The World Health Organization estimates 80 million people of having moderate to severe chronic obstructive pulmonary disease (WHO) globally (1). In the UK itself, around 3 million people are affected with only 900 000 cases being diagnosed. Most of the patients are not diagnosed until they are fifty. The cost of providing care in the National Health Service (NHS) as estimated by the National Institute for Health and Clinical Excellence (NICE) is more than £800 million each year. Of these, more than half is related to the provision of care in the hospital (2). A regional survey done in the UK of hospital admissions found that the percentage of men and women admitted in the age range of 65-74 years old are 73% and 32% respectively (3). Mortality rate has however been shown to increase in women as compared to men. This might be attributed to the increased number of female smokers and exposure of cooking gases without proper ventilation. COPD is predicted to be the third leading cause of mortality worldwide by 2030 (4).
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COPD is a common progressive disorder characterised by airflow limitations with little or no reversibility. Airflow limitations are caused by a mixture of chronic bronchitis and emphysema with the relative contributions differing between patients (5). Smoking is the major risk factor for COPD and smoking cessation has a significant benefit in stopping the progression of the disease. Besides that, other chronic inhalation of noxious particles and gases will also lead to COPD. They generate an inflammatory response by activating neutrophils, macrophages and CD8+ lymphocytes which will consequently release chemical mediators such as the tumor necrosis factor-α, interleukin-8 and leukotriene B4. These then cause widespread destructive changes in the airways, pulmonary vasculature and lung parenchyma (6). Goblet cells proliferate with excess mucus production, hence obstructing the airways. Thickness of the airway tissues increases because of the chronic inflammation, oedema and fibrosis. Consequentially, symptoms such as productive cough, wheezing, dyspnoea and acute exacerbations with infections appear (7).
Acute exacerbation of COPD is defined as acute and sustained (lasts over 48hours) worsening of the symptoms namely dyspnoea, cough and/or sputum production that is beyond the normal daily variations. It represents a further augmentation of inflammatory response in the lungs. During exacerbations, hyperinflation and air trapping in the lungs are increased with reduced expiratory flow. Therefore, increased dyspnoea is experienced by the patient (5). Other symptoms often associated with exacerbations are chest tightness, fluid retention, increased fatigue, and increased sputum purulence and volume. Frequent exacerbations have a negative impact on patient whereby physical activity is reduced, lung function decline is accelerated and risk of mortality is increased. The most common cause of exacerbation constituting around 40-50% is bacterial infections. Isolated bacterial organisms associated with the exacerbation of COPD include Haemophilus influenza, Moraxella catarrhalis, Streptococcus pneumonia and other Gram negative organisms (8). Other causes are non-compliance to medications and environmental factors (10-20%), and 30% are of unknown aetiology (9).
The acute exacerbation of COPD is managed with controlled oxygen therapy (in hospital settings), bronchodilators, corticosteroids and antimicrobial therapy if at least two of symptoms out of increased dyspnoea, increased sputum volume and increased sputum purulence occur. Patient's dyspnoea is associated with hypoxia and oxygen is used to improve tissue oxygenation hence relieving the symptom (2). Short acting β2-agonists such as salbutamol relax bronchial smooth muscle and cause bronchodilation by stimulating the enzyme adenyl cyclase which increases the formation of cyclic adenosine monophosphate. β2-agonists are also thought to improve mucocilliary clearance and have an onset of action of 5-10minutes. On the other hand, antimuscarinic bronchodilator such as ipratroprium bromide has a slower onset of action (15-20minutes) and produces bronchodilation by inhibiting the muscarinic receptors in bronchial smooth muscles (10). The action of acetylcholine which leads to the production of cyclic guanosine monophospate (a bronchoconstriction mediator) is hence blocked. Corticosteroids such as prednisolone are potent anti-inflammatory agents. They reduce capillary permeability to decrease mucus, inhibit the release of proteolytic enzymes from leukocytes and also inhibit the action of prostaglandins. During acute exacerbations, IV hydrocortisone is usually given followed by oral prednisolone within 12-24hours.
2.0 Evidence for treatment of the condition(s)
The management of acute exacerbations of COPD generally aims for the relief of symptoms and airflow obstruction, to maintain adequate oxygenation, and to treat any precipitating factors or co-morbid conditions that are thought to be causing respiratory deterioration (9).
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2.1 Oxygen therapy
During exacerbations, patients may be severely hypoxic. The use of oxygen during exacerbations should be done with care as high concentrations of oxygen (hyperoxia) may cause respiratory depression or ultimately, respiratory failure. The targeted PaO2 level is more or equals to 60 mm Hg or SpO2 of more or equals to 90%. Oxygen should be delivered via a Venturi mask (24-28%) or via nasal prongs (1-2 L/min) although more accurate delivery is associated with the former. To ensure acidosis does not happen in patients and to ensure adequate oxygenation is achieved, arterial blood gases (ABG) should be checked 30-60 minutes later and monitored regularly depending on the patient's condition (5, 9).
The use of short acting β2-agonists is generally preferred and is recommended in most guidelines (2, 5, 9) during acute exacerbation of COPD. In stable COPD, short acting β2-agonists were shown to have significant benefit over placebo. A review using the Cochrane Collaboration trials register, searched for randomised controlled trials dating back from May 2002. Of these, 13 studies of 1-8weeks duration on 237 patients aged 56-70 years old with FEV1 60-70% predicted were chosen. The results showed a small but significant increase in the FEV1 (weighted mean difference (WMD) = 0.14 L, 95% confidence interval (CI) = 0.04-0.25) and FVC (WMD= 0.30 L, 95% CI= 0.02-0.58) value compared to placebo when the values are taken after the use of the short acting β2-agonist bronchodilator. The peak expiratory flow rate (PEFR) measured in the morning (WMD = 29.17 L/min, 95% CI= 0.25-58.09) and evening (WMD= 36.75 L/min, 95% CI= 2.56-70.94) also showed a significantly higher value than placebo (11). Both spirometric and PEFR measurements showed no significant differences in readings compared to those before bronchodilator treatment.
Short acting antimuscarinic agent is considered if the patient's symptom is not well controlled with β2-agonists despite increased doses of the latter. Similar to the short acting β2-agonists, short acting antimuscarinic agent has also been shown to be superior over placebo in stable COPD. A randomized double blind study comparing the effect of salmeterol (long acting β2-agonist) and ipratropium (short acting antimuscarinic agent) with placebo was carried out in 2001 (12). Salmeterol 42 micrograms were given twice daily to 132 patients, ipratropium bromide36 micrograms given four times a day to 138 and placebo to 135 patients over 12 weeks. Bronchodilator response was assessed every 3 weeks for 12 hours. The results revealed significantly higher FEV1 and FVC values (p < 0.001) of ipratropium when compared to the placebo. The values are also slightly higher than that of salmeterol with faster onset although the duration of action only lasts for 6 hours as compared to 12 hours with salmeterol. Another study comparing formoterol with ipratropium bromide also show significant superiority of both drugs (p < 0.001) over placebo (13). It is worth noting that both studies reveal an insignificant improvement in patients' symptoms and quality of life. The latter study concluded formoterol to be better than ipratroprium bromide in projecting clinical benefit that can be recognized by the patients.
The above evidences are applied to the use in stable COPD. There has been no study carried out to investigate the effect of β2-agonists compared to placebo during acute exacerbations. However, there was a study by Polverino et al in 2007 that investigates the effect of nebulised salbutamol during acute exacerbations and its association with pulmonary gas exchange (14). It was observed that the abnormality of pulmonary exchange did not worsen during exacerbation following administration of salbutamol. A small aggravation in gas exchange response was however observed during recuperation in the same patients whose baseline lung function had shown improvement. Although this study was limited by its small number of participants (n =9), it provides evidence to support the use of short acting β2-agonists in acute exacerbations of COPD.
There were a few studies found to have compared between the use of β2-agonists and antimuscarinic agents (usually represented by ipratropium bromide) in acute settings. Two Cochrane reviews carried out in the span of 7 months in 2001 by searching literatures in various databases have yielded a total of 6 studies (15, 16). The β2-agonists and antimuscarinic agents were found to show an overall increase in FEV1 following administration in up to 90 minutes. However, there was no significant additive effect shown by using both agents concurrently. Ipratropium bromide also did not show a greater bronchodilation compared to the β2-agonists. It might be noteworthy that the β2-agonists used in the studies are not the ones that are used in current settings for example salbutamol and terbutaline.
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The delivery of drugs either via nebuliser or metered dose inhaler should be decided by assessing the patient's overall condition. The European Respiratory Society states that both method of inhalation are equally effective in producing bronchodilation during acute exacerbations of COPD (17). Nebulisers are generally preferred by the hospital staff as they are independent of the patient's inhaler technique. Thus they are particularly useful in acute settings where the delivery of drugs needs to be quick and efficient. Small doses of drugs (for example salbutamol 100-200 micrograms) are usually recommended to be delivered via metered dose inhalers while higher doses can be delivered more conveniently with nebulisers (18). It is also worth mentioning that the cost of nebulisers is higher than that of metered dose inhalers.
Systemic corticosteroids are recommended for patients during acute exacerbation of COPD provided that the patient is known not to be contraindicated. A randomized double blind trial of systemic corticosteroids given for 2 and 8 weeks versus placebo was studied in 1999 (19). 80 patients were given an 8 week course of IV methylprednisolone (for the first 3 days) followed by oral prednisolone, another 80 were given both agents for 2 weeks followed by placebo capsules, and 111 patients were given IV dextrose followed by placebo capsules over 8 weeks of study. The outcome was assessed by measuring treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, patients readmitted to hospital, or the need of boosting drug therapy. The results revealed very significantly higher rates of treatment failure in placebo group as compared to both the corticosteroid groups. The latter groups also showed a reduction in the duration of hospitalisation with FEV1 improving by 0.10 L over the placebo group within a day of admission. Corticosteroids administered for 8 weeks however did not show significant benefit over the 2 weeks group.
A more recent randomized double blind trial compared the effect of nebulised budesonide, oral prednisolone and placebo in a total of 199 patients hospitalized for acute exacerbations of COPD (20). The patients were given all standard treatments of exacerbation. Results revealed a significantly greater FEV1 value of budesonide (0.10 L) and prednisolone (0.16 L) over placebo with 95% CI. The difference between both corticosteroids was however insignificant suggesting nebulised budesonide to be a probable alternative to systemic corticosteroid in managing acute exacerbations. In comparing between the effect of corticosteroid administered orally or intravenously, it was found in a study by de Jong, Y. P. et al that the treatment failure in both groups were similar (21). It was then concluded that the oral route is preferred as it is less invasive compared to the IV route.
The use of antibiotics during acute exacerbations is recommended in the presence of purulent sputum or with clinical signs of pneumonia as demonstrated by the patient in this case. The main causative organism associated with pneumonia is Streptococcus pneumonia so it is imperative that the antibiotics used in this patient provide coverage against its activity. Antibiotics have been shown to be beneficial during exacerbations. A meta-analysis was performed by searching for randomized trials dating from 1955 to 1994 to study the effectiveness of antibiotics in treating exacerbations (22). Nine trials were found to satisfy all the inclusion criteria and it was observed that antibiotics produced an overall statistically significant improvement of the patients' conditions.
The patient in this case was given azithromycin and cefuroxime for 3 and 6 days respectively. There was no study comparing the effect of either agent with placebo in acute exacerbation of COPD. However, a randomized double blind trial comparing the efficacy of telithromycin with cefuroxime axetil showed eradication of pathogen in 76.0% and 78.6% of patients respectively (23). On the other hand, the effect of azithromycin was shown by the results of a randomized clinical trial comparing its effect with that of dirithromycin (24). Patients reported similar improvement of symptoms such as dyspnoea and sputum production in both agents. All of these findings could indirectly be translated as cefuroxime and azithromycin having a beneficial effect in managing infections during exacerbations.
Generally, it can be said that the patient's management during acute exacerbation followed that as recommended by the guidelines. Oxygen therapy was given via nasal prongs in this patient and although the use of venturi mask is more recommended, nasal prongs has been proven to give similar benefits and with a lower cost. Salbutamol was given via metered dose inhaler as required as the patient is alert and conscious hence will not be having difficulty using it. It was not understood why ipratropium bromide was given via nebuliser instead but it is easier to be administered by the hospital staff in acute settings. There are many evidences showing the beneficial effect of corticosteroid in acute exacerbations of COPD and the patient was ensured of this by the administration of IV hydrocortisone followed by oral prednisolone for 5 days. Lastly, the antibiotics used in managing the underlying pneumonia in this patient was also thought to be accurate as both azithromycin and cefuroxime has been shown to eradicate infections in patients during exacerbations.