EXACERBATIONS IN ADULTS WHEN TO REFER

Transcription

1 06 Bronchial Asthma Contributors: Dr Chong Phui Nah Dr Tang Wern Ee PRESENTATION AND DIAGNOSIS CLASSIFICATION OF ASTHMA BY LEVEL OF CONTROL ASSESSMENT OF ASTHMA CONTROL USING THE ASTHMA CONTROL TEST ASTHMA MANAGEMENT BASED ON LEVELS OF CONTROL MANAGEMENT OF ASTHMA EXACERBATIONS: - HOW SEVERE IS THE ASTHMA ATTACK? MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN CHILDREN MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN ADULTS WHEN TO REFER Advisors: Prof Lim Tow Keang A/Prof John Abisheganaden A/Prof Daniel Goh Yam Thiam A/Prof Lynette Shek 56 nhg_guideline_ _1112.indd 56

2 BRONCHIAL ASTHMA PRESENTATION AND DIAGNOSIS Features supportive of diagnosis of asthma Frequent episodes of wheeze (more than once a month) Activity induced cough or wheeze Nocturnal cough in periods without viral infections Symptoms persist after age 3 *Either of these tests can be used PEF is the least reliable as PEF is highly effort dependent Office spirometry may be used to assess bronchodilator response < 5 years old Reversible episodic wheeze and cough Nocturnal symptoms YES *Home PEF Variability (PEF diary) >20% diurnal variation YES 5 years old *Reversible airway obstruction Bronchodilator response: > 20% FEV 1 & 200ml increase in FVC or FEV 1 after bronchodilator challenge Supportive Evidence Atopic features Family history of asthma / atopy *Bronchial provocation Exercise Methacholine Histamine Exclude Alternative Diagnosis Children Recurrent viral infections with wheezing Chronic rhino-sinusitis Gastro-oesophageal reflux Bronchopulmonary dysplasia Chronic lung disease of prematurity Aspiration syndromes including foreign body aspiration/ recurrent silent aspiration Congenital malformations of lung Congenital heart disease Do CXR if other diagnosis suspected or consider other diagnostic tests in the presence of: Neonatal / early onset Failure to thrive, LOW Frequent vomiting / choking Focal lung signs, haemoptysis Vocal cord dysfunction Commence on trial of asthma therapy Review diagnosis if response is poor Adult: Ca lung, bronchiectasis COPD, emphysema Pulmonary tuberculosis Suppurative lung disease Pulmonary oedema Upper airway obstruction / inhaled foreign body Vocal cord dysfunction 57 nhg_guideline_ _1112.indd 57

3 BRONCHIAL ASTHMA Notes 1. Investigations Investigations are usually not necessary except in severe or atypical cases, and in patients who do not respond to therapy. Some investigations which may be considered are (i) Chest X-ray to exclude foreign body or chronic chest infection or to exclude complications in severe acute episodes. (ii) Pulmonary Function Tests - Peak expiratory flow rate (PEFR) / Spirometry. The demonstration of diurnal variation of PEFR 20 or bronchodilator response resulting in improvement of FEV1 (Forced expiratory volume in one second) by 12% is indicative of airway hyper-responsiveness and airflow reversibility. (iii) Skin Prick Test: This is useful for the demonstration of atopy, especially in patients with no clinical signs of eczema or family history of atopy. Skin prick tests may be useful in guiding patient advice on environmental control. Other allergy tests such as antigen specific IgG, IgG4, intradermal skin tests are not useful. Food allergy testing is also not useful for evaluation of asthma per se. (iv) Exhaled nitric oxide This provides a non-invasive assessment of airway inflammation that is not specific but useful for monitoring of disease and compliance to inhaled corticosteroids. (v) (vi) Airway Challenge Tests using exercise or with inhalation of methacholine or histamine. Exercise challenge is also useful for evaluation of exercise-induced asthma. Other tests to exclude other medical conditions Mantoux test to exclude Mycobacteria infection Otolaryngologic evaluation of the sinuses and/ or CT scan of the sinuses Gastroesophageal reflux studies, e.g. esophageal ph monitoring Bronchoscopy to exclude structural anomalies Immunological investigations, e.g. HIV, Serum Immunoglobulin titres 58 nhg_guideline_ _1112.indd 58

4 BRONCHIAL ASTHMA 2. Other Modes of Presentation Cough variant asthma without wheezing May be the group over-diagnosed as asthma. Rule out rhinitis and sinusitis Hypersecretory asthma Cough and excessive secretions. Usually young patients; more crepitations than wheezing First acute wheeze Exclude infections, foreign body aspiration Recurrent viral wheezing in 0-2 year age group without atopy may not respond to asthma treatment In cigarette smoker, consider COPD with asthma Exercise-induced bronchoconstruction 3. Asthma Management should include: Good doctor-patient relationship Identification and reduction of exposure to risk factors such as dust mites, molds, pets, pollen and cigarette smoke Assessment, treatment and monitoring of Asthma Manage asthma exacerbations Patient education including Written Asthma Action Plan 59 nhg_guideline_ _1112.indd 59

5 BRONCHIAL ASTHMA CLASSIFICATION OF ASTHMA BY THE LEVEL OF CONTROL The Global Initiative for Asthma (GINA) guidelines define the control of asthma into 3 categories: Controlled Partly Controlled and Uncontrolled Level of Asthma Control CHARACTIERISTIC CONTROLLED (All of the following) PARTLY CONTROLLED (Any Measure Present In Any Week) UNCONTROLLED Daytime symptoms None (twice or less/week) More than twice/week Limitations of activities Nocturnal symptoms / awakening Need for reliever / rescue treatment None None None (twice or less/week) Any Any More than twice/week Three or more features of partly controlled asthma present in any week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) Exacerbations None one or more/year* * Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate. By definition, an exacerbation in any week makes that an uncontrolled asthma week. Lung function is not a reliable test for children 5 years and younger One in any week High Risk Patients are patients who: Have 2 or more exacerbations per month requiring acute care Have 2 or more hospitalizations for asthma in 3 months Require the use of rescue medication 3 or more times a week Have history of severe asthma exacerbations requiring care in the High Dependency or Intensive Care Unit 60 nhg_guideline_ _1112.indd 60

6 BRONCHIAL ASTHMA ASSESSMENT OF ASTHMA CONTROL USING THE ASTHMA CONTROL TEST Asthma Control Test (ACT) This is a 5-item, patient-administered questionnaire for assessing asthma control (Figure 1). It is a simple, objective, robust and validated method for monitoring control by doctors (and patients), which is being used internationally. A management plan based on ACT assessment is provided below (Figure 3). There is also a 7-item Asthma Control Test For Children Aged 4-11 Years Old (Figure 2). Figure 1: Asthma Control Test (ACT) for adults and children aged 12 and above 2002, by QualityMetric Incorporated. Asthma Control Test is a trademark of QualityMetric Incorporated , GlaxoSmithKline Group of Companies. All Rights Reserved. Based on a five-point scoring system, a maximum score of 25 will indicate total control of asthma. Well controlled asthma is defined as a score of 20-24, and a score of less than 20 will imply poor control. 61 nhg_guideline_ _1112.indd 61

7 BRONCHIAL ASTHMA Figure 2: Asthma Control Test For Children Aged 4-11 Years Old , GlaxoSmithKline Group of Companies. All Rights Reserved. A score of 19 or less suggests poor asthma control. A score of 20 or above suggests the child s asthma may be under control. A score of 27 indicates Total control of asthma. 62 nhg_guideline_ _1112.indd 62

8 BRONCHIAL ASTHMA Management Approach Based on Control For Children Older Than 5 Years, Adolescents and Adults Level of Control Controlled Partly Controlled Uncontrolled Exacerbation Reduce Increase Treatment Action Maintain and find lowest controlling step Consider stepping up to gain control Step up until controlled Treat as exacerbation ACT score > 20 ACT score < 20 Reduce Treatment Steps Increase Step 1 Step 2 Step 3 Step 4 Step 5 Asthma Education Environmental Control Controller Options*** Select one Low-dose inhaled ICS* Leukotriene modifier ** Select one Add one or more Add one or both Medium- or high-dose ICS Low-dose ICS plus leukotriene modifier Low-dose ICS plus sustained release theophylline Leukotriene modifier Sustained release theophylline Figure 3: Management of Asthma to Achieve Control Oral glucocorticosteroid (lowest dose) Anti-IgE Treatment * ICS (inhaled glucocorticosteroids) ** Receptor antagonist or synthesis inhibitors *** Preferred controller options are shown in shaded boxes Alternative reliever treatments include inhaled anticholinergics, short-acting oral β 2 -agonists, some long-acting β 2 -agonists, and short-acting theophylline. Regular dosing with short and long-acting β 2 -agonist is not advised unless accompanied by regular use of an inhaled glucocorticosteroid. 63 nhg_guideline_ _1112.indd 63

9 BRONCHIAL ASTHMA ASTHMA MANAGEMENT BASED ON LEVELS OF CONTROL Management in Adults, Adoloscents and Children Older Than 5 Years The patient s current treatment and level of control determine the selection of pharmacologic treatment. If asthma is not controlled on the current treatment, treatment should be stepped up until control is achieved. Control is usually maintained for at least 3 months before an attempt is made to step down the treatment, with the aim to establish the lowest step and dose of treatment that maintains control. Figure 3 shows the steps 1-5 for achieving control. Each step represents treatment options in steps of increasing efficacy. In the management scheme described in Figure 3, the dose of daily asthma medication is adjusted according the ACT scores evaluated at each clinic visit. Patients who do not achieve good asthma control despite Step 4 levels of treatment have refractory asthma and should be reviewed by a specialist. Management at Step 5 should be supervised directly by specialists. Patients should also be taught how to implement a Written Asthma Action Plan for self-management of exacerbations between visits. Patients may also be advised to perform monthly self-monitoring using the ACT between clinic visits. Management in Children aged 5 and younger The available literature on treatment of asthma in children aged 5 and younger precludes detailed treatment recommendations. The best documented treatment is inhaled glucocorticosteroids. Consider referral to Paediatric specialist if the patient s response to treatment is not as good as expected or if the child remains symptomatic. Recommended inhaler devices for children <4 years MDI with spacer + a facemask 4-6 years MDI with spacer with mouthpiece >6 years MDI with spacer with mouthpiece or accuhaler >9 years MDI with spacer with mouthpiece or turbuhaler 64 nhg_guideline_ _1112.indd 64

10 BRONCHIAL ASTHMA Management in Children Aged 5-12 Estimated Equipotent Daily Doses of Inhaled Glucocorticosteroids for Children Drug Low Daily Dose (mcg) Medium Daily Dose (mcg) High Daily Dose (mcg) Beclomethasone Diproprionate > >400 Budesonide > >400 Fluticasone > >500 Add on therapy: To be considered if not achieving adequate control despite: i. good compliance; and ii. satisfactory inhaler technique; and iii. proper trigger avoidance Alternatives as add-on therapy include: i. Inhaled long acting β2-agonists (LABA) ii. Leukotriene modifier Note: LABAs should NOT be used without concomitant inhaled corticosteroids. Indications for referral to the Paediatric specialist for further evaluation and management: 1. Patients with high risk asthma with poor control 2. Patients aged less than 3 years old requiring high doses of inhaled steroids 3. Patients who remain symptomatic despite suboptimal response to therapy 4. Patients requiring high doses of inhaled steroids BDP/BUD 400 mcg/day 65 nhg_guideline_ _1112.indd 65

11 BRONCHIAL ASTHMA MANAGEMENT OF ASTHMA EXACERBATIONS: HOW SEVERE IS THE ASTHMA ATTACK? SEVERITY MILD MODERATE SEVERE RESPIRATORY/ASSEST IMMINENT SYMPTOMS Breathless While walking While talking (infantsofter, shorter cry) While at rest Can lie down Prefer sitting Hunched forward Feeding (infant) Feeds normally Difficulty feeding Stops feeding Talks in. Sentences Phrases Words Alertness May be agitated Usually agitated Usually agitated Drowsy or confused SIGNS Respiratory rate* Increased Increased Often > 30/min (in adults) Use of accessory muscles / suprasternal retractions Usually not Usually Usually Paradoxical thoraco abdominal movement Wheezes Moderate, often only end expiratory Loud Usually loud, throughout inhalation and exhalation Absence of wheeze Pulse rate* FUNCTIONAL ASSESSMENT < 100/min (adults /min (adult) > 120/min (adults) Bradycardia PEF > 80% Approx. 60% - 80% <60% predicted or personal best in servre asthma exacerbation Pulse Oximetry PaO 2 (on air) >95% 91% - 95% < 90% * The presence of several parameters, but not necessarily all, indicate the general classification of the attacks. Note also any prior usage of bronchodilator as this may alter the presenting clinical pictures. Please refer to the Guide to Normal Respiratory and Pulse Rates in Infants and Children, found on the last page of this chapter. 66 nhg_guideline_ _1112.indd 66

12 BRONCHIAL ASTHMA MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN CHILDREN Assess Severity Assessment in the very young may be difficult. Children with severe attack may not appear distressed. Bear in mind foreign body aspiration. Mild / Moderate Asthma Exacerbation Mild / mod tachypnea, no / minimum chest retractions, No / minimum use of accessory muscles, SaO % 1. Weight 10kg: Salbutamol MDI 5 puffs x 2 cycles at 15 min intervals Weight > 10kg: Salbutamol MDI 10 puffs x 2 cycles at 15 min intervals 2.For moderate exacerbation: a. Oral prednisolone 1mg/kg (max 40mg) stat b. Add Ipratropium (Atrovent ) 2 puffs 3.Keep SaO 2 > 95%, add 4L/min via nasal prongs if necessary 4.Review after 2 cycles 5.Convert to Nebulizer if child is fatigued Neb: Salbutamol : Ipratropium : Normal Saline Weight 10 kg: 0.5 mls 0.5 mls 3 mls Weight > 10 kg: 1 ml 1 ml 2 mls Reassess after 15 min 30min No improvement Severe Asthma Exacerbation Tachypneic+, chest retractions, Use of accessory muscles ++, SaO 2 <91% Life-threatening Asthma Exacerbation Respiratory: Cyanosis / Tachypnea, Exhaustion / Silent Chest / SaO 2 <91% Neurological: Confusion / drowsiness Cardiovascular: Pulsus paradoxus Deterioration in condition despite maximal therapy Neb: Salbutamol : Ipratropium : Normal Saline Weight 10 kg: 0.5 mls 0.5 mls 3 mls Weight > 10 kg: 1 ml 1 ml 2 mls 1. Repeat x 1-2 cycles as needed 2. Oral prednisolone 1mg/kg (max 40mg) stat 3. High flow O2 via mask (6-10L/min) to achieve SaO2 > 95% 4. Review after 1-2 cycles, refer to hospital A&E if no improvement / deterioration Arrange transfer to Hospital immediately Improved Discharge with appropriate advice and follow-up* Check MDI technique KIV spacer and set a TCU date Some improvement Improved Repeat salbutamol MDI via spacer or Neb Improved No improvement No improvement Refer to Hospital A&E Using a spacer with a metered-dose inhaler has been shown in clinical studies to be as effective as using a nebulizer in the delivery of a bronchodilator in the treatment of an acute asthma exacerbation. *A short course of oral steroids should be considered if the child meets one of the following criteria: 1. requires frequent β 2 agonists therapy (more frequently than 4 hourly) 2. has a past history of life-threatening asthma exacerbation 3. is on high dose inhaled steroid or low dose oral maintenance steroid therapy. For patients with moderate to severe exacerbations, a dose of prednisolone 1-2 mg/kg/day [max 40mg] can be given for 3 to 5 days without a need to taper the dose. Paediatric patients requiring prolonged or repeated courses of oral steroid to control their asthma should be referred to a specialist for further evaluation and management. 1. High flow O2 via mask (6-10L /min) to achieve SaO2 >95% 2. IV access 3. IV hydrocortisone 4mg/kg stat (max 100mg) 4. Nebulized salbutamol with ipratropium every 20 minutes while awaiting transfer to hospital Neb: Salbutamol: Ipratropium: Normal Saline: Weight 10 kg: 0.5 mls 0.5 mls 3 mls Weight > 10 kg: 1 ml 1 ml 2 mls s/c or ETT adrenaline 1: ml (0.01 ml/kg) only for those above 2 yr old 67 nhg_guideline_ _1112.indd 67

13 BRONCHIAL ASTHMA MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN ADULTS Assess Severity of Asthma Exacerbation Mild / Moderate Asthma Exacerbation Mild / mod tachypnea, No / minimum use of accessory muscles, SaO % 1. MDI bronchodilator via Spacer steps #* : 4 puffs Salbutamol + i.e. 8 puffs every 10-15minutes 4 puffs Ipratropium Patient to inhale 2-3 x via the mouth/lips after every 2 puffs.repeat 2-4 cycles as needed 2. Doctor to review after every 2 nd or 3 rd cycle 3. May stop before 4th cycle if patient is no longer symptomatic 4. To repeat cycles as needed 5. Oral prednisolone 30-60mg stat 6. To refer to hospital A&E if no improvement after 8 cycles (or earlier as clinically indicated) *Convert to nebulizer if patient is fatigued: Neb Salbutamol : Ipratropium : Normal Saline 1 ml 2mls 1 ml Refer to A&E if no improvement after 2 rounds of nebulization or equivalent Severe Asthma Exacerbation Can t complete sentences, Tachypneic Pulse > 110/min Resp Rate > 25/min PEF < 50% predicted or best SaO 2 <91% 1. High flow O2 via mask 6-10L/min to achieve SaO2 >95% 2. IV access 3. IV hydrocortisone 200mg stat 4. Neb Salbutamol : Ipratropium : Normal Saline 1 ml 2mls 1 ml 5. To repeat above nebulization if indicated 6. Review after 30minutes 7. Refer to A&E if no improvement after 2 rounds of nebulization. Life-threatening Asthma Exacerbation Respiratory: Cyanosis / Tachypnea, Exhaustion / Silent Chest / SaO 2 <91% PEF < 33% predicted or best Neurological: Confusion / drowsiness Cardiovascular: Pulsus paradoxus Deterioration in condition despite maximal therapy Arrange transfer to Hospital immediately # Clinical equivalence to single round of nebulisation (neb): 1 round of neb = 3-4 cycles of the following treatment: 4 puffs salbutamol + 4 puffs Ipratropium i.e. 8 puffs every 10-15minutes MDI + Spacer Method a. Prime the spacer with 8 to 10 puffs of Salbutamol b. Load the spacer with 2 puffs each time, patient to inhale 2 3 times (tidal breaths) after every 2 puffs (if patient can cooperate, deep breaths with breath holding recommended). c. Oxygen can be administered concurrently via nasal prongs if required maintain SAO 2 >95% for patients with asthma. d. Nurse to administer puffs, ensure inhalation via the mouth/lips e. Patient can self-administer bronchodilator treatment with supervision by medical staff 1. High flow O2 via mask 6-10L/min to achieve SaO2 >95% 2. IV access 3. IV hydrocortisone 200mg stat 4. Nebulized salbutamol with ipratropium every minutes while awaiting transfer to hospital 5. Neb Salbutamol : Ipratropium : Normal Saline 1 ml 2mls 1 ml 6. Consider s/c adrenaline 1: ml (0.01ml/kg) 68 nhg_guideline_ _1112.indd 68

14 BRONCHIAL ASTHMA MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN ADULTS (Continued) Clinical Assessment after Bronchodilator Treatment Symptoms, physical examination, O2 saturation, PEF, other tests as needed Good Response Response sustained 60 minutes after last treatment Physical examination is normal PEF >70% predicted No stress O2 saturation > 90% Incomplete Response History of high-risk patient Physical examination: Mild to moderate symptoms PEF >50% - 70% O 2 saturation not improving Poor Response History of high-risk patient Physical examination: Symptoms severe, drowsiness,confusion PEF <30% pco 2 >45 mmhg O 2 saturation <90% Action: Discharged Continue treatment with inhaled β 2 agonists Consider course of prednisolone 30mg om for 5-7 days in most cases Initiate or continue inhaled glucocorticosteroids Reinforce patient education, action plan and close follow-up Action: ARRANGE URGENT TRANSFER TO HOSPITAL via ambulance immediately High flow O 2 via mask 6-10L/min to achieve SaO 2 >95% Nebulized salbutamol with ipratropium every minutes while awaiting transfer to hospital i/v Hydrocortisone 200mg if not already administered earlier Consider s/c adrenaline 1: ml (0.01ml/kg) Possible intubation & mechanical ventilation Action: Refer to Hospital A&E O 2 via mask 6-10L/min to achieve SaO 2 >95% Nebulized salbutamol with ipratropium every minutes while awaiting transfer to hospital i/v Hydrocortisone 200mg stat if not already administered earlier 69 nhg_guideline_ _1112.indd 69

15 BRONCHIAL ASTHMA WHEN TO REFER Acute Asthma Severe or Frequent Exacerbations 1. A life-threatening asthma exacerbation. 2. Frequent exacerbations: acute exacerbations 2-3 times a year, or more than once every six months, despite compliance with medications and good inhaler (or inhaler and device) technique 3. Need for continuous oral corticosteroid therapy or Step 5 therapy Chronic Asthma Difficult or Poor Control 1. Failing goals of therapy after 3 to 6 months of treatment. 2. Uncontrolled Asthma 3. Under age 3 and requiring step 3 or 4 care. 4. Steroid use: continuous oral corticosteroid therapy, or require more than two bursts of oral corticosteroids in 1 year, or high-dose inhaled corticosteroids Risk factors for death from asthma Prior intubation and mechanical ventilation for asthma Hospitalization or emergency care visit for asthma in the past year Current use of systemic corticosteroids or recent withdrawal from systemic corticosteroids Not currently using inhaled corticosteroids Use of >1 canister of inhaled short-acting β 2 agonists within 1 month History of psychiatric disease or psychosocial problems Patients at high risk of dying with asthma require special attention, monitoring and care, particularly intensive education, including advice to seek medical care early during an exacerbation. Diagnosis 1. Atypical signs and symptoms. 2. Other conditions complicate asthma or its diagnosis, e.g. heart failure, COPD, unsure of diagnosis. 3. Additional diagnostic testing is indicated. 4. Suspicion of occupational asthma. 70 nhg_guideline_ _1112.indd 70

16 BRONCHIAL ASTHMA Abbreviations < Less than Less than or equal to > More than More than or equal to BDP Beclomethasone diproprionate BUD Budesonide Ca Carcinoma COPD Chronic obstructive pulmonary disease CXR Chest x-ray ETT Endotracheal tube FEV 1 Forced expiratory volume in 1 second i/v LOW MDI mths O2 PEF s/c TCU Yr Intravenous Loss of weight Metered dose inhaler Month(s) Oxygen Peak expiratory flow Subcutaneous To-see-you (i.e. review appointment) Year(s) Guide to Normal Respiratory and Pulse Rates in Infants and Children AGE RESP RATE (MIN) AGE PULSE RATE (MIN) < 2 months < months < months < years < years < years < years < 110 References 1. Ministry of Health, Singapore. MOH Clinical Practice Guidelines Management of Asthma, January Global Initiative for Asthma. Global strategy for asthma management and prevention, Updated Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113: Cates CC, Bara A, Crilly JA, Rowe BH. Holding chambers versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2003;(3):CD Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, FitzGerald JM. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med 1998;157(6 Pt 1): Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near- fatal asthma. Eur Respir J 1994;7(9): Ernst P, Spitzer WO, Suissa S, Cockcroft D, Habbick B, Horwitz RI, et al. Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 1992;268(24): Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near- fatal asthma. Eur Respir J 1994;7(9): Joseph KS, Blais L, Ernst P, Suissa S. Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers. BMJ 1996;312(7023): nhg_guideline_ _1112.indd 71