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In Western countries, asthma is found to be among the most typical chronic respiratory illness. It often manifests during childhood and its prevalence in children and adults is around 14% and 8% respectively. This equates to approximately 5 million of the population of United Kingdom. As a consequence, it is estimated that the yearly healthcare expenses of the UK is close to £3 billion.3
The manifestation of asthma involves inflammation of air passages, resulting in repeated episodes of breathlessness, wheezing, tightness of the chest, and coughing in individuals who are susceptible.15 These repeated episodes may differ during the day (deteriorate during beginning and end of day) and may be precipitated by cold air, exercise, allergens (pollen) or drugs (non-steroidal anti-inflammatory drugs, or beta-blockers).1 They are due to obstruction of airflow which is often reversible, either spontaneously or when treatment is used.2
Airflow obstruction is due to inflammation of air passages, consequently causing manifestation of changes of the air passages, leading to bronchoconstriction, hyperresponsiveness of the bronchioles, and airway oedema (hypersecretion of mucus which obstructs airflow).5,15
Bronchial hyperresponsiveness occurs as a result of an inflammatory process whereby inflammatory mediators are released from mass cells, eosinophils, neutrophils, monocytes and macrophages. Histamine which is liberated results in an immediate bronchial reaction whereas liberation of prostaglandin and leukotrienes (metabolites of arachidonic acid from both the cyclo-oxygenase and lipoxygenase pathway) produce a more sustained bronchoconstriction.4 These mediators interact to increase secretion of mucus which is hard to dislodge and damages the ciliated epithelium. When the protective epithelial barrier is breached, hyper-reactivity occurs resulting in bronchoconstriction, breathlessness and wheeze. Asthma is a polygenic/atopic disorder whereby those with a genetic loci for increased production of IgE have an increased incidence of asthma.4
Diagnosis of chronic asthma is made primarily by a history of recurrent episodes of breathlessness, wheezing, tightness of chest, coughing, and confirmation using a spirometry. A history of increased symptoms precipitated by stimuli also suggests asthma. Asthma is usually confirmed when spirometry demonstrates obstruction in airflow, where the ratio of FEV1 vs FVC is lower than 80%, with reversibility after administration of inhaled beta2-agonist (≥12% improvement in FEV1).2
There are three classifications of acute asthma are their diagnosis is summarized in Table 1.
Table 1: Diagnosis of acute asthma
Able to talk
Respiration < 25 breaths per min; CHILD 2-5 years ≤ 50 breaths per min; 5-12 years ≤ 30 breaths per min
Pulse < 110 beats per min; CHILD 2-5 years ≤ 130 beats per min; 5-12 years ≤ 120 beats per min
Arterial oxygen saturation ≥ 92%
Peak flow > 50-75% of predicted/best
Cannot finish sentences in one breath
Respiration ≥ 25 breaths per min; CHILD 2-5 years > 50 breaths per min; 5-12 years > 30 breaths per min
Pulse ≥ 110 beats per min; CHILD 2-5 years > 130 beats per min; 5-12 years > 120 beats per min
Arterial oxygen saturation <92%
Send immediately to hospital
Feeble respiration, cyanosis, hypotension, bradycardia, arrhythmia, confusion, reduced level of consciousness, or coma
Arterial oxygen saturation <92%
PaO2 < 8 kPa
Peak flow < 33% of predicted or best; CHILD 5-12 years < 33% of predicted/best
Send immediately to hospital; refer for intensive care
Adapted from 1
2. Drug therapy and their pharmacology
2.1 Anticholinergics and short acting beta2 agonists
Patient with acute asthma, which was severe, was commenced on treatment via nebulised A:V:N (2:1:2) which was Atrovent (ipratropium bromide), Ventolin (salbutamol) and normal saline. Patient also was commenced on MDI salbutamol 2 puffs when required for occasional relief of symptoms for chronic asthma.
Ipratropium bromide is an anticholinergic.4 Anticholinergics are effective bronchodilators but are less potent than beta2-agonists.2 Its mechanism of action is by competitively inhibiting the receptor of acetylcholine at vagal nerve endings that constrict bronchial smooth muscle,4,15 producing bronchodilation only in bronchoconstriction which is cholinergic-mediated.2 Examples of unwanted effects contributed by anticholinergics are mouth dryness, nausea, headache, and constipation.6
Salbutamol is a short-acting beta2-agonist. Short-acting beta2-agonists are the most effective bronchodilators available. Their mechanism of action is by stimulation of the beta2 adrenergic receptors, which then activates adenyl cyclase and elevates cyclic adenosine monophosphate in the cells, ultimately relaxing smooth muscles and stabilizing membrane of mast cells. The use of short-acting beta2-agonists is mainly for symptom relieve, and only when there is the necessity.2 Side effects include tremor, nervousness, headache and palpitation.6
Patient was also started on IV hydrocortisone 100 mg four times a day, which was subsequently replaced by prednisolone tablets 20 mg once daily, both of which are corticosteroids used for her acute condition. MDI beclometasone dipropionate, a corticosteroid, 2 puffs 2 times daily, had also been given to her for the long-term control of her chronic asthma. The mechanism of action of corticosteroids is by sensitizing beta2-adrenoceptors as well as elevating the sum of these receptors. As a result, there would be reduced hypersecretion of mucus, bronchial hyperresponsiveness and airway oedema.2 Side effects such as reduction in bone mineral density and adrenal suppression are more common in higher doses of inhaled corticosteroids.6,14
Patient was also started on bromhexine hydrochloride tablets 8 mg three times a day. Bromhexine hydrochloride is a mucolytic, and its mechanism of action is by reducing the viscosity of the mucus secretions, breaking down mucus, and aiding its clearance through coughing.7
3. Treatments and their evidence
3.1 Acute Asthma - Salbutamol and ipratropium bromide via nebulizer
In accordance to SIGN 101, short-acting beta2 agonist should be given through a spacer or nebulizer together with an addition of ipratropuim bromide, 500 µg also via nebulizer if patients' response is poor, in acute cases.1 Patient was given Atrovent:Ventolin:Normal Saline in the ratio of 2:1:2 in terms of volume, through the nebulizer. 1 ml of Ventolin respirator solution (5 mg/ml) consisted of 5 mg of salbutamol sulphate while 2 mls of Atrovent nebulizer solution (250 µg/ml) consisted of 500 µg of ipratropium bromide, which was in accordance to the BNF.6
A meta-analysis of 10 studies which were double-blind, randomized, controlled trials, and which consisted of a total number of 1483 patients who were having acute asthma and who were treated with short-acting beta2 agonist with/without addition of ipratropium bromide in the emergency department were studied. Results revealed significant benefit from treatment with additional ipratropium where the pooled effect size of pulmonary function was 0.14, p<0.01 and indicated a 10% increment in FEV1 or PEFR which favoured the group treated with ipratropium as compared to the control group. Pooled results from 4 trials revealed that additional treatment with ipratropium in patients who had FEV1 of less than 35% had significant improvement while pooled results from 5 trials revealed that ipratropium therapy in conjunction with short-acting beta2 agonist significantly reduced rates of hospital admission, p<0.01.11
Another meta-analysis conducted confirmed the effectiveness ipratropium therapy with short-acting beta2 agonist in acute asthma. It also compared the effectiveness of treatment with short-acting beta2 agonist with/without ipratropium in acute emergency cases of asthma. 32 RCTs were included and results indicated significant decrease in incidence of admission to hospital in children and adults, both p<0.05, and significant rise in parameters measured by spirometry after 1-2 hours in children and adults who were treated with combined therapy.16
3.2 Acute Asthma - Oral prednisolone or intravenous hydrocortisone
In accordance to SIGN 101, treatment of acute patients involves administering 40-50 mg of oral prednisolone. Another option was given, which involves administering 100 mg of hydrocortisone via the IV route. Patient was initially started with IV hydrocortisone 100 mg four times a day upon admission and it was then replaced by prednisolone 40 mg when patient was stabilised.
A meta-analysis of 30 RCTs was conducted where results showed that the effectiveness of systemic steroids in acute cases resolved the acute asthma quicker, reduced hospitalizations, and was effective in the prevention of relapse in those who were treated as outpatients. In acute cases of asthma, it was also found that both forms of administration of steroids, oral or intravenous had similar effects on pulmonary function.12
A Cochrane review of 6 RCTs was conducted to determine the effectiveness of systemic corticosteroids (oral, IV, IM) therapy in asthmatic patients who had acute attacks by administering in higher doses as compared to lower doses. Corticosteroid dose was divided into three catagories; low (≤80 mg), moderate (>80 mg but ≤360 mg) and high (>360 mg). These doses were the equivalent doses of prednisolone per day. Results at 24, 48 and 72 hours among the 3 groups of varying doses revealed no clinical or statistical significance in the differences in % FEV1 predicted. As for incidence of adverse effects of respiratory failure rates among the 3 comparison groups, results revealed no significant differences. It appeared that corticosteroids in low doses (prednisolone ≤80 mg or hydrocortisone ≤400 mg over 24 hours) are as effective compared to higher doses in the treatment of asthmatic patients who had severe acute attacks.13
A Cochrane review including 6 RCTs was conducted, where the aim was to investigate the advantages of systemic corticosteroids (oral, IV, IM) vs placebo treatment in patients (adults and children) who were discharged after being treated for acute exacerbation of asthma. Results found that patients treated with corticosteroids had a significantly lower risk of relapse within the first week of discharge, and this risk remained low throughout the first 3 weeks. Those treated with corticosteroids during acute exacerbation also had a significantly less requirement for beta2 agonist to relieve their symptoms and they had a lower risk for following hospital admissions.17
3.3 Chronic Asthma, Step 1- MDI Salbutamol (inhaled short-acting beta2 agonist)
In conformance to SIGN 101, chronic asthma management includes 5 steps. Step 1 is the step where symptom relief is obtained by the use of SABA through inhalation.1 For her chronic asthma, MDI salbutamoll two puffs for ease of symptoms was given.
A Cochrane review was conducted, with the aim of determining the benefits of treatment of asthma with SABA through inhalation either routinely or only for relief of symptoms. Results found that there was no statistical difference between the two methods for reduction in airway obstruction as well as the risk of an asthma exacerbation occurring. It was also revealed that those who were treated regularly had a lesser symptoms associated with asthma.19
3.4 Chronic Asthma, Step 2 - MDI Beclometasone dipropionate (inhaled regular standard-dose corticosteroid)
In accordance to SIGN 101, the second step is where steroid at a regular-standard dose via inhalation is added.1 Patient was on MDI beclometasone dipropionate (100 µg) 2 puffs twice a day.
A Cochrane review comparing inhaled beclometasone formulated either with hydrofluoroalkane-134a (HFA) or chlorofluorocarbon (CFC) propellant with placebo for management chronic asthma, included 60 studies and 6542 participants. Results showed that there were significant improvements in FEV1 and morning PEFR, p<0.05, and also a decline in use of beta2-agonist for relief in patients not treated with oral steroids and using CFC-beclometasone as compared to placebo. Results also revealed that FEV1 indicated significant improvements, both morning as well as evening PEFR, and significant reductions in recurrent episodes of symptoms of asthma and daily use of beta2-agonist in patients not treated with oral steroids and using HFA-beclometasone as compared to placebo. These effects were noticeable after a treatment period of 6 weeks.8
Another Cochrane review assessing the presence of correlation between dose and response for patients treated with beclometasone, showed that results from 2 trials indicated only a small improvement advantage in morning PEFR, results from 1 trial indicated only a small improvement advantage in FEV1, and results from another 1 trial indicated minimal decrease advantage in night-time symptoms when patient was on beclometasone 800 µg/day as compared to 400 µg/day. These results were compared to baseline.9
3.5 Chronic Asthma, Step 3 - LABA and regular standard-dose corticosteroid
In conformance to SIGN 101, the third step for treatment in chronic asthmatic is where inhaled LABA is added.1 As the patient is currently on Step 2, she should only move up to Step 3 if improvement of control of her chronic asthma is needed. If she is moved up to Step 3, she would have to continue using her MDI beclometasone dipropionate (100 µg) 2 puffs twice a day plus a MDI LABA.
A Cochrane review comparing the efficacy and clinical safety of the plus-on of inhaled LABA to corticosteroid, also inhaled, with inhaled corticosteroid alone, showed that addition of the inhaled LABA caused a significant improvement in FEV1, p<0.05, a reduction by 19% in exacerbation risk needing steroids administered systemically, a decrease in usage of short-acting beta2 agonist for relief of symptoms, a decrease in withdrawals and an elevation in proportion of days which are free of symptom. Between the two groups, the risk of adverse effects or withdrawals as a result of adverse effect was not significant.10
A Cochrane review was underwent, to study in depth the risk of adverse events in patients with salmeterol (long-acting beta2 agonist) plus inhaled corticosteroids and corticosteroids alone. The corticosteroids in both cases were the same. 30 RCTs were included and it was found that there was no statistical difference between the occurrence of deaths in the combination group and the corticosteroids alone group. As for adverse effects which were not death related, it was also found that statistical difference was insignificant among two comparison groups.18
To conclude, choice of therapy for the patient with severe AEBA was suitably supported, based on SIGN 101 as well as many reviews and meta-analysis done. She was treated acutely with salbutamol and ipratropium bromide through the nebulizer, at the correct doses, according to the SIGN guideline, and evidence have shown that nebulized salbutamol and ipratropium bromide significantly increased pulmonary function and reduced hospital admission rates. She was also treated acutely with IV hydrocortisone which was subsequently replaced with oral prednisolone, both doses were correct, according to the SIGN guideline, and evidence have shown that the use of these corticosteroids in acute treatment were significantly effective in improving pulmonary function, reducing hospitalization, reducing relapses, and reducing need for short-acting beta2 agonist for symptom relief.
She was also given salbutamol when necessary for her chonic asthma, which was also according to the SIGN guideline. She was also on MDI beclometasone dipropionate, which indicates she was on step 2 on for her management of chronic asthma. Evidence have shown that beclometasone dipropionate significantly improved PEFR as well as morning FEV1, significant reductions in daytime symptoms as well as reduction in need to use short-acting beta2 agonist for symptom relief. Thus, the therapeutic management of the patient is evidence based.