water and cough.
    3. Weather changes
    4. Infection – viral, fungal (aspergillosis), bacterial (B. Pertussis), and parasitic (Toxocara, ascariasis)
    5. Exercise (70 % of all asthmatics)
    6. Emotional factors
    7. Gastroeosophageal reflux – (Nocturnal Symptoms)
    8. Allergic rhinitis
    9. Endocrine – menstrual cycles, oral contraceptive pills and hyperthyroidism.
    10. Sinusitis (Nocturnal symptoms)
    Steps at Cellular level:

    - IgE antibodies are synthesized by plasma cells, which are present on surface of respiratory tract.

    - These IgE antibodies become reversibly fixed to surface receptors of mast cells & basophils (sensitized)

    - Antigen attaches to the specific IgE on sensitized mast cells resulting in activation of mast cells and a cascade of biochemical reactions.

    - This results in degranulation and release of preformed mediators (early phase mediators - histamine, ECF, NCF, heparin, PAF) within 30 minutes.

    - Arachidonic acid is formed through activation of phospholipase.

    - From arachidonic acid Leukotrienes are formed via the lipooxygenase pathway and prostaglandins via the cyclooxygenase pathway.

    - These late phase mediators are responsible for late reaction, which develops 6 – 8 hrs after exposure to allergen. (leukotrienes, C4, D4, E4 ,collectively called Slow releasing substance of anaphylaxis previously)

    Clinical Features

    Classical presentation of recurrent prolonged cough , often with breathlessness or wheeze , suggests asthma. Demonstration of a favorable clinical response to bronchodilators and, when measurable, bronchodilation by Pulmonary function test confirms the diagnosis. A positive family history for allergic diseases or asthma, although not essential, tends to support a suspected diagnosis of asthma.

    The main symptoms and signs in asthma are cough, wheeze, tachypnea, dyspnea, and prolonged expiration. Other findings include anxiety, use of accessory muscles, monosyllabic speech, diaphoresis, fatigue, pulsus paradoxicus, cyanosis, hyperinflation, tachycardia, abdominal pain and vomiting. The symptoms may come up acutely (exposure to aero-allergen) or insidiously (following viral infections).

    Asthma is mainly diagnosed by history and physical examination, but may be difficult in infants and young children. The diagnosis and estimation of asthma severity in smaller children depends on the history and response to therapy as assessed by inconstant third-party observations. In older children direct history and as well as more objective assessment is possible.

    Asthma management strategies require identification of the clinical pattern of disease in the patient.

    These clinical patterns include:
    • Intermittent : Patients have episodic illness, with extended symptom-free periods. Episodes are most commonly triggered by viral respiratory infections or exposure to an environmental allergen or irritant.

    • Chronic: Patients experience virtually daily symptoms and, in the absence of continuous therapy, do not have extended symptom-free periods.

    • Seasonal allergic: Patients experience virtually daily symptoms during an inhalant allergy season. Allergens and patterns will vary with the geographic region. Seasonal symptoms may be in reaction to molds, pollens, or a combination of both.

      There is potential overlap among these clinical patterns. For example, patients with chronic disease often have intermittent exacerbations from viral respiratory illness and may have seasonal allergic exacerbations. Nonetheless, identification of the clinical pattern contributes to the determination of a therapeutic strategy.

      Severity , as assessed by degree of morbidity, is independent of the clinical pattern. Both intermittent and chronic disease may range from relatively benign to life threatening. Severity should be judged by the frequency and intensity of urgent care requirements, missed school or work, and interference with activity or sleep.

      The most important cause of death in an asthmatic is failure to identify severe exacerbation of disease. There are various scores to diagnose severity of asthma. Following features are seen in a patient who has Severe acute symptoms :

      Sensorium – Irritable or drowsy

      Speech – Unable to talk more than a few words at a time.

      Posture – Sit up leaning forward with support of back with hands (tripod) or Limp.

      Color – Cyanosis, pale, sweating

      Use of accessory muscles of respiration

      Respiratory rate – Tachypnoea or decreasing respiratory rate.

      Pulse – pulsus paradoxux, tachycardia hypotension.

      Chest findings – Loud wheeze, absence of wheeze, reduced air entry

      O2 Saturation – less than 90 – 92 % in room air

      PEFR – less than 30 – 50 % of normal

      Wheeze need not be present for diagnosis of asthma. If there is not a firmly established alternative diagnosis asthma should be considered when patients present with following symptoms:

      Recurrent/chronic lower respiratory tract wheezing

      Recurrent/chronic cough

      Repeated diagnosis of bronchitis

      Repeated diagnosis of pneumonia not consistent with pyogenic infections

      The diagnosis may be confirmed by demonstrating the complete response of symptoms, or spirometric measurement of airway obstruction, to an inhaled b agonist and/or 5 to 10 day course of oral steroids.
    Pointers to asthma diagnosis:
    1. History:


      2. Cough (especially in night)

      Recurrent wheeze (absence does not rule out diagnosis)

      Recurrent dyspnea

      Recurrent chest tightness

      All above complaints are classically episodic, nocturnal, seasonal and exertional atopy.

    2. Precipitating or aggravating with specific factors:


      3. Airborne chemicals or dusts

      Animals with fur or feathers

      Changes in weather

      Exercise

      House dust mites (mattresses, upholstery, carpets)

      Menses

      Nighttime

      Pollen

      Smoke (tobacco, wood)

      Strong emotional expression (laughing, crying)

      Viral infection

    3. Reversibility and variability:


      4. Variations in PEFR during the day(>=20%)

      Reversible symptoms with treatment

      If all or some of above present, confirm diagnosis by spirometry and response to bronchodilator drugs. If response is good, asthma is most probable and assess severity and give appropriate medications. If response is not good consider other diagnosis or check compliance of anti asthma drugs.

    Differential diagnosis

    All that wheezes is not asthma. Alternative or additional diagnosis should be considered when the history is atypical or the response to proper medical treatment is poor. It is important to realize that asthma may often coexist with other conditions.

    History not consistent with asthma:

    Sudden onset of symptoms

    Coughing or wheezing with feedings

    Neonatal / early onset (less than 2-3 months)

    Neonatal requirement for ventilatory support

    Symptoms of stridor

    Vomiting / choking

    Signs not consistent with asthma:

    Clubbing (cystic fibrosis, bronchiectasis, Interstitial lung disease, congenital heart disease)

    Activity level

    Failure to thrive and vomiting

    Productive cough

    Speech - hoarseness

    Stridor or choking

    Ability to speak or cry normally-( infant and young child)

    Focal lung signs

    CVS signs

    Chronic infection

    A large number of conditions can result in symptoms suggestive of asthma. Common conditions to be considered in atypical cases include:
      Laryngo-tracheomalacia

      Foreign bodies in airway or esophagus

      Chronic viral infections (including HIV related infections of the lungs)

      Bronchiolitis

      Endobronchial tuberculosis

      Pertussis

      Croup

      Aspiration syndromes

      Bronchiectasis

      Immuno-deficiency diseases

      Cystic fibrosis

      Tropical Eosinophilia

      Congenital anomalies of Respiratory, gastrointestinal or cardiovascular systems
    The differential diagnosis of the child with wheezing can be approached on an age group basis. Infants are at a higher risk for congenital abnormalities and most infectious conditions. Aspiration of a foreign body and cystic fibrosis may occur most commonly early in life but can be seen in any age. GER with pulmonary involvement may occur at any age but more common in smaller children. Vocal cord dysfunction and the hyperventilation syndrome merit consideration mainly in the adolescent age group.

    The investigations to be considered are chest xrays, sinus xrays, lung function tests, bronchial challenge tests, mantoux test, sweat test, immune function studies, ciliary studies and reflux studies. Along with these studies response to bronchodilator therapy should also be assessed. If response is good and other tests are negative then consider asthma alone or in association with other diseases.
    Investigations:

    Peak expiratory flow rate/Spirometry:

    Objective measurement of pulmonary function is important whenever possible not only to confirm the clinical diagnosis but to monitor asthma as well. Patient's subjective symptoms and doctor's subjective assessment correlate poorly with pulmonary functions and declines in pulmonary functions may predate acute deteriorations in asthma. This has been stressed in the new guidelines for management of asthma. Expiratory spirometry should be used as soon as the child is old enough to cooperate. Peak flow monitoring and pulmonary function measurements can generally be done by age 6 or 7 years and in some children peak flow measured as young as 3 to 4 years old.

    Peak expiratory flow rate (PEFR):

    • Peak expiratory flow rate (PEFR) is the fastest rate at which air can move through the airways during a forced expiration.
    • And can be easily measured by a simple device the peak flow meter.
    • The peak flow during forced exhalation occurs after about 25 % of the vital capacity has been exhaled .It does not require a complete exhalation like a spirometer, even a dyspneic patient is able to perform the test.
    • PEFR provides simple, quantitative measure of airflow obstruction, which can be performed in home, school, work place for a quick measure of lung function.
    • PEFR should be done at least once a day in all individuals who have more than mild asthma severity. PEFR can provide direct assessment of airflow limitations, diurnal variation and reversibility. The test should be done in the morning and compared with the patient's best effort.
    • Patient's best effort is taken as the average reading taken when the patient is a symptomatic over a period of 2 – 3 weeks.
    PEFR measurements instructions:

    1. Place indicator at the base of the scale
    2. Stand up and take deep breath
    3. Place meter in mouth and close lips around the mouth piece
    4. Blow out as hard as possible (same as blowing a balloon)
    5. Write down achieved measurement
    6. Repeat process two more times
    7. Record the highest of the values achieved
      Reinforcement of proper technique at every visit is important. Same PEFR meter to be used by the patient at all times. Good control is maintaining PEFR at above 80 – 90 % of normal . A drop in more than 50 – 60 % is indication that the attack is severe and medical help may be needed. Daily monitoring can also help in monitoring environmental triggers.

    Spirometry:

    The findings in asthma are:

    • Increased total lung capacity, Functional residual capacity and residual volume.
    • Decrease in vital capacity
    • Decreased dynamic tests of air flow i.e. FEV1, FVC, Maximum expiratory flow between 25 – 75 % of vital capacity
    FEV1 is considered single best measure of lung function to assess asthma severity. FEV25-75 is used to assess function of smaller airways in children.

    Indications for spirometry:

    1. At the time of initial diagnosis
    2. After patient has stabilized on treatment
    3. At least 1 – 2 yearly for periodic check on PEFR in moderate to severe asthmatics
    4. When reducing the dosage of medications
    Other Investigations:

    • Hemogram : Leucocytosis may indicate infection, stress of severe asthma and can be seen in excessive use of epinephrine. Eosinophilia may not necessarily mean an allergic etiology.
    • A chest x-ray should be obtained at least once in any child with asthmatic symptoms sufficient to require hospitalization.
    • Xray of the sinuses when needed.
    • Sweat Test : Child who has had several exacerbations of asthma requiring in-hospital treatment or who has had a history of recurrent pneumonia should be considered a candidate for a sweat chloride test to rule out cystic fibrosis.
    • Children with recurrent wheezing who have repeated bronchopneumonia confirmed by x-ray film should have an immunologic evaluation, including quantitative immunoglobulins and possibly specific antibody titers.
    • The determination of specific IgE antibody by skin or in vitro tests is useful to evaluate potential allergic trigger factors in children with asthma or when a history suspicious of atopic etiology is obtained. Allergy testing in vitro or skin testing should be done in moderate to severe asthmatic.
    • Electrolytes: Hypokalemia due b 2 agonists.
    • Arterial blood gases are important when the patient is admitted with a severe exacerbation. The changes seen in asthma depends on the severity:
    Initial changes - â PaO2 & . β

    Moderate severity - β β PaO2 & β or normal PaCO2

      Severe - β PH, β β β PaO2 & α PaCO2

    • Eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) can be used in the diagnosis ad follow up of patients. The urinary concentration of eosinophil-derived neurotoxin can be especially valuable in young children, because in this age group quantification of lung function cannot be performed and blood sampling can be difficulty.
    Asthma management guidelines

    Various expert committees and global expert panels have reviewed scientific literature over the past many years and have recommended the stepwise management of asthma according to asthma severity. Nearly all the national asthma programs have been following these guidelines. This definite and practical approach has been used world wide with both the patient and doctor satisfaction.

    Among the few recommendations are:
    • Stepwise approach to using medications and early use of anti-inflammatory medication especially in persistent asthma to gain and maintain control of asthma.
    • Classifications of asthma severity linked to treatment alternatives.
    • Prevention of asthma and its risk factors by reducing exposures to environmental allergens and secondhand tobacco smoke helps in optimal asthma control and reducing the dose of medications.
    • Identifying specific allergens for each patient by detail history and allergy testing, and recommendations for reducing exposures to these allergens
    • Emphasis on teaching asthma self-management and prevention risk factors to patients
    • Treatment according to patient’s cultural, ethnic and economic factors
    • Objective measurement to be recommended wherever possible (PEFR meter)
    Assessing asthma severity

    First step in the patients stepwise therapy is assess the patients disease severity. This is done by evaluating the symptoms, history including financial history, current treatment/medications and the response, clinical examination and when possible objective measurement of lung function to establish base line and assess severity. It is recommended that spirometry, which measures lung function, be used in an initial diagnostic work-up.

    Classification of Asthma severity

    Severe persistent asthma - Step 4

    • Continuous complaints. Frequents acute attacks. Limited physical activity.
    • Frequent or daily night symptoms.
    • FEV1/PEFR £ 60 % PEFR variability > 30 %
    Moderate persistent asthma - Step 3

    • Daily complaints. Needs daily-inhaled b 2 agonist. Gets acute attacks twice a week.
    • Nocturnal symptoms more than once a week.
    • FEV1/PEFR 60 - 80 % PEFR variability > 30 %
    Mild persistent asthma - Step 2

    • Complaints more than twice a week but less than once a day. Acute attacks affect daily activity.
    • Nocturnal symptoms more than twice a month.
    • FEV1/PEFR 80 % PEFR variability 20-30%
    Mild intermittent asthma - Step 1

    • Complaints twice a week.
    • No complaints in the night. PEFR normal between attacks. Attacks short duration and less than twice a month.
    • FEV1/PEFR 80 % PEFR variability < 30 %
      Individual is assigned to the most severe grade in which any of the above parameter occurs. Individual's classification may change over time. At any level patient can have mild, moderate or severe exacerbation of asthma.

      For patient management in the stepwise plan the asthma drugs are divided into two groups. This classification reflects how we use the medication, not what the mechanism of action is.

    Asthma medications

    1. Long term therapy or controller drugs (maintenance)

    1. Inhaled and oral steroids
    2. Cromolyn sodium and Nedocromil sodium
    3. Leukotriene antagonist
    4. Long acting b 2 agonist (inhaled salmeterol or sustained release salbutamol )
    5. Methylxanthines sustained released
    2. Quick relief therapy or short acting bronchodilators

    1. Inhaled short acting b 2 agonist (salbutamol, terbutaline)
    2. Inhaled anticholinergics (ipratopium bromide)
    3. Oral steroids
    Depending on asthma severity the above medications are recommended alone or in combinations and varying dosages.


    Stepwise therapy summary:
    • First intervention should be a b 2 agonist delivered promptly by an age-appropriate inhalation device. This is given repeatedly when needed. It is also the treatment of choice for prophylaxis of exercise-induced asthma.
    • An oral b 2 agonist syrup may be appropriate for infants and toddlers with trivial symptoms who have never required emergency care, in order to avoid the expense and bother of a nebulizer.
    • If sub responsiveness to beta-2 agonists is present, then high dose oral corticosteroids should be given and continued until the patient is symptom-free for 24 hours. This usually requires 5 to 10 days of therapy.
    Step 2:

    • If poor response or needs daily use of short acting brochodilators, one of these drugs given twice a day, can be started to prevent asthma exacerbations, depending on preference for inhaled or oral medication.
      1. Inhaled low dose corticosteroids.
      2. Slow-release theophylline
      3. Inhaled cromolyn or nedocromil sodium.
      4. Consider Leukotriene antagonists for older patients.
    • Most prefer low dose inhaled steroids. Cromolyn administered by nebulizer solution may be an alternative for young children who cannot use a metered dose inhaler, even with an assist device. However, this modality is more costly and time consuming, requiring multiple daily treatments.
    Step 3:

    • If symptoms are not controlled or daily short acting brochodilators are needed then two drugs may be required for proper control.
    • Try with moderate dose of inhaled steroids first.
    • Add slow release theophylline or inhaled salmeterol if no response.
    • Alternate-morning administration of shorter-acting oral corticosteroids such as prednisone, prednisolone, or methylprednisolone can be given as an alternative to inhaled corticosteroids for most patients who cannot or will not comply with inhaled corticosteroids.
    • One or two maintenance medications at a twice-daily schedule with judicious use of a pre-exercise beta-2 agonist and appropriate measures of intervention, is generally sufficient for control of asthma.
    Step 4:

    • Patients who are still not free from symptoms and need more than once a day short acting bronchodilators need at least two drugs for prevention of asthma.
    • High dose inhaled steroids are given.
    • And long acting bronchodilator (inhaled or oral b 2 agonist or theophylline)
    • And / Or oral steroids
      All patients requiring maintenance medication should, in general be evaluated to determine the role of environmental factors involved in their symptoms. This evaluation involves careful history and skin testing for specific IgE. This would be particularly relevant for patients requiring more than either theophylline or low-dose inhaled steroids for maintenance. Specific immunotherapy may be tried in severe asthma who need two drugs for control. Each visit special attention is taken to evaluate the compliance and method of delivery of drugs .

    Iniation of therapy :

    • Better to start at higher step than patient's severity and then step down.
    • Achieve rapid control of symptoms by short oral course of steroids.
    • Alternately one can start at a step consistent with patient's severity and step up if needed.
    Maintenance therapy:

    • Start and maintain therapy as mentioned above with either single or combination therapy.
    • Regular patient follow up every 1 – 6 months to decide if changes are needed in stepwise therapy.
    • Before making any changes in step wise therapy check patient's compliance and environmental control measures.
    Intervention alone is sufficient for treatment of those with intermittent asthma. However, patients with chronic disease need maintenance medication in addition, to prevent their daily symptoms. Patients with seasonal allergic disease may require maintenance medication, but only seasonally, and patients with chronic disease may require seasonal increases in their maintenance medication during seasonal allergic exacerbations. Adding or increasing maintenance medication at the times when increased symptoms are anticipated avoids morbidity and decreases the likelihood that urgent care will be needed.

    Treatment goals:

    Although there is no cure for asthma at present, asthma stepwise treatment along with environmental control measures is designed to provide optimal control of asthma and simultaneously limiting side effects of drugs. The following goals should be aimed for:

    1. Prevent symptoms including nocturnal symptoms and exercise-induced symptoms.
    2. Near normal pulmonary functions.
    3. Maintaining normal physical activity and sleep patterns.
    4. Try to eliminate exposure to allergens and triggers and hence reduce exacerbations.
    5. Reduce need for emergency visits for acute exacerbations and hospitalization.
    6. Reduce dosage and side effects of drugs.
    7. Use of inhaled beta-2 agonist < twice-daily.
    8. Use of short courses of high dose daily oral corticosteroids < 4 times yearly.
    9. Satisfaction of patients and relatives.
    Common drugs used in asthma:

    Maintenance drugs:

    Corticosteroids

    • Recognition of importance of inflammation in the pathogenesis has led to early use of inhaled steroids and is considered the first line of therapy by most in persistent asthma.
    • Steroids exert multiple effects on the pathogenesis of inflammation which includes interference with arachidonic acid metabolism, synthesis of leukotrienes and prostaglandins, prevention of activation of inflammatory cells and increased responsiveness of b receptors.
    • Systemic corticosteroids should be considered in the management of acute asthma when the patient does not respond readily to bronchodilators.
    • Early use of corticosteroids shortens the course of asthma, prevents relapses, and reduces the need for hospitalization. The early use of corticosteroids is of particular importance in patients who have a history consistent with fatality-prone asthma.
    • Intravenous corticosteroids may be lifesaving in the treatment of severe intractable asthma.
    • After episodes of severe intractable asthma, complete restoration of pulmonary function may require weeks of treatment. Therefore after such events, corticosteroids should be continued at least until symptoms are controlled and pulmonary function is restored.
    • Inhaled steroids are the primary drugs of choice for persistent asthma. Currently available inhaled preparations include Beclamethasone diproprionate, Budesonide, Fluticasone, flunisolide and triamcinolone.
    • Benefits of inhaled steroids are seen after 2 – 4 weeks of therapy. Aim is to get a daily dose that controls asthma and then step down to minimum dose, which can maintain that control.
    • Moderate to severe asthmatic require high doses inhaled steroids along with inhaled long acting bronchodilators or theophylline.
    • Because of the potential for significant side effects from the prolonged use of systemic corticosteroids (and possibly high-dose inhaled corticosteroids), the need for oral corticosteroids should be monitored by pulmonary function tests, and inadequate control with maximal use of other treatment approaches should be a prerequisite for the long-term administration of systemic corticosteroids.
    • Adverse effects on linear growth from inhaled steroids are dose dependent. There is no evidence growth retardation occurs with the dose of inhaled steroids being less than 400 m g / day.
    • Use of spacers can reduce the dose and side effects and should be used in any patient taking moderate to high doses of steroids.
    • For interventional therapy predinisolone or such equivalent can be given in the dose between 1 - 2 mg/kg per day in 2 - 3 divided doses. Dosage should be continued until the patient is free from symptoms and signs of asthma. The average duration of therapy is 7 days. Dosage should be discontinued without tapering. Oral corticosteroids are as effective as parenteral unless they are not retained.
    Doses of inhaled steroids

    Drug Low dose
    (m g/day)    		 Medium dose
    (m g/day)    		 High dose
    (m g/day)
    Beclamethasone dipropionate 200 – 400 400 - 600 600 – 800
    Budesonide 200 – 400 400 - 600 600 – 800
    Fluticasone 125 – 250 250 - 500 500 – 750

    Cromolyn sodium and Nedocromil sodium

    • Cromolyn remains the safest drug in asthma.
    • It modulates mast cell mediator release and eosinophil recruitment. Cromolyn has the ability to attenuate both early and late-phase IgE-mediated reactions.
    • It is not effective in acute episodes and may not be useful below 1 year of age.
    • In mild persistent asthma under 5 years of age it can be tried before low dose steroid therapy. Cromolyn can be effective in many patients, alone or in conjunction with bronchodilators, in preventing the symptoms of mild-to-moderate asthma.
    • Two inhalations of the standard metered dose inhaler 4 times daily is the recommended dose.
    • Maximum effect may take 1 – 2 months.
    • Cromolyn can be effective in preventing or diminishing exercise-induced asthma when given 15 to 30 minutes before exercise.
    • Available as inhalers, spinhaler capsules and nebulizer solution.
    Theophylline

    • For the treatment of acute severe asthma, theophylline is less effective than inhaled or injected B2-selective agonists.
    • Bronchodilator effect by: phosphodiesterase inhibition, intracellular calcium modulation and prostaglandin antagonism.
    • Maintenance therapy with theophylline is effective in reducing the frequency and severity of the symptoms of chronic asthma. It may be similar in effectiveness to cromolyn or b -2 agonists. It is generally used along with low dose steroids or cromolyn sodium.
    • Sustained release preparations allow for effective control of nocturnal symptoms.
    • Dose varies with age and other factors, begin dose at 10 mg/kg per day in two divided doses. Final dosage is usually based on the peak serum concentration measurement obtained at steady state.
    • Patients with mild chronic asthma may be controlled at steady-state theophylline serum concentrations less than 10 ug/ml; patients with more severe disease may require concentrations greater than 10 ug/ml for effective control of symptoms.
    • The rate of theophylline metabolism varies greatly among patients and is influenced by numerous medical conditions and other drugs. The rate of theophylline metabolism is reduced, leading to increased serum levels, in such conditions as cardiac decompensation, respiratory failure, hepatic cirrhosis, sustained high fever, viral infections, hypothyroidism, and after administration of cimetidine, oral contraceptives, erythromycin, ciprofloxacin, and disulfiram. In contrast, factors such as cigarette or marijuana smoking, hyperthyroidism, rifampin, phenytoin, carbamazipine, and phenobarbital increase the rate of metabolism.
    • Oral slow-release formulations provide stable serum concentrations and increases patient compliance. However, the rate and extent of absorption vary between formulations, between individuals, and possibly in the same individual from time to time. Food ingestion may also affect the rate of absorption in different ways depending on the specific formulation.
    • Do not –
      1) Increase the dose if it is already at lower end of range.
    2) Maintain any dose that is not tolerated

    3) Allow generic substitution

    Leukotriene antagonists and inhibitors.

    • First new class of anti asthma drugs in more than 25 years.
    • They can either block leukotriene receptors (Zafirlukast, Montelukast) or inhibit enzyme 5 lipoxygenase ( Zileuton).
    • They produce long-term bronchodilatation.
    • Main advantage is that they can be taken orally once or twice a day.
    • They may be used instead of steroids in children more than 5 years of age who have mild persistent asthma. They can also be used along with steroids to reduce the doses of steroids. Exact role in management is still evolving.
    Long acting Inhaled b 2 agonist

    • They are used as adjunct to inhaled steroids and other anti-inflammatory agents. Never to be used as single drug therapy.
    • Can be used in nocturnal symptoms.
    • Not to be used for acute attacks.
    • Available as Rotacaps , Inhaler or diskhaler.
    • Given as 25 m g per dose twice a day.
    Intervention drugs

    Short acting b agonist
    • B-agonist bronchodilators vary in their degree of selectivity from non-selective(e.g., isoproterenol) to relatively b -selective agonists ( b 2 -agonists) (e-g., Salbutamol or albuterol, terbutaline). It is preferable to use a selective b -agonist because they have a longer duration of action and are less likely to produce cardiovascular side effects.
    • Inhaled b 2-agonists are preferable to oral drugs the treatment of chronic asthma because rapid onset of action, are generally more effective than other routes of administration, and infrequently produce adverse reactions. Inhaledb 2 -agonists are generally the safest and most effective treatment for acute asthma. In general, oral ß2-agonists should not be administered for the treatment of acute severe asthma. They are available in inhaler, nebulized solution and oral forms.
    • Inhaled b 2-agonists may be more effective when administered on an as needed basis rather than on a regular basis in the treatment of chronic asthma. If greater than eight inhalations per day (or approximately one canister per month) are needed, the addition of cromolyn, nedocromil, or inhaled cortosteroids should be considered.
    • The administration of b 2-agonists in the treatment of acute or chronic asthma is not a substitute for the early use of anti-inflammatory drugs.
    • Spacers attached to inhaled b 2-agonists improve drug delivery in patients who do not correctly use inhalers. Patients must be carefully instructed, often more than once, in the use of inhaled B2-agonists because a large percentage of patients fail to use inhaler devices correctly.
    • Inhaled B2-agonists are generally considered the agent of choice for prevention of exercise induced asthma. It should be taken 15 to 30 minutes before exercise.
    • Tolerance to B2-agonists may develop after continued use of these drugs and can be associated with an unrecognized decrease in efficacy and delay in seeking medical attention. This may be reversible after the administration of corticosteroids,
    • Tremor and central nervous system effects are minimized by inhalation of B2-agonists, although hypokalemia and significant cardiovascular effects can occur when these drugs are administered by this route. Serious adverse effects from the administration of B2-agonists, when administered in recommended doses, are uncommon when given orally and extremely uncommon when administered by inhalation.
    • B2-agonists when administered by inhalation, can produce a sudden paradoxical increase in bronchospasm, which may be life-threatening in some asthmatic patients.
    Inhaled anticholinergic agents

      • Drugs such as ipratropium, appear to be more effective when used to treat patients with chronic mild to moderate asthma.
      • Ipratropium, may be indicated in whom alternative agents have not been sufficiently effective, are inappropriate because of other medical conditions, or have produced unacceptable side effects.
      • Inhaled anticholinergic medication is not sufficiently effective to be used as a single agent in the treatment of acute severe asthma but may benefit when combined with a B-agonist or other primary therapeutic agent
    Other drugs:

    Antihistamines

    • Antihistamines can be safely used in most patients with asthma.
    • Based on their ability to block late-phase responses to allergen exposure, newer antihistamines may play a greater role in the future treatment of asthma.
    • There is a strong clinical impression that improvement of upper respiratory tract symptoms by antihistamines in patients who have concomitant allergic rhinitis and asthma may facilitate the treatment of lower respiratory tract symptoms.
    Hydration and pharmacomucolytic agents

    • Adequate hydration is recommended for patients with asthma, but careful monitoring of fluid and electrolyte balance should prevent overhydration. Dehydration may occur with severe asthma and should be corrected. However, fluid overload may have adverse pulmonary and circulatory effects and must be prevented by careful monitoring of fluid and electrolyte balance.
    • Guaifenesin and potassium iodide may be worth a trial in some asthmatic patients, although the mechanisms of action are unclear.
    Antibiotics/antivirals

    • Infections associated with asthma exacerbations are almost always viral in origin and do not require antibiotic therapy.
    • Bacterial infections, such as acute and chronic sinusitis, should be treated appropriately, including the prompt and adequate use of antibiotics.
    • Influenza can be associated with increased asthma. Therefore appropriate immunization is essential in patients with moderately severe or severe asthma.
    Immunizations

    • Routine vaccinations are not contra-indicated in patients with asthma or other allergic conditions. Patients who have a history of egg sensitivity should be skin tested with the vaccination material.
    • Short-term, low-to-moderate dose systemic corticosteroids, alternate-day corticosteroids, or topical corticosteroids are not immunosuppressive and are not a contraindication for immunization.
    • Influenza vaccine and pneumococcal vaccine are recommended for patients with chronic pulmonary disease including asthma.
    Drug delivery:

    • Where ever possible inhaled route of drug delivery is the preferred route in asthma except for theophylline.
    • Metered dose inhaler (MDI) can be used for a child who is about 6 – 7 years and is trained properly with the technique. It is better to use an assist device or spacer when using MDI for children.
    • Inhaled therapy with the metered dose inhaler (MDI) has been effectively used for smaller children with the aid of a mask.
    • MDI with spacer should be the device of choice in children as it is simple and convenient form of therapy and can be used in an acute exacerbation.
    • Children who are unable to take medication with MDI or cannot tolerate it can be given the medication via the nebulizer.
    • Dry powder inhalers are other simple devices for use in children over 4 – 5 years of age.
      Physicians and patients have several options to use the inhalation drugs in asthma and the device selected will depend on age, cost and convenience of the patient.

    Control of precipitating factors

    • There is a strong link between inhaled allergens and asthma. Exposure to irritants or allergens, which the patient is sensitive to, increases the symptoms and precipitates asthma exacerbations.
    • It is very important to take a careful history to identify such factors. History is usually adequate for seasonal allergies.
    • If available, skin testing and in vitro testing for specific IgE antibodies may be useful to identify perennial indoor allergens.
    • Once asthma triggers have been identified the next step is to reduce the exposure to those triggers. Avoidance of triggers requires a high level of commitment on part of the patient and family.
    • Avoidance is most important in moderate to severe asthmatics and may help in reducing the dosage or need for medication. Aspects of responsibility for treatment may apply to all environments in which the child spends a significant amount of time, such as preschool, school, or day care. The greatest effort is spent in relation to the bedroom, where children spend a major part of their time.
    Recommendations (where ever possible):

    • Annual influenza vaccine for patients with persistent asthma.
    • Skin testing / invitro testing for at least in persistent asthma.
    • Not to use chemicals to kill house dust mites / cockroaches.
    • Aspirin not to be used in persons sensitive to it.
    • Avoid exposure to all tobacco smoke limiting exposure to allergens they are sensitive to, other irritants, as well as to house dust mite, cockroach, mold, animal, and pollen allergens . .
    • Avoid exertion when air pollution levels are high.
    • Exercise-induced bronchospasm is common in children. Pretreatment with B2-agonists and/or cromolyn sodium can prevent symptoms. Optimal control of chronic asthma by anti-inflammatory therapy also can decrease the frequency and intensity of exercise induced asthma.
    • Avoid taking nonselective b -adrenergic antagonists (blockers for migraine, stage fright)
    • Consider allergen immunotherapy when connection between symptom and exposure to unavoidable allergen is clear and symptoms occur during most of the year.
    • The use of acyclovir and/or varicella immune globulin should be considered in children who have a negative varicella history and/or antibody titer and who receive or recently have received systemic steroids and have been exposed to varicella.
    Managing coexisting disease:

    Asthma is better managed and drug therapy may be drastically reduced if coexisting diseases are managed. Examples of such diseases include rhinitis, sinusitis, Gastroesophageal reflux disease.

    Assessment, monitoring, follow-up:

    • The condition of a patient's asthma will change depending on the environment, patient activities, management practices, and other factors. Thus, even when patients have their asthma under control, monitoring and treatment are needed to maintain control.
    • Consider signs, symptoms, pulmonary functions, quality of life, functional status, and history of asthma exacerbations, current drug therapy patient education, drug delivery techniques and patient satisfaction. Home monitoring of PEFR is an important aspect of asthma treatment.
    • Patients should receive routine follow-up at scheduled intervals to assess control and assure safety of treatment.
    • Measurement of pre- and post-bronchodilator pulmonary function with office spirometry should be performed at each visit.
    • Growth and weight gain should be monitored, because both asthma and treatment with maintenance inhaled or alternate-morning oral corticosteroids have the potential to slow growth.
    • Blood pressure measurement and eye exam for cataracts should be performed on all patients receiving maintenance corticosteroids. In susceptible patients, increased blood pressure may be a systemic effect of corticosteroids. Also, an increased risk of cataracts has been demonstrated even from inhaled corticosteroids.
    • Frequency of follow-up. Patients with an intermittent pattern of asthma can be followed with annual checkups if they meet criteria for control. However, more frequent visits may be required to reinforce instructions.
    • Patients with a chronic pattern of asthma should be followed closely until criteria for control are met. Once disease control is achieved moderate to severe asthmatics should follow up every 3 months. Patients on low doses of inhaled corticosteroid or other single-maintenance medication may be followed once every 6 months.
    Patient education

    • Education of patient and active partnership of patient and doctor is the cornerstone of asthma management.
    • Starting patient and family education at the time of diagnosis, integrating it into every step of clinical asthma care, and tailoring it specifically to the needs of each patient, with sensitivity to cultural beliefs and practices.
    • Patient education covers
      1. Basic asthma facts - Taught to understand their asthma; to know how to recognize symptom patterns indicating that their asthma is getting out of control. This can prevent emergency room visits and hospitalizations
      2. Roles of medications – difference between quick relief and long term control
      3. Skill needed for inhaler and spacer use and self monitoring with PEFR meter
      4. Environmental control measures and avoidance measures.
      5. When and how to take rescue steps, written treatment plans.
    Management of acute exacerbation of asthma

    Asthma exacerbations are acute episodes of progressive worsening of breathing, cough, wheeze and chest tightness. These exacerbations are characterized by decrease in PEFR whish in turn can be easily quantified by PEFR meter or spirometer. These objective measurements indicate severity more accurately than symptoms.

    The aim in management of acute asthma is:

    1. Correct significant hypoxemia – (O2, mechanical ventilation rarely needed)
    2. Reverse airflow obstruction as rapidly as possible.
    3. Reduce inflammation and risk of recurrence by intensifying therapy.

      Early treatment is important to prevent hospitalization and/or the attack from becoming severe. The following points are important for the same:

      1. Written instruction to patient for self treatment.
      2. Early diagnosis of worsening by PEFR meter or spirometer.
      3. Early contact with doctor regarding clinical or PEFR changes.
      4. Early increase in therapy (ß 2 agonist, oral steroids).
      5. Remove precipitating factor if any.
      Patients with high risk for asthma deaths need extra attention.

    High risk factors for death in asthma:

    1. Past history of severe exacerbations.
    2. History of intubation mechanical ventilation for asthma.
    3. More than two hospitalizations for asthma in past one year.
    4. History admission to Pediatric intensive Care unit for asthma.
    5. Use of oral steroids for current attack.
    6. Excessive use of ß agonist.
    7. Frequent emergency visits for acute asthma.
    8. Associated cardio-respiratory diseases.
    Management

    The diagnostic phase in a child with acute asthma should be short and comprise a brief history taking, inspection and auscultation of the thorax, transcutaneous oxygen measurement and, if possible, peak flow measurement ( PEFR ).

      • Patients should be treated immediately with oxygen , which should always be humidified.
      • ß 2-agonists should be given immediately by inhalation if they are capable of effective inhalations or by injection if severely dyspneic. Frequent doses should be given and the duration and effect can be monitored by clinical assessment and PEFR measurement.
      • High dose corticosteroids should be administered promptly by mouth if there is no concern regarding retention, and parenterally if the patient is obtunded or vomiting.
      • Monitor clinical parameters, pulse oximetry and PEFR. PEFR should be monitored every 30 minutes until patient is out of danger.
      • Blood gases should be done if : 1) O2 saturation < 94 % at room air and patient dyspneic or 2) O2 saturation < 90 % regardless of clinical findings.
    After initial management one has to decide if patients needs hospitalization or needs to be sent home on medication.

    Guidelines for admission:

    Do not admit if:

    1. Comfortable at rest.
    2. No chest retractions.
    3. Not using accessory muscles of respiration.
    4. O2 saturation > 90 % at room air.
    Admit if :

    1. Labored respirations continue.
    2. O2 saturation < 90 % at room air.
    3. Dehydration, which requires intravenous fluids.
    4. Past history of rapid deteriorations.
    5. PEFR < 50 % or diurnal variation > 25 %.
    6. Presence of complications such as subcutaneous emphysema and pneumothorax.
    Do not keep patient for observation with simple measures for more than 3 – 4 hours, it is better to admit such patients for more intensive therapy and observation.

    Treatment after admission:

    • Continue humidified oxygen monitoring pulse oximeter.
    • Continue inhaled ß2 agonist frequently depending on clinical and PEFR findings.
    • Intravenous fluids are needed in most with severe asthma as they are dehydrated due to - increased metabolism, increased insensible losses, decreased intake, vomiting. Dehydration can increase viscosity of secretions, thereby increasing bronchiolar plugging and atelectasis. Over hydration can cause pulmonary edema. Hence correct the dehydration, then provide maintenance fluids, monitor fluid and electrolytes and correct accordingly.
    Medications:

    1. Inhaled ß 2-agonist by nebulization either ½ hr to 1 hourly or continuous (continuous nebulization 0.1 to 0.3 mg/kg/hr to max 10-15mg/hr).
    2. Corticosteroids are the most important drugs in treating asthma
        • Can be given oral if patient can take PO steroid without emesis
        • Intravenous methyprednisolone 1-2mg/kg/dose q6hrs, then depending on clinical course should be continued orally.
        • Inhaled therapy may be as effective as IV in acute therapy.
    1. Anticholinergics: ipratropium bromide can be used and has additive effect to B-agonists. Can be given as 250mcg (1cc) nebulization every 3 – 4 hourly.
    2. Aminophylline drip may be useful by increasing diaphragm contractility, increasing mucociliary clearance, anti-inflammatory properties and bronchodilatation, so it may be of some added benefit in patients with poor response to B-agonist.
    3. Others routes of ß 2 agonist
      1. Subcutaneous epinephrine or terbutaline may also be given as an alternative. This route is selected if no other route is available/acceptable.
      2. Salbutamol intravenous may be tried if minimal effect with inhalation therapy.
      3. Intravenous continuous infusion (terbutaline, isoproterenol, albuterol) can be used when no improvement with inhaled bronchodilators. Terbutaline - bolus 10mcg/kg over 30 min, infuse with 0.1mcg/kg/min. Needs close monitoring of heart rate, cardiogram and oximeter
    4. Other drugs:
      1. Antibiotics - no role for routine use. May use if there is evidence of infection(sputum predominantly PMNs , sinus infection, pneumonia, suspicion of Mycoplasma or Chlamydia).
      2. Magnesium SO4 – Used as bronchodilator. The mechanism is not clear, but may be due to inhibition of Ca++ mediated smooth muscle contraction or direct inhibition of smooth muscle contraction. There are no controlled studies in children and has been tried IV in the dose of 30-70 mg/kg over 20-30 min. (max=2g).
    1. Blood gases: Hypoxemia in asthma is because of either V/P mismatch or respiratory failure and only pulse oximetry will not be able to differentiate the two, blood gases are important at this stage. Blood gases should be asked for when:
      • O2 saturation is less than 94% on room air and patient is dyspneic.
      • Or if O2 saturation < 90% regardless of signs or symptoms.
    1. Other investigations may be needed:
      1. WBC - demarginated PMNs due to stress, steroids and infection.
      2. Electrolytes – i. hypokalemia due to ß agonist
        ii. bicarbonate low due to metabolic acidosis
      3. Xray chest to look for complications.
    Indications to transfer to PICU:

      1. Altered consciousness
      2. Exhaustion
      3. Sitting position accompanied by diaphoresis
      4. Severe decrease air entry
      5. Monosyllable speech
      6. PCO2 rising, near normal, elevated,
      7. Pneumothorax, subcutaneous emphysema.
      8. Drug toxicity
      9. No improvement with standard therapy as above.
      10. Cardiac/respiratory arrest
      11. Metabolic acidosis
      12. PFT's deteriorating despite treatment.
    Indicators of impending respiratory failure:

      1. Altered Level of Consciousness.
      2. Monosyllable or not able to speak.
      3. Markedly decreased or absent breath sounds
      4. Cyanosis
      5. Severe chest retractions and use of accessory muscles.
      6. Pulsus paradoxus > 10mm Hg
    Treatment in PICU:

    • Continue IV bronchodilators, continuous nebulizations, anticholinergics, steroids and O2.
    • Treatment of acidosis:
      • acidosis is caused by hypoxemia, hypoperfusion and respiratory failure. acidosis.
      • It leads to myocardial depression, decreased effectiveness of B-agonists and ineffective rapid shallow breathing.
      • Correct metabolic by giving bicarbonate (keep pH > 7.20) 1 meq/kg.
    • Sedatives
      • May be given to prevent ineffective ventilation and interference with nebulization therapy.
      • Preferably use those with bronchodilating effect e.g. Haloperidol or ketamine.
      • Use only in PICU setting or when patient on ventilator.
    • Mechanical Ventilation
      • Indications:
        1. Cardiorespiratory arrest
        2. Severe altered mental status
        3. Progressive exhaustion
        4. Failure to respond to maximal medical treatment (acidotic, pCO2 > 50 and rising, minimal chest movements, cyanosis and hypoxemia).
        5. Pneumomediastinum
      • Goals of ventilation:
      1. Oxygenate and ventilate.
      2. Let trapped air escape
      3. Prevent barotrauma
      4. Give rest to respiratory muscles
      5. Give time for anti-inflammatory medications to work
    • Non-conventional interventions
      • CPAP/ non-invasive positive pressure ventilation
      • Inhalation anesthetics
      • Bronchoscopy
      • Heliox
      • ECMO
      • NO 
    • Patients may be discharged if they are comfortable at rest without retractions or use of accessory muscles of respiration, and if O2 saturation is greater than 90% on room air. Early follow-up is important.
    Out patient management summary

    Main areas: Treatment, education and follow-up 

    Treatment – Start or continue appropriate anti-inflammatory drugs (inhaled steroids). Use Bronchodilators when needed and also to prevent exercise induced asthma. Change to MDI in hospital before discharge. Treat exacerbating factors (GER, sinusitis, allergies).

    Education – About signs and symptoms of asthma, what are the precipating factors and how to detect and remove them, what to do if an attack occurs, importance of follow-up regularly and use of PEFR meter

    References

    1. National Asthma Education and Prevention Program, Expert Panel Report II. Guidelines for the diagnosis and management of asthma. NIH publication 97-4051, April, 1997.
    2. Colasurdo GN, Larsen GL: Airway hyperresponsiveness. In: Busse W, Holgate S, eds. Asthma and Rhinitis. Boston, Blackwell Scientific Publications, Inc., 1994, pp 1044-1056.
    3. Martinez FD, Wright AL, Taussig LM, et al: Asthma and wheezing in the first six years of life. N Engl J Med 332:133-138, 1995.
    4. Sears MR, Rea HH, Fenwick J, et al: Deaths from asthma in New Zealand. Arch Dis Child 61:6-10, 1986.
    5. Pedersen S, O'Byrne P: A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 52(suppl 39):1-34, 1997.
    6. Drazen JM, Israel E, O'Byrne PM: Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 340:197-206, 1999.
    7. Wenzel SE: New approaches to anti-inflammatory therapy for asthma. Am J Med 104:287-300, 1998.
    8. Knorr B, Matz J, Bernstein JA, et al: Montelukast for chronic asthma in 6- to 14-year-old children. A randomized, double-blind trial. JAMA 279:1181-1186, 1998.
    9. Kemp JP, Dockhorn RJ, Shapiro GG, et al: Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr 133:424-428, 1998.
    10. de Jong VM, Janssens HM, Heijnen EMEW, et al: Spacer handling and variability of aerosol delivery in wheezy infants [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    11. Janssens HM, Heijnen EMEW, de Jong VM, et al: Variability of aerosol delivery via spacer devices in wheezy infants in daily life [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    12. Heijnen EMEW, Janssens HM, de Jong VM, et al: Spacers and electrostatic charge in daily life [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    13. Roorda RJ, Mezei G, Bisgaard H, et al: Response of pre-school children with asthma symptoms to inhaled fluticasone propionate: results from two multicenter studies [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    14. Mandelberg A, Tsehori S, Houri S, et al: Nebulized aerosol treatment in the pediatric emergency department — is it essential? Comparison with a metal spacer device for MDI [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    15. Lampl KL, Dixon SJ, Bonuccelli CM: Long-term safety and efficacy of zafirlukast (Accolate) in pediatric patients with mild-to-moderate asthma [Session A41]. ALA/ATS International Conference, San Diego, Ca, 1999.
    16. British Asthma Guidelines Coordination Committee. British guidelines on asthma management: 1995 review and position statement. Thorax 1997; 52: S1-24
    17. Keeley D, Rees J. New guidelines on asthma management. Br Med J 1997 Feb 1; 314: 315-6
    Last created on 06-11-2000
    Last updated on 01-07-2006
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