The Dutch College of General Practitioners (NHG) Practice Guideline

This NHG Practice Guideline is a translation of the Dutch guideline. It is specifically written for Dutch general practitioners in the Dutch enviroment. The advice which is given may therefore not be in accordence with the views of general practitioners in other countries.

NHG Practice Guideline 'Adult asthma: treatment'  

R.M.M. Geijer, W. van Hensbergen, B.J.A.M. Bottema, C.P. van Schayck, A.P.E. Sachs, I.J.M. Smeele, H.A. Thiadens, C. van Weel, C.F.H. Rosmalen

This practice guideline and its scientific basis have been updated with respect to the previous version (published in NHG Practice Guidelines for the General Practitioner 1, 1999). The key messages are:

What's new:

 

INTRODUCTION  

The NHG Practice Guideline 'Adult asthma: treatment' provides guidance for management of asthma in adults and in children aged 12 years and older. The diagnosis of asthma and COPD and the treatment of COPD are covered in the two other practice guidelines on asthma and COPD.1 For the terminology used as well as background information, see the NHG Practice Guideline 'COPD and adult asthma: diagnosis'.

It is assumed that the diagnosis has been established in accordance with the guidelines in the NHG Practice Guideline 'COPD and adult asthma: diagnosis', and that the most important symptom of asthma has been confirmed: namely, reversibility of the bronchial obstruction.

The objectives of management are:

In addition to general measures, such as avoiding smoking and thorough cleaning when there is an allergy to house dust mites or other indoor allergens, management consists of providing information and drug therapy. A distinction is made between symptomatic treatment with bronchodilators and preventive treatment with anti-inflammatory agents. For intermittent asthma, the combination of general measures and  symptomatic management with short-acting beta2 sympathomimetic agents is sufficient. For mild persistent asthma or a more serious form of asthma, treatment consists primarily of anti-inflammatory agents (preferably inhaled glucocorticoids), temporarily supplemented by a short-acting beta2 sympathomimetic agent during exacerbations. If the treatment objectives are not attained with a moderate dose of inhaled glucocorticoid (budesonide or beclomethasone 400 µg twice daily or fluticasone 250 µg twice daily), the choice is between increasing the dose of inhaled glucocorticoid or adding a long-acting inhaled beta2 sympathomimetic agent. Prior to this step, the diagnosis and management should be reviewed, and if in doubt, a pulmonologist should be consulted.

 

MANAGEMENT GUIDELINES  

Information and supervision  

The general practitioner should provide information on the following:

 

Preconditions  

The care of patients with asthma and COPD can be partially delegated to a well-trained practice assistant or to a practice nurse who can perform some or all of the following tasks:

 

Non-pharmacological therapy   

Smoking can result in more rapid deterioration of pulmonary function and shortening of life expectancy. In addition, smoking is a non-specific irritant that exacerbates asthma. Smoking cessation has been shown to delay further deterioration of pulmonary function. Advise patients to quit smoking and to avoid passive smoke inhalation to the greatest extent possible.6

Patients with asthma should be invited for an annual influenza vaccination.7

Cleaning. Studying the extent to which cleaning measures benefit the clinical picture is complicated. It is difficult to assess the effect of separate interventions, since there is a lack of methodologically good research with sufficient numbers of patients. When there is a proved allergy to house dust mites or other indoor allergens (such as from pets), consider the following, taking into account the patient's financial resources:8

There is no benefit from extra vacuum cleaning. Recommendations for avoiding non-specific irritants depend on the individual situation. There may be cases in which a primary care pulmonary nurse can come to the home, identify problems, and provide information and advice on cleaning. She also has a practical role in supervising patients with severe asthma who are very limited in daily activities. For practical advice, refer to the brochures of the Dutch Asthma Foundation.

If there are indications that the symptoms are worsening due to work-related factors, advise the patient to contact the Occupational Health and Safety Department about options for making adjustments in the work or changing jobs. If work-related factors are putting the patient's job or career track in jeopardy, referral to a pulmonologist is indicated.

 

Drug therapy: general principles  

Medications used to treat asthma are most often administered by inhalation. Two different methods are used:9

With metered-dose aerosols, neither the dose delivered nor the average particle size are dependent on the inspiratory force; rather, deposition in the lung is primarily determined by hand-lung coordination. The problem of coordination can be overcome by using a spacer or a 'breath-actuated' metered-dose aerosol. With dry powder inhalers, the dose delivered and the average particle size do depend on the inspiratory force, which therefore largely determines the deposition in the lung. Most types of dry power inhalers—with the exception of the multidose inhalers—are somewhat awkward to prepare for use. Deposition in the lung is greater with some of the dry powder inhalers (due to the physical properties of the device) and some metered-dose aerosols (due to a smaller particle size). Because of this, there may be different recommended doses for the same preparation, depending on the type of inhaler or metered-dose aerosol. The above properties and the patient's facility with the device should be taken into consideration when choosing the type of inhaler. In general, patients with adequate inspiratory force and adequate hand-lung coordination can use either a dry powder inhaler or a metered-dose aerosol. For older patients who have inadequate inspiratory force and/or poor coordination, use of a metered-dose aerosol with a spacer is preferred. When prescribing multiple medications, the general practitioner should aim for consistency in the method of administration. Only in exceptional cases should oral therapy with beta2 sympathomimetic agents or inhalation using an electric-powered jet nebulizer be considered.

The following inhalation instructions should be given:

 

A distinction is made between:

There are three groups of bronchodilators: beta2 sympathomimetic agents, 10-13 anticholinergic agents,14 and theophyllines.15 These drugs reduce bronchial obstruction but have no anti-inflammatory effect. Maintenance treatment with a bronchodilator alone for moderately severe to severe asthma can result in more rapid deterioration of pulmonary function. In  mild asthma, this risk is probably small.10 High doses of beta2 sympathomimetic agents can cause side effects such as hand and finger tremors, headache, peripheral vasodilation, increased heart rate, and (with concomitant use of an inhaled glucocorticoid or theophylline) hypokalaemia.

Ipratropium bromide is the only anticholinergic agent available for inhalation. It has almost no side effects, even at high doses.

Due to their narrow therapeutic spectrum and the availability of good alternatives, theophyllines are not recommended for treatment of asthma in primary practice.

There are two types of anti-inflammatory agents: glucocorticoids and cromoglycate or nedocromil.

Glucocorticoids are the most effective anti-inflammatory agents and are used to prevent or reduce hyperresponsiveness and allergic reactions.16 The most common local side effect is oropharyngeal candidiasis, which occurs in 5-13% of adults using these agents, but rinsing the mouth and spitting out the fluid after inhalation reduces the risk. The risk of systemic side effects increases at higher doses of inhaled glucocorticoids (1,600 µg budesonide or beclomethasone or 1,000 µg fluticasone per day),.

Cromoglycate and nedocromil are not as effective as inhaled glucocorticoids. Cromoglycate is more effective for allergic asthma and for exercise-induced asthma. The efficacy peaks only after several weeks.17 Nedocromil can be used for allergic and non-allergic asthma and exercise-induced asthma; it has no obvious value over the other older anti-inflammatory agents.18

Other medicinal options: Oral antihistamines did not appear to be sufficiently effective, while monoclonal antibodies to IgE have not been studied adequately. The role of antileukotrienes, such as montelukast, is still unclear, and no opinion has yet been formulated on the role of immunotherapy.19

 

Asthma and pregnancy. Little is known about the risks of asthma medication for the foetus. Short-acting beta2 sympathomimetic agents, ipratropium bromide, cromoglycate, and beclomethasone can usually be given during pregnancy (not enough is known about other inhaled glucocorticoids). Use of long-acting beta2 sympathomimetic agents during pregnancy is not recommended. In acute severe asthma, prevention of hypoxemia outweighs the risks of systemic glucocorticoids for the foetus (possible elevated risk of cleft palate from use during the first trimester) and for the pregnant woman (elevated risk of pre-eclampsia).20

 

Drug therapy: stepwise management  

Some asthma patients present with recurring long episodes of coughing ('bronchitis'), while others present with a more pronounced clinical picture of dyspnoea and wheezing.

Two main categories have been defined for medicinal management:

For management of severe dyspnoea see the section: 'Guidelines for acute severe dyspnoea'.

Before increasing the dose of medication, consider possible reasons why the treatment objective has not been reached:

Specifically, review the diagnosis and the treatment policy when moving from Step 2 to Step 3. When the treatment objective has been achieved for about 3 months, try to reduce the medication or to take one step back.

 

Step 1. Intermittent asthma (symptoms not more than once  weekly)  

If symptoms are infrequent (once weekly or less), start with a short-acting beta2 sympathomimetic agent (see Table 1). Asthma patients above 60 years of age can be started on ipratropium bromide, if needed.14

For exercise-induced asthma, 1 or 2 puffs of a short-acting beta2 sympathomimetic agent taken 10-15 minutes before exercising provides about 2 hours of protection.11

 

Table 1. Short-acting bronchodilators   

Indication  

Medication  

Powder inhaler 'as needed' (up to 6 times daily)  

Metered-dose aerosol as needed (up to 6 times daily)

Lower doses apply to some metered-dose aerosols or dry powder inhalers: consult the Farmacotherapeutisch Kompas

Occasionally/temporarily for:

  • intermittent asthma (Step 1)
  • exacerbations, as well as for continuous use of long-acting beta2 sympathomimetic agents
  • exercise-induced asthma  

Salbutamol*  

100-400 µg, depending on the type of inhaler   

200 µg

Terbutaline*  

500 µg

250 µg

Fenoterol*  

200µg  

200 µg

Occasionally for intermittent asthma at  >60 years of age. (Step 1). Maintenance treatment for severe asthma (Step 4).   

Ipratropium bromide#  

40 µg  

20 µg

* beta2 sympathomimetic agents  # anticholinergic agent

 

Step 2. Mild persistent asthma (symptoms more than once weekly)  

Start 'new' patients with frequent symptoms (more than once weekly) on an inhaled glucocorticoid at a low to moderate dose (see Table 2).

For patients with intermittent asthma who need 2 or more inhalations of a bronchodilator daily for 2-4 weeks, changing to an inhaled glucocorticoid is advised.

Cromoglycate is a possible alternative in allergic asthma. If it has insufficient effect in 4-6 weeks, it can be replaced by an inhaled glucocorticoid.

If  after 3 months of treatment with a moderate dose of an inhaled glucocorticoid the complaints persist or the dose cannot be reduced, the reason should be investigated.

 

Table 2. Inhaled glucocorticoids, cromoglycate   

Indication  

Medication  

Low dose  

Moderate dose  

High dose

Lower doses apply to some metered-dose aerosols or dry powder inhalers: consult the Farmacotherapeutisch Kompas  

Maintenance treatment for mild, moderately severe, or severe asthma (Steps 2-4)  

Beclomethasone  

200 µg

twice daily  

400 µg

twice daily  

800 µg

twice daily

Budesonide  

200 µg

twice daily  

400 µg

twice daily  

800 µg

twice daily

Fluticasone  

100 µg

twice daily  

250 µg

twice daily  

500 µg

twice daily

Instead of an inhaled glucocorticoid for mild (allergic) asthma (Step 2), if necessary  

Cromoglycate  

metered-dose aerosol, 5 mg 4 times daily 1 (twice daily 2)  

 

Step 3. Moderate persistent asthma (objective not reached despite 3 months on a moderate dose of inhaled glucocorticoid)  

Before moving to Step 3, the diagnosis and management should be reviewed, which may also take the form of a consultative referral. If the objective is not reached despite correct diagnosis and adequate treatment with a moderate dose of an inhaled glucocorticoid, moderate persistent asthma is present. There are two options:

Adding a long-acting beta2 sympathomimetic agent to a moderate dose of inhaled glucocorticoid results in slightly more symptom-free days and nights than does a high dose of inhaled glucocorticoid.

 

Table 3. Long-acting beta2 sympathomimetic agents   

Indication  

Medication  

Dose (maximum)

Lower doses apply to some metered-dose aerosols or dry powder inhalers: consult the Farmacotherapeutisch Kompas

Maintenance treatment to supplement an inhaled glucocorticoid for moderately severe asthma (Steps 3 and 4)  

Salmeterol  

50 µg twice daily 1 (twice daily 2)

Formoterol  

6-12 µg twice daily 1 (twice daily 2)

 

Step 4. Severe persistent asthma (objective not reached despite Step 3 medication)  

If the objective is not reached using one of the two medicinal options in Step 3, then severe persistent asthma is present. This is an indication for collaboration with a pulmonologist. For patients with severe persistent asthma there are several options:

 

Follow-up 

 

Consultation or referral  

 

Guidelines for acute severe dyspnoea  

An exacerbation is defined as a period of increased dyspnoea, sometimes with coughing or mucus production. In most cases it involves mild or moderately severe exacerbations without dyspnoea at rest or respiratory failure.23 Non-severe exacerbations can usually be treated by starting a short-acting beta2 sympathomimetic agent or increasing the dose. In a few patients, an exacerbation can lead to increased dyspnoea at rest or even to respiratory failure within a short time. The treatment of an exacerbation and the frequency of follow-ups for it are determined by the severity of the current clinical picture and the effectiveness of therapy prescribed for previous exacerbations.

The general practitioner:

Criteria for acute severe dyspnoea are:

Treat acute severe dyspnoea as follows: (see Table 4)

For a severe exacerbation the patient should be referred if:

These are alarm signs for which emergency hospital admission is indicated. 

 

Table 4. Drug therapy of acute severe dyspnoea   

Medication  

Dosage and administration   

Comments

beta2 sympathomimetic agent, such as salbutamol  

metered-dose aerosol with spacer; 4-10 puffs of 200 µg (1 puff at a time in spacer)  

Repeat inhalations after several minutes and if improvement is not adequate, give additional ipratropium bromide (2-4 puffs, one puff at a time).

if necessary by SC injection (1 ml of 0.5 mg/ml) or nebulizer (0.5 ml of 5 mg/ml)  

Refer if there is no improvement within half an hour.

Prednisone or prednisolone  

orally, 30 mg once daily for 7-10 days  

Stop abruptly, but to prevent relapse, an adequate maintenance dose of inhaled glucocorticoid is needed.

 

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The guidelines are based in part on other consensus texts.1-4 The guidelines are in keeping with other NHG practice guidelines on asthma and COPD.5-6

  1. Anonymous. Global strategy for asthma management and prevention. NHLBI/WHO report. National Institutes of Health. National Heart, Lung, and Blood Institute. Publication number 95-3659, 1995.
  2. National Heart, Lung, and Blood Institute. International consensus report on diagnosis and treatment of asthma. Eur Respir J 1992;5:601-41.
  3. British Thoracic Society. Guidelines for management of asthma in adults: II - acute severe asthma. BMJ 1990;301:797-800.
  4. British Thoracic Society. Guidelines for management of asthma in adults: I - chronic persistent asthma. BMJ 1990;301:651-3.
  5. Geijer RMM, Thiadens HA, Smeele IJM, et al. NHG-Standaard COPD en Astma bij Volwassenen: Diagnostiek [NHG Practice Guideline 'COPD and adult asthma: diagnosis']. Huisarts Wet 2001;44:58-68.
  6. Geijer RMM, Van Schayck CP, Van Weel C, et al. NHG-Standaard COPD: behandeling [NHG Practice Guideline 'COPD: treatment']. Huisarts Wet 2001;44:5-94.

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Fear and shame appear to be correlated with limitations in daily functioning and a risk of hospitalization.1-3

  1. Kaptein AA. Psychological correlates of length of hospitalization and rehospitalization in patients with acute, severe asthma. Soc Sci Med 1982;16:725-9.
  2. Kaptein AA, Dekker FW, Dekhuijzen PNR, et al. De 12 minuten-looptest bij patiënten met chronische uitademingsstoornis. II. Lopen in het laboratorium en lopen in het leven [The 12-minute walking test for patients with chronic respiratory disease. II. Walking in the laboratory  and walking in daily life]. Ned Tijdschr Geneeskd 1987;131:1717-21.
  3. Schrier AC, Dekker FW, Kaptein AA, et al. Quality of life in elderly patients with chronic non-specific lung disease seen in family practice. Chest 1990;98:894-9.

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Approximately three-quarters of the patients make one or more mistakes using the inhaler. Inhalation technique seems to improve with instruction.1,2

  1. Dompeling E, Van Grunsven PM, Van Schayck CP, et al. Treatment with inhaled steroids in asthma and chronic bronchitis: long term compliance and inhaler technique. Fam Pract 1992;9:161-6.
  2. Marang MKP, Huygevoort JATCM, Dekker FW. Effect van voorlichting op de kwaliteit van het inhalatorgebruik van patiënten met chronische aspecifieke respiratoire aandoeningen [Effect of instruction on the quality of inhaler use in patients with chronic non-specific respiratory disorders]. Pharm Weekbl 1990;125:458-62.

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Compliance is moderate in asthma patients.1 A study in Dutch general practice revealed that only one-fourth of asthma patients took at least half of  the prescribed daily dose of maintenance medication.2 In a more recent study, 82% of the patients were found to use inhaled glucocorticoids as prescribed and an even higher percentage used beta2 sympathomimetic agents correctly.3

  1. Cluss PA, Epstein LH. The measurement of medical compliance in the treatment of disease. In: Karoly P, (ed). Measurement strategies in health psychology. New York: John Wiley and Sons, 1985:403-32.
  2. Dieleman FE, Dekker FW, Kaptein AA. Compliance with asthma medication. Huisarts Wet 1989;32:43-7, 50.
  3. Dompeling E, Van Grunsven PM, Van Schayck CP, et al. Treatment with inhaled steroids in asthma and chronic bronchitis: long term compliance and inhaler technique. Fam Pract 1992;9:161-6.

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Opinions are divided on the efficacy of self-monitoring programmes using a peak flow meter at home.1-5 In a six-month randomized prospective study in 70 asthma patients in an asthma outpatient clinic, self-monitoring using the peak flow meter in combination with a self-management programme resulted in fewer sick days, fewer exacerbations, and better lung function values.1 A study in 569 asthma patients found that self-monitoring by means of a peak flow meter at home did not result in lower morbidity or mortality.2 In a study in 801 patients, an extensive year-long patient education programme in a subgroup with severe asthma (n = 42) led to 50% fewer hospital admissions than in a control group (n = 47).3-5 It has been recommended self-treatment advice (in writing and verbally) and a peak flow meter should be provided to adults with severe asthma, those with a variable pattern their asthma, and those who have been hospitalized for asthma.4 A review of the literature on self-management of asthma with inhaled glucocorticoids concluded that there is still insufficient evidence supporting the usefulness of self-management strategies with inhaled glucocorticoids, especially in general practice.6 In the absence of published scientific research on the follow-up policy, the recommendations for follow-ups in this guideline are based on consensus within the work group.

  1. Ignacio-Garcia JM, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-9.
  2. Drummond N, Abdalla M, Beattie JAG, et al. Effectiveness of routine self monitoring of peak flow in patients with asthma. BMJ 1994;308:564-7.
  3. Osman LM, Abdalla M, Beattie JAG, et al. Reducing hospital admission through computer supported education for asthma patients. BMJ 1994;308:568-71.
  4. Partridge MR. Asthma: guided self management. BMJ 1994;308:547-8.
  5. Lahdensuo A, Haahtela T, Herrala J, et al. Randomised comparison of guided self-management and traditional treatment of asthma over one year. BMJ 1996;312:748-52.
  6. Van Grunsven PM, Van Schayck CP, Smeele I, Van Weel C. Zelfbehandeling van astma met inhalatiecorticosteroďden; een literatuuronderzoek [Self-management of asthma with inhaled corticosteroids. A review of the literature]. Huisarts Wet 1996;39:56-60.

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In 20-30% of all cigarette smokers, pulmonary function decreases so rapidly that disability or death can occur by about the age of 60 years.1,2 Smoking cessation reduces this rapid deterioration in pulmonary function. Smoking cessation at an early stage can even result in such diminished deterioration of FEV1 that the curve (at a lower level) is again parallel to that of non-smokers.3

Nicotine replacement. A meta-analysis of the effect of nicotine replacement on smoking cessation included 53 trials, with over 18,000 subjects, in 42 trials with chewing gum, 9 with patches, 1 with nasal spray, and 1 with inhalation.4 The probability of smoking cessation over 6-12 months was 19% in the nicotine replacement groups compared with 10% in the control groups (odds ratio 1.71, 95% CI 1.56-1.87). In a study (n = 227) with a follow-up of more than 3 years, the final percentages of non-smokers were 50% lower than after 1 year. The relative difference between treatment and placebo remained constant, abstinence after 1 year being 28% with nicotine spray and 13% with placebo, and abstinence after 3 years being 15% with nicotine spray and 6% with placebo.5

In a placebo-controlled study (n = 237), use of nicotine patches for 5 months and nicotine nasal spray for 1 year was more effective than using nicotine patches alone: smoking abstinence after one year was 27% compared with 11%, and after six years it was 16% compared with 9%.6 Nicotine replacement therapy is also recommended in British guidelines for smoking cessation.7

Antidepressants.  In a placebo-controlled study (n = 893), after 12 months, smoking abstinence in the group treated with the antidepressant bupropion for 9 weeks, with or without the addition of nicotine patches, was higher than for placebo: abstinence after 12 months was 15.6% for the placebo (point prevalence), 16.4% the for nicotine patch, 30.3% for bupropion, and  35.5% for bupropion plus nicotine patch. For continuous abstinence (not smoking for an entire year) the figures were lower in each case: 5.6% for placebo, 9.8% for the nicotine patch, 18.4% for bupropion, and 22.5% for the combination. The drop-out rate was 34.8%. Since there was no intention-to-treat analysis, the absolute percentages are somewhat inflated. The study population was recruited via advertisements.8 In three other placebo-controlled studies with bupropion there was a positive abstinence percentage after 1 year (point prevalence).7 Only one of these three studies has been published fully.10 In one study abstinence after 6 months was 30% in those receiving fluoxetine and 20% in those receiving the placebo.9 There was also higher abstinence after 6 months in persons receiving nortriptyline than in those receiving a  placebo.11

Anxiolytics.  In two studies buspirone was no more effective than a placebo after 12 months, and in another study it was just as effective as a nicotine patch.9 Other studies have shown diazepam, meprobamate, and beta-blockers to be ineffective.

Conclusions:

  1. Postma DS, Sluiter HJ. Prognosis of chronic obstructive pulmonary disease: the Dutch experience. Am Rev Respir Dis 1989;140:S100-5.
  2. Postma DS, Steenhuis EJ, Sluiter HJ. Longemfyseem, een verloren zaak [Pulmonary emphysema, a lost cause]? Ned Tijdschr Geneeskd 1981;125:265-70.
  3. Anthonissen NR, Connett JE, Liay JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. JAMA 1994;272:1497-505.
  4. Silagy C, Mant D, Fowler G, Lodge M. Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. Lancet 1994;343:139-42.
  5. Stapleton JA, Sutherland G, Russell MAH. How much does relapse after one year erode effectiveness or smoking cessation treatments? Long term follow-up of randomised trial of nicotine nasal spray. BMJ 1998;316:830-1.
  6. Blondal T, Gudmundsson LJ, Olafsdottir I, Gustavsson, Westin A. Nicotine nasal spray with nicotine patch for smoking cessation: a randomization trial with six year follow-up. BMJ 1999;318:285-9.
  7. Raw M, McNeill A, West R. Smoking cessation guidelines for health professionals. A guide to effective smoking cessation intervention for the health care system. Thorax 1998;53(Suppl5):S1-9.
  8. Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685-91.
  9. Hughes JR, Stead LF., Lancaster T. Anxiolytics and antidepressants for smoking cessation. (Cochrane review). In: The Cochrane Library, issue 3, 1999. Oxford: Update Software.
  10. Hurt RD, Glover ED, Sachs DPL, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195-202.
  11. Hall SM, Reus VI, Munoz RF, et al. Nortryptiline and cognitive-behavioral therapy in the treatment of cigarette smoking. Arch Gen Psychiatric 1998;55:683-90.
  12. NHG-DKB. Stoppen met roken - cahier [Smoking cessation - workbook]. Utrecht; Nederlands Huisartsen Genootschap [Dutch College of General Practitioners], 1995.

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Van Essen GA, Sorgdrager YCG, Salemink GW, Govaert ThME, Van den Hoogen JPH, Van der Laan JR. NHG-Standaard Influenza en influenzavaccinatie. [NHG Practice Guideline 'Influenza and influenza vaccination']. In: Thomas S, Geijer RMM, Van der Laan JR, Wiersma Tj (eds). NHG-standaarden voor de huisarts II [NHG Practice Guidelines for the General Practitioner II]. Utrecht: Nederlands Huisartsen Genootschap [Dutch College of General Practitioners], 1996.

 

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Large numbers of house dust mites are found mainly in the bedroom, particularly on carpeted floors and upholstered furniture, in open cupboards, and in mattress and pillows.1-3 Many mites are also found on the scalp.4 A meta-analysis of placebo-controlled studies of the use of chemical measures (acaricides) and physical measures (vacuum cleaning, air filters, allergen-proof covers, etc.) included 23 rather small studies with an average follow-up of 19 weeks. Thirteen involved physical measures and four involved a combination of chemical and physical measures. Five studies measured the effect of allergen-proof mattress and pillow covers, usually in combination with other measures. Outcome indicators were symptoms, subjective well-being, and pulmonary function measurements.5 Reduction of house dust mites occurred in six studies, not in 12, and was not specified in five. The method of randomization was not usually described. The difference between the treatment and placebo groups in the number of patients that improved was not significant (38/117 vs. 41/113, odds ratio 1.20, 95% CI 0.66-2.18). One possible explanation is that the measures taken did not result in adequate reduction of house dust mites (the areas of the head covered with hair may play a role, for this is a forgotten reservoir). In addition, patients with asthma are often susceptible to multiple irritants and allergens.4-6 The results of this meta-analysis conflict with a review article (which also included uncontrolled trials, however) that concluded that there is a small beneficial effect, while at the same time stating that there is an urgent need for adequately controlled trials with sufficient power and covering a longer period (12 months).7 In various responses to this meta-analysis it has been suggested that the negative results could be explained by insufficient reduction of allergens and the absence of a distinction between different populations. It was suggested that allergen reduction can be especially effective as an early intervention for individuals with the initial symptoms of asthma; the author of the meta-analysis responded that this hypothesis requires further study.8

In a controlled study in the Netherlands in157 patients with mild asthma (inhaled glucocorticoid not needed), the use of allergen-proof covers and spraying with acaricides in bedrooms and the living room was compared with the use of cotton covers and a placebo spray for 20 weeks. The concentration of house dust mites on the mattress decreased to just under 10% of the initial value. The use of acaricides did not significantly change the concentration of house dust mites on the floors, compared with use of a placebo. No effect on clinical parameters was found, possibly because follow-up was too short.9 In another 12-month partly-double-blind, placebo-controlled Dutch study in 59 adults with asthma and house dust mite allergy, using allergen-proof mattress and pillow covers appeared to cause a greater reduction in house dust mite allergens in mattress dust than did treating the mattress with acaricides.10 The hyperresponsiveness (PC20 histamine) in the 'cover' group decreased significantly after 6 and 12 months, but the change was minimal. It was not compared with placebo covers, the randomization method was not described, assignment of the covers was not at random, and there was no clinical outcome indicator. In a 6-month, double-blind trial involving 45 asthmatic adults with house dust mite allergy (50% also allergic to a pet and pollen), in three groups, the effect of air filters was compared with use of mattress and pillow covers in combination with either placebo air filters or active air filters.11 The reduction in house dust mite allergens in mattress dust was substantial in the 'cover' groups. In the active air filter group there was no reduction in house dust mites on the mattress. The three groups did not differ in the reduction of house dust mites on the bedroom or living room floors, perhaps because the placebo air filter apparently also collected dust, and the relatively heavy particles with dust mite allergen did not float in the air long enough after air turbulence. The hyperresponsiveness decreased markedly in the group using covers combined with active filters, and not in the other two groups. There was no clinical effectiveness indicator.

An update of a report made for the Volksgezondheid Toekomst Verkenningen [Public Health Investigations for the Future]12 drew the following conclusions based on four reviews:5,7,13,14

Conclusion: The studies and reviews discussed have many methodological limitations. The quality of research was complicated by the fact that multiple allergens and non-allergic irritants were often significant factors. There were often combinations of interventions (physical and chemical measures) in various locations (bedclothes, furniture, floor coverings, bedrooms, and/or living rooms, etc.). The effect of allergen-proof covers on the reduction of house dust mites on the mattress has been well demonstrated, but such covers do not reduce house dust mites in other places, such as the bedroom floor. The effects of covers on clinical parameters (complaints, etc.) are much less clear. The efficacy of other measures (air filters, acaricides) on the reduction of house dust mites and clinical parameters has not been clearly demonstrated and there are objections to these measures (noise pollution from filters, resistance to the use of chemical agents). Based on these considerations, the cleaning recommendations made in the previous version of the practice guideline are being continued.

  1. Arlian LG, Bernstein IL, Gallagher JS. The prevalence of house dust mites, Dermatophagoides spp., and associated environmental condition in homes in Ohio. J Allergy Clin Immunol 1982;69:527-32.
  2. Van Bronswijk JEMH. Dermatophagoides pteronyssinus in mattress and floor dust in a temperate climate (Acari: Pyroglyphidae). J Med Entomol 1973;10:63-70.
  3. Carswell F, Robinson DW, Oliver J, et al. House dust mites in Bristol. Clin Allergy 1982;12:533-45.
  4. Naspitz CK, Diniz C, Rizzo MC, Fernandez-Caldas E, Solé D. Human scalps as a reservoir of domestic mites. Lancet 1997;349:404.
  5. Götzsche PC, Hammarquist C, Burr M. House dust mite control measures in the management of asthma: meta-analysis. BMJ 1998;317:1105-10.
  6. De Veth HC. Review: measures to control house dust mites are not effective in patients with asthma who are sensitive to mites. Evidence Based Medicine 1999;4:80.
  7. Custovic A, Sinpson A, Chapman MD, Woodcock A. Allergen avoidance in the treatment of asthma and atopic disorders. Thorax 1998;53:63-72.
  8. Control of house dust mite in managing asthma [letters]. BMJ 1999;318:870-2.
  9. Cloosterman SGM, Schermer TRJ, Dijl-Hofland ID, et al. Effects of house-dust mite avoidance on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids. Clin Expermental Allergy 1999;29:1336-46.
  10. Van der Heide S , Kauffman HF, Dubois AEJ, De Monchy JGR. Allergen avoidance measures in houses of house dust mite allergic asthmatic patients: effects of acaricides and mattress encasings. Allergy 1997;52:921-7.
  11. Van der Heide S, Kauffman HF, Dubois AEJ, De Monchy JGR. Allergen reduction measures in houses of allergic asthmatic patients. Effects of air cleaners and allergen impermeable mattress encasings. Eur Resp J 1997;10:1217-23.
  12. Laurant MGH, Jacobs JE, Schermer TRJ, et al. Effecten van interventies bij COPD en astma [Effects of interventions on COPD and asthma]. Nijmegen: WOK, 2000.
  13. Van Lynden-van Nes AMT. Factors influencing effectiveness of mite allergen avoidance. In: Effective mite allergen avoidance in households with asthmatic children. Clinical, technical and behavioral aspects [thesis]. Eindhoven: University press facilities, 1999.
  14. Marks GB. House dust mite exposure as a risk factor for asthma: benefits of avoidance. Allergy 1998;53 (suppl 48):108014.

note 9     terug naar tekst  

Inhalation therapy can be administered with a dry powder inhaler or a metered-dose aerosol.1 With a dry powder inhaler, deposition in the lung depends primarily on the inspiratory force; lower force results in lower delivery and larger particle size, hence less deposition in the lung. With a metered-dose aerosol, deposition depends primarily on hand-lung coordination and the inspiratory force has no effect on either dosage delivery or average particle size. If deliberate inhalation is not feasible, a metered-dose aerosol with a spacer is preferred. If deliberate inhalation is feasible, the patient's inspiratory force and coordination determine the choice between a metered-dose aerosol (whether or not 'breath-actuated' or with a spacer) and a dry powder inhaler.

A rare side effect of metered-dose aerosols is bronchoconstriction. Bronchoconstriction occurred after inhalation of a metered-dose aerosol in 1.5 percent of 11,000 patients, probably caused by one of the excipients.2 The recommendations for the use of a spacer are taken from an editorial.3 There are differences of opinion about the best way to inhale.4 The great variety of inhalers makes it difficult to choose the one most suited to the individual patient. Despite the known disadvantages, a metered-dose aerosol (whether or not 'breath-actuated' or with a spacer) remains a simpler and less expensive method of administration for many patients.5

  1. Dekhuijzen PNR. Inhalatiemedicatie bij volwassenen met obstructieve longaandoeningen: poeder of aërosol [Inhaled medication for adults with obstructive lung diseases: powder or aerosol]? Ned Tijdschr Geneeskd 1998;142:1369-74.
  2. Shaheen MZ, Ayres JG, Benincasa C. Incidence of acute decreases in peak expiratory flow following the use of metered-dose inhalers in asthmatic patients. Eur Respir J 1994;7:2160-4.
  3. O'Callaghan C, Barry P. Spacer devices in the treatment of asthma. Amount of drug delivery to the patient can vary greatly. BMJ 1997;314:1061-2.
  4. Jackson C, Lipworth B. Optimizing inhaled drug delivery in patient with asthma. Br J Gen Practice 1995;45:683-7.
  5. Anonymous. Inhaler devices for asthma. Drug Therapeutic Bull 2000;38:9-14.

note 10     terug naar tekst  

An association between the use of beta2 sympathomimetic agents and increased mortality and morbidity from asthma, as reported in other countries, has not been observed in the Netherlands.1-3 Yet there are indications, also in Dutch studies, that pulmonary function deteriorates with continuous use of these agents, particularly if used as monotherapy.4,5 Other studies put this into perspective, however. In a randomized, cross-over study in 341 patients with moderately severe asthma treated with 200 µg salbutamol 4 times daily for 2 weeks or salbutamol on an as-needed basis for 2 weeks, peak flow values did not differ but regular administration of salbutamol was associated with fewer daytime and nocturnal complaints.6 Eighty-three patients with mild symptoms (27 with asthma and 56 with chronic bronchitis) were studied for 4 years, half being treated continuously at random with bronchodilators and the other half on an as-needed basis.7 No difference was found in peak flow variation or in the yearly deterioration of pulmonary function. In a placebo-controlled study in 983 asthma patients, 90% of whom were using inhaled glucocorticoids, the use of salbutamol 4 times daily for 12 months did not lead to more numerous exacerbations.8

Conclusion: Beta2 sympathomimetic agents are generally recommended as occasional symptomatic treatment for acute relief. If the patient continues to require the medication several times per day, treatment with an inhaled glucocorticoid is advised.9-11 The practice guideline follows these recommendations. The distinction between mild, moderate, and severe asthma is arbitrary.12 The recommendation of this practice guideline that treatment be changed to an inhaled glucocorticoid when beta2 sympathomimetic agents are required daily for 2-4 weeks is based on consensus in the work group. The use of an inhaled glucocorticoid is also advised for a new patient in whom symptoms have been present daily for a long time.

  1. Nelson HS, Szefler SJ, Martin RJ. Regular inhaled beta-adrenergic agonists in the treatment of bronchial asthma: beneficial or detrimental? Am Rev Respir Dis 1991;144:249-50.
  2. Lammers J-WJ. b-agonisten en astmasterfte in Nederland. [b-agonists and asthma mortality in the Netherlands]. Geneesmiddelen Bull 1991;25:50-2.
  3. Wever AMJ, Wever-Hess J. b-adrenerge agonisten en sterfte en morbiditeit wegens astma [Beta-adrenergic agonists and death and morbidity from asthma]. Ned Tijdschr Geneeskd 1992;136:460-5.
  4. Van Schayck CP, Dompeling E, Van Herwaarden CLA, et al. Bronchodilator treatment in moderate asthma or chronic bronchial: continuous or on demand? BMJ 1991;303:1426-31.
  5. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391-6.
  6. Chapman KR, Kesten S, Szalal JP. Regular vs as-needed inhaled salbutamol in asthma controls. Lancet 1994;343:1379-82.
  7. Van Schayck CP, Dompeling E, Van Herwaarden CLA, et al. Continuous and on demand use of bronchodilators in patients with non-steroid dependent asthma and chronic bronchitis, a four-year follow-up randomized controlled study. Br J Gen Practice 1995;45:239-44.
  8. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma controls: the TRUST randomization trial. Lancet 2000;355:1675-9.
  9. Anonymous. Global strategy for asthma management and prevention. NHLBI/WHO report. National Institutes of Health. National Heart, Lung, and Blood Institute. Publication number 95-3659, 1995.
  10. National Heart, Lung, and Blood Institute. International consensus report on diagnosis and treatment of asthma. Eur Respir J 1992;5:601-41.
  11. British Thoracic Society. Guidelines for management of asthma in adults: I - chronic persistent asthma. BMJ 1990;301:651-3.
  12. Barnes N. Treatment of mild asthma. Eur Respir Rev 1996;6:61-6.

 

note 11     terug naar tekst  

In a 12-week, placebo-controlled study in 110 patients with exercise-induced asthma, montelukast (10 mg once daily) was more effective than a placebo.1 No drug tolerance was observed. No controlled trials comparing montelukast and short-acting beta2 sympathomimetic agents have  been reported. Two puffs of a short-acting beta2 sympathomimetic agent 10-15 minutes before exercising provided over 2 hours of protection against exercise-induced asthma, and two puffs of salmeterol 10-15 minutes before exercising provided 10-12 hours of protection.2 With long-term use of salmeterol the duration of the protective effect decreases, however.3 Cromoglycate and nedocromil are effective for exercise-induced asthma, but beta2 sympathomimetic agents are more effective and are therefore preferred.2

  1. Leff JA, Busse WW, Pearlmann D, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339:147-52.
  2. McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;331:1362-7.
  3. Nelson JA, Strauss L, Skowronski M, Ciufo R, Novak R, McFadden ER. Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998;339:141-6.

note 12     terug naar tekst  

Regular use of beta2 sympathomimetic agents has been observed to increase bronchial sensitivity to irritants; apart from that, the bronchodilatory effect is sustained.1 In this regard, there seems to be a clear difference between beta2 sympathomimetic agents and ipratropium bromide.

In 13 stable patients with allergic asthma, the protective effect against bronchoconstriction decreased when the patient was exposed to allergens during 2 weeks of regular use of salbutamol (200 µg 4 times daily).2 The results of other studies are not all consistent with regard to the diminished protective effect of beta2 sympathomimetic agents. There is little evidence of acquired tolerance to the direct bronchodilating effect of beta2 sympathomimetic agents.

These observations support the policy of not prescribing long-term daily monotherapy with beta2 sympathomimetic agents.

  1. Britton J. Tolerance to beta-agonists in asthma. Lancet 1993;342:818-9.
  2. Cockroft DW, McParland CP, British, SA, Swyston VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergens. Lancet 1993;342:833-7.

note 13     terug naar tekst  

Long-acting versus short-acting beta2 sympathomimetic agents. Long-acting and short-acting beta2 sympathomimetic agents were compared in several studies. In a 14-week, double-blind, controlled study on quality of life in 140 adult asthma patients, salmeterol was more effective than either a placebo or salbutamol.1 In another double-blind, randomized trial in 99 patients (age 44, FEV1 66% of the predicted value) for 12 weeks, formoterol (12 µg twice daily) was compared with salbutamol (200 µg 4 times daily). In patients on formoterol there was less additional use of short-acting beta2 sympathomimetic agents and there was a higher morning peak flow. No significant differences were found in the other outcome indicators (FEV1, evening PEF, general opinions of patient and investigator, nocturnal sleep).2 In a third double-blind, randomized general practice study in 25,180 asthma patients, salmeterol (50 µg twice daily) was compared with salbutamol (200 µg 4 times daily). The most important outcome indicators were all of the severe complications and the drop-out rate. There was a lower drop-out rate for medical reasons in patients using salmeterol (2.9 vs. 3.8%, p = 0.0002). There was a slightly (but not significant) higher mortality in patients using salmeterol. Asthma was controlled better with salmeterol.3

Doubling the dose of inhaled glucocorticoid versus adding a long-acting beta2 sympathomimetic agent to a moderate dose of inhaled glucocorticoid. A meta-analysis discussed the results of nine double-blind, randomized studies in which doubling the dose of inhaled glucocorticoid was compared with adding salmeterol to a moderate dose of inhaled glucocorticoid.4 The total population consisted of 3,685 patients who had symptoms despite use of inhaled glucocorticoids and in whom there was a more than 10-15%  increase in the peak flow or FEV1 after inhalation of a short-acting beta2 sympathomimetic agent. In the salmeterol group there were about 2% fewer patients with an exacerbation, both the morning peak flow and FEV1 were somewhat higher after 3 months (22 l/min and 100 ml, respectively), and there was a small difference in the number of symptom-free nights (-5%) and days (-12%).

Adding formoterol to treatment with inhaled glucocorticoids has been studied less thoroughly. A study in 852 patients divided into four groups compared the effect on the number of exacerbations of adding formoterol or a placebo to a low dose (100 µg twice daily) and a high dose (400 µg twice daily) of budesonide.5 The greatest reduction in severe exacerbations occurred in the group receiving formoterol plus high doses of budesonide. High doses of budesonide reduced the number of severe exacerbations more than did adding formoterol to a low dose. For other effectiveness indicators, low-dose budesonide plus formoterol was somewhat better than high-dose budesonide plus the placebo. In another study, formoterol added to inhaled glucocorticoids in 125 patients with mild to moderately severe asthma apparently produced subjective and objective improvement compared with a placebo.6 However, this was not compared with doubling the dose of inhaled glucocorticoid.

One of  the possible drawbacks of maintenance treatment on long-acting beta2 sympathomimetic agents is reduced sensitivity to short-acting beta2 sympathomimetic agents. This was studied in 17 asthma patients (FEV1 64% of the predicted value, age 34) for 8 weeks in a placebo-controlled, crossover study.7 A 2.5 to 4 times higher dose of salbutamol was needed in the salmeterol group to obtain the same bronchodilatory response as in the placebo group.2 A review of the literature on possible disadvantages of long-acting beta2 sympathomimetic agents found no signs of poorer control of asthma, accelerated deterioration of pulmonary function, or elevated bronchial hyperreactivity. There is no evidence of a link between long-acting beta2 sympathomimetic agents and higher mortality from asthma.8 In a 6-month, crossover study in 87 patients with mild or moderately severe asthma, the use of inhaled glucocorticoids was 17% lower in the group treated with salmeterol, yet pulmonary function improved.9

Conclusion: Long-acting beta2 sympathomimetic agents have practical advantages (particularly for nocturnal symptoms) over short-acting beta2 sympathomimetic agents and are given in addition to inhaled glucocorticoids. In patients who continue to have symptoms on a moderate dose of inhaled glucocorticoid, adding a long-acting beta2 sympathomimetic agent is slightly more effective than doubling the dose of inhaled glucocorticoid. How the use of long-acting beta2 sympathomimetic agents affects the action and dose of short-acting beta2 sympathomimetic agents is not yet clear.

  1. Juniper EF, Johnston PR, Borkhoff CM, Guyatt GH, Boulet L-P, Haukioja. Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med 1995;151:66-70.
  2. Stalenheim G, Wegener T, Grettve L, et al. Efficacy and tolerance of a 12-week treatment with inhaled formoterol in patients with reversible obstructive lung disease. Respiration 1994;61:305-9.
  3. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034-7.
  4. Shrewsbury S, Pyke S, Britton. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320:1368-73.
  5. Pauwels RA, Löfdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-11.
  6. Van de Molen T, Postma DS, Turner MO, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. Thorax 1997;52:535-9.
  7. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995;346:201-6.
  8. Devoy MA, Fuller RW, Palmer JB. Are there any detrimental effects of the use of inhaled long-acting beta 2-agonists in the treatment of asthma? [Review] Chest 1995;107:1116-24.
  9. Wilding P, Clark M, Thompson Coon J, et al. Effect of long term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997;314:1441-6.

note 14     terug naar tekst  

Patients over the age of 60 who have characteristics of COPD respond better to ipratropium bromide.1-3

  1. Ullah MI, Newman GB, Saunders KB. Influence of age on response to ipratropium bromide and salbutamol in asthma. Thorax 1981;36:523-9.
  2. Van Schayck CP, Folgering H, Harbers H, et al. Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis. Thorax 1991;46:355-9.
  3. Rennard SI, Serby CW, Chafouri M, Johnson PA, Friedman M. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. Chest 1996;110:62-70.

note 15     terug naar tekst  

Xanthine derivatives produce bronchodilation through a mechanism that is not yet entirely understood. Due to individual variation in absorption and clearance, there is no fixed relation between the dose and serum concentration. Furthermore, the therapeutic and toxic doses are very close (narrow therapeutic spectrum) and side effects are fairly frequent. 1

In recent years, there has been a minor reassessment of theophylline. In a 3-month, placebo-controlled study in 62 patients, adding theophylline (250-375 mg twice daily) to a moderate dose of budesonide (400 µg twice daily) proved to be more effective (on pulmonary function and beta2 sympathomimetic use) than doubling the dose of inhaled glucocorticoid. Both treatments were well tolerated.2

  1. Lam A. Newhouse MT. Management of asthma and chronic airflow limitation. Are methylxantines obsolete? Chest 1990;98:44-52.
  2. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997;337:1412-8.

note 16     terug naar tekst  

Two review articles on the efficacy and safety of inhaled glucocorticoids for asthma concluded that their effect has been convincingly proved for bronchial hyperreactivity, pulmonary function, and symptoms, both in adults and in children. Side effects rarely occur at the usual doses (up to 400 µg in children and up to 800 µg in adults).1,2 There is, however, a highly individual sensitivity to suppression of endogenous cortisol production. Regular use of low-dose inhaled glucocorticoids for asthma is associated with a lower risk of death from asthma (in an epidemiological study in over 30,000 individuals, 77 of the 562 deaths were due to asthma).3

The frequency of administration is usually twice daily, but four times daily may be preferable in severe asthma and once daily may be sufficient in mild asthma. A single dose of 1,000 µg beclomethasone in the late afternoon or evening appeared to be just as effective as twice-daily administration of 500 µg.4

Various studies of the efficacy of monotherapy with bronchodilators compared with inhaled glucocorticoids in heterogeneous patient populations have confirmed the beneficial effect of inhaled glucocorticoids.5-8 Two of these studies (Haahtela et al.) were in patients with mild asthma (FEV1 84-88% of the predicted value) and they make a case for using an inhaled glucocorticoid as Step 1 for mild asthma.5,6 However, it is debatable whether the risks of long-term treatment with inhaled glucocorticoids offset the risk of more rapid deterioration of pulmonary function if mild asthma is treated with beta2 sympathomimetic agents alone. Since this has not been adequately proved, there is at present no reason to change the usual therapeutic regimen.9

A review concluded that the maximum effect of inhaled glucocorticoid (budesonide, beclomethasone) is reached at a dose of 1,600 µg per day.10 There is no convincing difference between budesonide and beclomethasone. In most cases a dose of 1,000 µg or less is sufficient if the patient inhales adequately. At doses of 1,600 µg or higher, the risk of local and systemic side effects increases. Adrenocortical suppression is unlikely at lower doses, although individual sensitivity varies widely. At doses above 800 µg, use of a large spacer is recommended because it reduces the risk of local side effects and improves deposition in the lung. An alternative is to divide the doses more widely over the day (e.g., 400 µg 4 times daily). In a cross-sectional study in 196 patients with mild asthma (FEV1 mean 93% of the predicted value), ages 20-40, who had been using inhaled glucocorticoids for an average of 6 years, a higher cumulative dose proved to be negatively correlated with bone density. Whether this ultimately results in an elevated risk of osteoporotic fractures at over 60 years of age is not known.11

In four studies in adults and two in children, fluticasone proved to be twice as potent as budesonide dipropionate per unit body weight. Fluticasone has no clear advantages over budesonide or beclomethasone, in either effectiveness or side effects.12,13 The risk of adrenocortical suppression increases at higher doses. This risk is most pronounced with fluticasone doses above 800 µg daily, and at therapeutically-equivalent doses it is definitely no less than with budesonide or beclomethasone.13,14 Little is known about systemic side effects (osteoporosis, subcapsular cataract, 'bruising') of fluticasone.13

Not enough is known about the necessary duration of treatment with inhaled glucocorticoids. In view of the underlying pathophysiological mechanisms and the chronic nature of the disorder, treatment for at least 3 months appears to be indicated. The rule of thumb to 'start high and decrease slowly' seems to have no foundation for adults.15,16

  1. Dekhuijzen PNR, Bootsma GP, Herwaarden CLA. Klinische effectiviteit en bijwerkingen van inhalatiecorticosteroďden bij astma [Clinical efficacy and side effects of inhaled corticosteroids for asthma]. Ned Tijdschr Geneeskd 1994;138:1408-13.
  2. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995;332:868-75.
  3. Suissa S, Severity P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332-6.
  4. Cagnon M, Cote J, Milot J, Turcotte H, Boulet LP. Comparative safety and efficacy of single or twice daily administration of inhaled beclometasone in moderate asthma. Chest 1994;105:1732-7.
  5. Haahtela T, Jĺrvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-5.
  6. Haahtela T, Jĺrvinen M, Kava T, et al. Comparison of a b2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92.
  7. Kerstjens HA, Brand PL, De Jong PM, Koeter GH, Postma DS. Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. Thorax 1994;49:1109-15.
  8. Dompeling E, Van Schayck CP, Van Herwaarden CLA, Molema J, Folgering H, Van Weel. Remming van een ongunstig beloop van astma en chronische bronchitis door toevoeging van inhalatiecorticosteroďden aan monotherapie met bronchusverwijders [Inhibiting poor clinical course of asthma and chronic bronchitis by adding inhaled corticosteroids to monotherapy with bronchodilators]. Ned Tijdschr Geneeskd 1993;137:1722-7.
  9. Drazen JM, Israel E. Treating mild asthma - when are inhaled steroids indicated? N Engl J Med 1994;331:737-9.
  10. Lipworth BJ. Clinical pharmacology of corticosteroids in bronchial asthma. [Review] Pharmacol Ther 1993;58:173-209.
  11. Wong CA, Walsh LJ, Smith CJP, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet 2000;355:1399-403.
  12. Centrale Medisch Farmaceutische Commissie van de Ziekenfondsraad. Farmacotherapeutisch Kompas [Central Medical-Pharmaceutical Committee of the Medical Insurance Board. Pharmacotherapeutic Compass]. Amstelveen: Ziekenfondsraad, 2000/2001.
  13. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy. A systematic review and meta-analysis. Arch Intern Med 1999;159:941-55.
  14. Brus R. Effects of high-dose inhaled corticosteroids on plasma cortisol concentrations in healthy adults. Arch Intern Med 1999;159:1903-8.
  15. Gershman NH, Wong HH, Liu JT, Fahy JV. Low-dose and high-dose fluticasone propionate in asthma; effects during treatment and after treatment stopped. Eur Resp J 2000;15:11-8.
  16. Van der Molen T, Kerstjens HAM. Starting inhaled corticosteroids in asthma: when, how high and how long. Eur Resp J 2000;15:3-4.

note 17    terug naar tekst  

Cromoglycate prevents both early and late allergic reactions.1 Two puffs 10-15 minutes before exercising is effective against exercise-induced asthma for slightly less than 2 hours; beta2 sympathomimetic agents are more effective for exercise-induced asthma.2 There are no side effects.1

  1. Anonymous. Global strategy for asthma management and prevention. NHLBI/WHO report. National Institutes of Health. National Heart, Lung, and Blood Institute. Publication number 95-3659, 1995.
  2. McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;331:1362-7.

note 18     terug naar tekst  

One review article discussed placebo-controlled, double-blind studies and the role nedocromil plays in the treatment of asthma.1 In patients treated with bronchodilators alone (n = 3,000), adding nedocromil had a beneficial effect compared with a placebo. In over 770 patients who were not satisfactorily stable on inhaled glucocorticoids, adding nedocromil (16 mg daily) produced improvement, but not in all parameters. Its effectiveness was greater in patients who used only bronchodilators than in those who used inhaled glucocorticoids as well. Three studies have compared nedocromil directly with inhaled glucocorticoids. In one study2 beclomethasone was more effective and in the second3 there was no difference between nedocromil and inhaled glucocorticoids. In a third study during 4-6 years in 1,041 asthmatic children, budesonide was more effective than nedocromil in decreasing hyperresponsiveness and controlling asthma.4

The question is whether there is an indication for nedocromil in addition to inhaled glucocorticoids and cromoglycate. The most significant objection is that while there is extensive documentation of the effectiveness of inhaled glucocorticoids, there is much less for nedocromil. In addition, extensive experience with inhaled glucocorticoids and cromoglycate has been acquired in daily practice.

  1. Edwards AM, Stevens MT. The clinical efficacy of inhaled nedocromil sodium (Tilade) in the treatment of asthma. Eur Respir J 1993;6:35-41.
  2. Bel EH, Timmers MC, Dijkman JH, Stark PJ. The long-term effects of nedocromil sodium and beclomethasone dipropionate on bronchial responsiveness to methacholine in nonatopic asthmatic subjects. Am Rev Respir Dis 1990;141:21-8.
  3. Bergmann KCh, Bauer CP, Overlack A. A placebo-controlled, blind comparison of nedocromil sodium and beclomethasone dipropionate in bronchial asthma. Curr Med Res Opin 1989;11:533-42.
  4. The childhood asthma management program research group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054-63.

note 19     terug naar tekst  

Antileukotrienes. Leukotrienes are mediators of inflammation in the pathophysiology of asthma. Two categories of antileukotrienes for oral administration are licensed for use in several countries.1 In the Netherlands, as of the year 2000, montelukast is the only antileukotriene licensed for use in patients whose symptoms are not adequately controlled by inhaled glucocorticoids and as-needed short-acting beta2 sympathomimetic agents. Its use is covered by medical insurance if a pulmonologist is the primary prescriber. In several studies in patients with mild or moderate persistent asthma, montelukast—usually as monotherapy—was more effective than a placebo (clinical picture, pulmonary function). There have been no good-quality studies comparing montelukast with the current reference therapy (montelukast monotherapy versus inhaled glucocorticoid monotherapy, montelukast added to inhaled glucocorticoid versus doubling the dose of inhaled glucocorticoid or versus long-acting beta2 sympathomimetic agents).2 Zafirlukast has also been compared with placebo, primarily as monotherapy, but not with the current standard therapy.3 There was no difference in side effects among montelukast, zafirlukast, and placebo.2,3 In post-marketing surveillance, rare cases of a  possible association with Churg-Strauss syndrome have been reported.2,3 In a study in 226 asthma patients on high doses of inhaled glucocorticoids, the dose of glucocorticoid could be reduced by 47% in those given montelukast, compared with 30% in those given a placebo (p = 0.046).4

A review article concluded that for mild persistent asthma either antileukotrienes or inhaled glucocorticoids can be chosen, weighing the greater efficacy of inhaled glucocorticoids against the higher expected compliance with use of antileukotrienes (because they are administered orally).5 Since good controlled studies comparing the latter with current standard therapy are lacking, the role of antileukotrienes such as montelukast and zafirlukast in the treatment of asthma is still unclear.2,3,6,7

Monoclonal antibodies. The effect of intravenously-administered recombinant antibodies to IgE A was studied in a 20-week, placebo-controlled trial in 317 adults patients with allergic asthma who needed inhaled or oral glucocorticoids. Small differences were observed in the symptom scores and the reduction in oral steroid use. The treatment was well tolerated.8 Monoclonal anti-IgE may be an option for severe asthma that requires the use of an oral glucocorticoid .9

Antibiotics.  Another therapeutic option suggests a possible connection between Chlamydia pneumoniae and asthma.10 In an open, non-controlled study, 50 patients who had moderately severe asthma (FEV1 67.8% of the predicted value, age 48 years) with antibodies to Chlamydia pneumoniae were treated with doxycycline, azithromycin, or erythromycin for 3-6 weeks, and then followed for 6 months. Approximately half improved, of whom 7 became symptom-free. Since this was an open, non-controlled study, no further conclusions can be drawn.

Antihistamines. An oral antihistamine can be tried for the combination of allergic rhinitis and allergic asthma. The effect of 10 mg cetirizine given once daily  was observed for 6 weeks during the pollen season in 93 patients in a double-blind, placebo-controlled study.11 Cetirizine was more effective than the placebo in reducing the complaints, but pulmonary function did not change in either group.

Immunotherapy. Based on 54 randomized, controlled studies, a systematic review by the Cochrane Collaboration on immunotherapy for asthma concluded that immunotherapy is effective (reduction in symptoms, asthma medication, and BHR, but no effect on pulmonary function).12 It is not clear whether immunotherapy is better than the standard medicinal therapy, whether mono-immunotherapy is better than a cocktail, or what is the optimal duration of therapy. Observation for 45 minutes after injection is necessary, ideally in a clinical setting. There is no consensus within the organization of pulmonologists about the role of immunotherapy for asthma. If necessary, the general practitioner can consult with a pulmonologist when he has questions about a possible indication in patients.

NO synthetase inhibitors. Nitrogen monoxide (NO) can damage lung tissue and reducing the concentration of NO relaxes the smooth muscles. Specific inhibitors of NO synthetase are potential future anti-asthma medications.13

  1. Diamant Z, Sterk PJ. Nieuwe therapie van asthma bronchiale: toepassing van leukotrieenreceptorantagonisten en leukotrieensytheseremmers [New therapy for bronchial asthma: use of leukotriene receptor antagonists and leukotriene synthesis inhibitors. Ned Tijdschr Geneeskd 1998;142:72-8.
  2. Anonymous. Montelukast. Prescrire 1999;8:131-4.
  3. Anonymous. Montelukast and zafirlukast in asthma. Drug Ther Bull 1998;36:65-8.
  4. Löfdahl C-G, Reiss TF, Leff JA, et al. Randomised, placebo-controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999;319:87-90.
  5. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. Drug Therapy 1999;340:197-206.
  6. Centrale Medisch Pharmaceutische Commissie van de Ziekenfondsraad. Farmacotherapeutisch Kompas [Central Medical-Pharmaceutical Committee of the Medical Insurance Board. Pharmacotherapeutic Compass]. Amstelveen: Ziekenfondsraad, 2000/2001.
  7. Van der Molen T. Onderhoudsbehandeling van astma [Maintenance treatment for asthma]. Geneesmiddelenbull 1998;32:135-41.
  8. Milfrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341:1966-73.
  9. Barnes PJ. Anti-IgE antibody therapy for asthma. N Engl J Med 1999;341:2006-8.
  10. Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Practice 1995;41:345-51.
  11. Grant JA, Nicodemus CF, Findlay SR, et al. Cetirizine in patients with seasonal rhinitis and concomitant asthma: prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 1995;95:923-32.
  12. Abramson MJ, Puy RM, Weiner JM. Allergen specific immunotherapy for asthma. In: Cochrane Collaboration. Cochrane Library. Issue 3. Oxford: Update Software, 1998.
  13. Ten Hacken NHT, Van der Mark ThW, Nijkamp FP, Postma DS, Folkerst G. Stikstofmonoxide en astma [Nitrogen monoxide and asthma]. Ned Tijdschr Geneeskd 1999;143:1606-11.

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Pregnancies in asthmatic women are associated with an elevated risk of premature parturition, low birth weight, and pre-eclampsia.1 Possible explanations for this are hypoxia, other physiological effects of poorly-controlled asthma therapy, or side effects of the medication being used. There are indications that adequately treated asthma is associated with fewer perinatal complications. Oral glucocorticoid use is associated with pre-eclampsia and, in the first trimester, with an elevated risk of cleft palate. These risks must be weighed against the risk of hypoxia in the pregnant woman and foetus in the event of severe asthma.1,2 Treatment with beclomethasone, short-acting beta2 sympathomimetic agents, ipratropium bromide, or cromoglycate can be continued during pregnancy.1,2 Most of the data on inhaled glucocorticoids concern beclomethasone. The patient information leaflets for budesonide and fluticasone state that not enough is known about their use during pregnancy; the least amount of practical experience is with fluticasone.1 No advice against use during pregnancy is provided with salmeterol,1,2 but the Pharmacotherapeutic Compass advises against taking salmeterol or formoterol during pregnancy, due to adverse effects on the embryo in animal studies.3

Conclusion: Treatment with beclomethasone, short-acting beta2 sympathomimetic agents, ipratropium bromide, or cromoglycate can be continued during pregnancy. The potential risks of using oral glucocorticoids during pregnancy (pre-eclampsia, elevated risk of cleft palate in the first trimester) must be weighed against the risks of hypoxia in the mother and foetus due to asthma. Since recommendations on the use of salmeterol and formoterol are contradictory, their use during pregnancy is not advised at present.

  1. Schatz M. Asthma and pregnancy. Lancet 1999;353:1202-3.
  2. Cydulka RK, Emerman CL, Schreiber D, et al. Acute asthma among pregnant women presenting to the emergency department. Am J Respir Crit Care Med 1999;160:887-92.
  3. Centrale Medisch Pharmaceutische Commissie van de Ziekenfondsraad. Farmacotherapeutisch Kompas [Central Medical Committee of the Health Insurance Funds Council. Pharmacotherapeutic Compass]. Amstelveen: Ziekenfondsraad, 2000/2001.

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In a study of 570 asthma patients in general practice, a revised version of an asthma severity index (wheezing at least once weekly, absence from school or work due to asthma, nocturnal wheezing attacks) was found to be accurately correlated with the peak flow measured during the consultation.

Jones K, Cleary R, Hyland M. Predictive value of a simple asthma morbidity index in a general practice population. Br J Gen Pract 1999;49:23-6.

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Van der Schans observed good results from postural drainage combined with certain breathing and coughing techniques.1 Others have not been convinced of the benefit of postural drainage.2 3 'Pursed lip breathing'—relaxed exhalation with the lips almost closed—was thought to help prevent airway collapse during exhalation. Patients have felt subjective relief, but the objective effect has not been determined conclusively.

Ambulant or clinical pulmonary rehabilitation is a useful approach for COPD.4 Even when there are severe limitations despite optimal care for asthma or asthma with persistent obstruction, this kind of combination of interventions (medical, nursing, and physiotherapeutic) seems useful.

  1. Van der Schans CP. Physiotherapy and bronchial mucus transport [Thesis]. Groningen: University of Groningen, 1991.
  2. Gulmans VAM. Beďnvloeding van mucociliair transport [Influencing mucociliary transport]. Ned Tijdschr Fysiotherapie 1989;10:2.
  3. Kirilloff LH, Owens GR, Rogers RM, et al. Does chest physical therapy work? Chest 1985;88:436-44.
  4. Geijer RMM, Van Schayck CP, Van Weel C, et al. NHG-Standaard COPD: Behandeling [NHG Practice Guideline 'COPD: treatment']. Huisarts Wet 1997;40:429-40.

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A review article based on consensus guidelines, reviews, and empirical data on 1,400 patients with acute severe asthma in a casualty department stated that most asthma attacks are not life-threatening.1 In over 10% there was tachycardia (>120 beats/min) and in 20% the respiratory rate was 30/min or higher. Transpiration, use of accessory respiratory muscles, and major fluctuations in blood pressure are indications of severe bronchoconstriction. Cyanosis, reduced consciousness, gasping respiration, and silent chest occur in only 1% of cases. Objective indicators for emergency care are a peak flow or FEV1 of 35% of the predicted value or less.  Recommendations for drug therapy are based on empirical data.2 Frequently-administered high doses of short-acting beta2 sympathomimetic agents are the preferred treatment: 10-12 puffs administered via a large spacer every 20 minutes for 1 hour. Nebulizers have no proved benefits. To promote recovery of somewhat longer duration, prednisone or prednisolone is often prescribed, but the benefits have not been adequately demonstrated in placebo-controlled trials. The effect can only be expected after 6-12 hours, regardless of whether administration is oral or intravenous.3 The usual doses vary greatly, from 30 to 40 mg prednisone or prednisolone per day in the Netherlands and England, to 200 mg prednisolone per day in the United States. If beta2 sympathomimetic agents do not provide adequate relief, adding ipratropium bromide can provide added bronchodilation. A meta-analysis of five studies revealed that adding ipratropium bromide reduced the number of hospital admissions (NNT 18 95% CI 11-17) and in patients with severe dyspnoea (FEV <35% of the predicted value), it had a clear effect on FEV1.4 An equivalent meta-analysis reached the same conclusion.5 Following the acute phase, attention is given to preventive medication: start an inhaled glucocorticoid or double the dose.

In a double-blind, placebo-controlled study in 80 adults with asthma attacks (age 42 years, FEV1 36% of the predicted value) who were treated in the casualty department of a hospital, the use of a metered-dose aerosol with a spacer proved just as effective as a nebulizer.6 With 12 puffs of 100 µg salbutamol distributed over 3 inhalations in short succession, with an interval of 30 minutes between sessions, maximal bronchodilation was achieved in 90% of the patients in 1˝ hours. Using a nebulizer, the dose required to achieve this was six times greater.

The British Thoracic Society recommends a dose of 2.0-5.0 mg (20-50 puffs, using a metered-dose aerosol).7

In another study in 35 patients with asthma attacks (age 24, FEV1 37% of the predicted value), repeated administration of salbutamol (4 puffs of 90 µg) via a spacer was just as effective as 2.5 mg salbutamol via a nebulizer.8 The authors of a review article on the treatment of severe acute dyspnoea in asthma and COPD concluded that a spacer is an effective and practical alternative to a nebulizer.9

A double-blind, randomized study compared two doses of methylprednisolone (1 and 6 mg per kg per day) in 47 patients with a severe acute asthma attack.10 The result (improvement in FEV1) was similar in the two groups.

In a placebo-controlled, double-blind study in 44 patients with severe acute asthma attacks (age 28, PEF 22% of the predicted value, 130 l/min), who were treated with a beta2  sympathomimetic agent and glucocorticoids, there was no difference between the effect of aminophylline given intravenously and a placebo.11

A placebo-controlled, double-blind study in 35 patients admitted to hospital with an acute asthma attack revealed no rebound effect when prednisolone was tapered off after a course of 40 mg for 10 days.12  The results of another study were similar.13 There were no indications of adrenocortical insufficiency. A 10-day course is recommended because the maximum peak flow is reached on day 10. A prerequisite for not tapering off the dose of oral glucocorticoid is an adequate dose of inhaled glucocorticoid (average 900 µg budesonide daily). In patients not yet using glucocorticoids who came to a casualty department because of an asthma attack, those treated with high doses of an inhaled glucocorticoid (1,600 µg budesonide) in addition to an oral glucocorticoid had fewer exacerbations in the following 3 weeks than those who received the oral glucocorticoid and a placebo.14

Conclusion: Frequent high doses of beta2 sympathomimetic agents (20-50 puffs of salbutamol administered via a spacer during 1˝ hours) is the preferred treatment for an acute severe asthma attack. Adding ipratropium bromide provides additional bronchodilation. Adding theophyllines has no proved benefit. The effect of a glucocorticoid can only be expected after 6-12 hours, regardless of how it is administered. A high-dose course of prednisolone does not have to be tapered off, provided that the patient uses adequate inhaled glucocorticoid. Thiazinamium is not recommended, in view of the fact that safe and effective alternatives are available. Antibiotics are not indicated for exacerbations.

  1. McFadden ER, Hejal R. Asthma. Lancet 1995;345:1215-20.
  2. Anonymous. Drugs for the doctor's bag revisited. Drugs Therapeutic Bull 2000;38:65-8.
  3. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department. Therapy of acute adult asthma: an evidence based evaluation. Chest 1999;116:285-95.
  4. Rodrigo G, Rodrigo C, Burschtin O. Ipratropium bromide in acute adult severe asthma: a meta-analysis of randomized controlled trials. Scan J Rehabil Med 1999;107:363-70.
  5. Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in acute asthma exacerbation in the emergency management of acute asthma exacerbations: a meta-analysis of randomized clinical trials. Ann Emerg Med 1999;34:8-18.
  6. Colacone A, Afilalo M, Wokove N, Kreisman H. A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest 1993;104:835-41.
  7. Statement of the British Thoracic Society, Research Unit of the Royal College of Physicians of London. Guidelines for the management or asthma in adults: II. Acute severe asthma. BMJ 1990;301:797-800.
  8. Idris AH, McDermott MF, Raucci JC, Morrabel A, McGorray S, Hendeles L. Emergency department treatment of severe asthma. Metered dose inhaler plus holding chamber is equivalent in effectiveness to nebulizer. Chest 1993;103:665-72.
  9. Van Grunsven PM . Behandeling van acute, ernstige dyspnoe bij astma en COPD in de huisartspraktijk. Een literatuuronderzoek [Treatment of acute, severe dyspnoea in asthma and COPD in general practice. A review of the literature]. Huisarts Wet 1997;40;54-62.
  10. Marquette CH, Stach B, Cardot E, et al. High-dose and low-dose systemic corticosteroids are equally efficient in acute severe asthma. Eur Respir J 1995;8:22-7.
  11. Murphy DG, McDermott MF, Rydman RJ, Sloan EP, Zalenski RJ. Aminophylline in the treatment of acute asthma when beta 2-adrenergics and steroids are needed. Arch Intern Med 1993;153:1784-8.
  12. O'Driscoll BR, Kalra S, Wilson M, Pickering CAC, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in acute asthma. Lancet 1993;341:324-7.
  13. Hatton MQ, Vathenen AS, Allen MJ, Davies S, Cooke NJ. A comparison of 'abruptly stopping' with 'tailing off' oral corticosteroids in acute asthma. Resp Med 1995;89:101-4.
  14. Rowe BHM, Bota GW, Fabris L, Therrien SA, Milner RA, Jacono J. Inhaled budesonide in addition to oral corticosteroids to prevent asthma relapse following discharge from emergency department: a randomized controlled trial. JAMA 1999;281:2119-26.
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