Acute Exacerbations of COPD

Publisher Summary

There has been considerable recent interest into the causes and mechanisms of exacerbations of chronic obstructive pulmonary disease (COPD) as COPD exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD. Earlier descriptions of COPD exacerbations had concentrated mainly on studies of hospital admission, though most COPD exacerbations are treated in the community and not associated with hospital admission. Exacerbation frequency is an important determinant of health status in COPD and is thus one of the important outcome measures in COPD. Factors predictive of frequent exacerbations included daily cough and sputum and frequent exacerbations in the previous year. In a further prospective analysis of 504 exacerbations, where daily monitoring was performed, there was some deterioration in symptoms, though no there were significant peak expiratory flow changes. Recovery was longer in the presence of increased dyspnoea or symptoms of a common cold at exacerbation. The changes observed in lung function at exacerbation were smaller than those observed at asthmatic exacerbations. The reasons for the incomplete recovery of symptoms and lung function are not clear, but may involve inadequate treatment or persistence of the causative agent. The incomplete physiological recovery after an exacerbation could contribute to the decline in lung function with time in patients with COPD. The association of the symptoms of increased dyspnoea and of the common cold at exacerbation with a prolonged recovery suggests that viral infections may lead to more prolonged exacerbations.

Epidemiology of COPD Exacerbation

There has been considerable recent interest into the causes and mechanisms of exacerbations of chronic obstructive pulmonary disease (COPD) as COPD exacerbations are an important cause of the considerable morbidity and mortality found in COPD [1]. COPD exacerbations increase with increasing severity of COPD. Some patients are prone to frequent exacerbations that are an important cause of hospital admission and readmission, and these frequent exacerbations may have considerable impact on quality of life, disease progression, and mortality [2] (Fig. 67.1 ). COPD exacerbations are also associated with considerable physiological deterioration and increased airway inflammatory changes [3] that are caused by a variety of factors such as viruses, bacteria, and possibly common pollutants. COPD exacerbations are commoner in the winter months and there may be important interactions between cold temperatures and exacerbations caused by viruses or pollutants [4].

Fig. 67.1.

Impact of COPD exacerbations.

Earlier descriptions of COPD exacerbations had concentrated mainly on studies of hospital admission, though most COPD exacerbations are treated in the community and not associated with hospital admission. A cohort of moderate-to-severe COPD patients was followed in East London, UK (East London COPD study) with daily diary cards and peak flow readings, who were asked to report exacerbations as soon as possible after symptomatic onset [2]. The diagnosis of COPD exacerbation was based on criteria modified from those described by Anthonisen and colleagues [5], which require two symptoms for diagnosis, one of which must be a major symptom of increased dyspnoea, sputum volume, or sputum purulence. Minor exacerbation symptoms included cough, wheeze, sore throat, nasal discharge, or fever (Table 67.1 ). The study found that about 50% of exacerbations were unreported to the research team, despite considerable encouragement provided and only diagnosed from diary cards. But there were no differences in major symptoms or physiological parameters between reported and unreported exacerbations [2]. Patients with COPD are accustomed to frequent symptom changes and thus may tend to underreport exacerbations to physicians. These patients have high levels of anxiety and depression and may accept their situation 6., 7.. The tendency of patients to underreport exacerbations may explain the higher total rate of exacerbation at 2.7 per patient per year, which is higher than that of previously reported by Anthonisen and co-workers at 1.1 per patient per year [5]. However in the latter study, exacerbations were unreported and diagnosed from patients’ recall of symptoms.

Table 67.1.

Causes of COPD exacerbations.

Viruses

Rhinovirus (common cold)

Influenza

Parainfluenza

Coronavirus

Adenovirus

RSV

Chlamydia pneumoniae

Bacteria

Haemophilus influenzae

Streptococcus penumoniae

Branhamella cattarhalis

Staphylococcus aureus

Pseudomonas aeruginosa

Common pollutants

Nitrogen dioxide

Particulates

Sulphur dioxide

Ozone

Using the median number of exacerbations as a cutoff point, COPD patients in the East London Study were classified as frequent and infrequent exacerbators. Quality of life scores measured using a validated disease-specific scale, the St. George’s Respiratory Questionnaire (SGRQ), was significantly worse in all of its three component scores (symptoms, activities, and impacts) in the frequent, compared to the infrequent exacerbators. This suggests that exacerbation frequency is an important determinant of health status in COPD and is thus one of the important outcome measures in COPD. Factors predictive of frequent exacerbations included daily cough and sputum and frequent exacerbations in the previous year. A previous study of acute infective exacerbations of chronic bronchitis found that one of the factors predicting exacerbation was also the number in the previous year [8], though this study was limited to exacerbations presenting with purulent sputum and no physiological data was available during the study.

In a further prospective analysis of 504 exacerbations, where daily monitoring was performed, there was some deterioration in symptoms, though no there were significant peak expiratory flow changes [9]. Falls in peak expiratory flow and FEV₁ at exacerbation were generally small and not useful in predicting exacerbations, but larger falls in peak expiratory flow were associated with symptoms of dyspnoea, ­presence of colds, and longer recovery time from exacerbations. Symptoms of dyspnoea, common colds, sore throat, and cough increased significantly during the prodromal phase, and this suggests that respiratory viruses may have early effects at exacerbations. The median time to recovery of peak expiratory flow was 6 days and 7 days for symptoms, but at 35 days peak expiratory flow had returned to normal in only 75% of exacerbations, while at 91 days, 7.1% of exacerbations had not returned to baseline lung function. Recovery was longer in the presence of increased dyspnoea or symptoms of a common cold at exacerbation. The changes observed in lung function at exacerbation were smaller than those observed at asthmatic exacerbations, though the average duration of an asthmatic exacerbation was longer at 9.6 days 10., 11..

The reasons for the incomplete recovery of symptoms and lung function are not clear, but may involve inadequate treatment or persistence of the causative agent. The incomplete physiological recovery after an exacerbation could contribute to the decline in lung function with time in patients with COPD. However to date, there is no evidence that patients with incomplete recovery of their exacerbation have a greater decline in lung function, and further studies on the natural history of COPD exacerbations are required. A recent audit performed by the Royal College of Physicians, London, showed that 30% of patients seen at hospital with an index exacerbation will be seen again and possibly readmitted with a recurrent exacerbation within 8 weeks [12]. In a cohort of moderate-to-severe COPD patients 22% of patients had a recurrent exacerbation within 50 days of the first (index) exacerbation, and this event can be separated discretely from the index exacerbation [13]. Thus, exacerbations are complex events and careful follow-up is essential to ensure complete recovery.

The association of the symptoms of increased dyspnoea and of the common cold at exacerbation with a prolonged recovery suggests that viral infections may lead to more prolonged exacerbations. As cold is associated with longer exacerbations, COPD patients who develop cold may be prone to more severe exacerbations and should be considered for therapy early at onset of symptoms. COPD exacerbations are also prone to recurrence in that one exacerbation is more likely to be followed by another one.

Inflammatory Changes at Exacerbation

COPD exacerbations are associated with rises in airway (upper and lower airway) and systemic inflammation 2., 14.. Increases in systemic markers seen at exacerbations are most likely driven by increases in airway inflammation with exacerbation as the changes in airway and systemic inflammation at exacerbation are directly related [14]. Obviously, biopsy studies are difficult to perform at exacerbation in COPD patients. However in one study, where biopsies were performed at exacerbation in patients with chronic bronchitis, increased airway eosinophilia was found, though the patients studied had only mild COPD [14]. With exacerbation, there were more modest increases observed in neutrophils, T-lymphocytes (CD3), and TNF-α⁺ cells, while there were no changes in CD4 or CD8 T-cells, macrophages, or mast cells. Qiu and co-workers have studied biopsies from COPD patients who were intubated and showed that there was considerable airway neutrophilia, neutrophil elastase expression with upregulation of neutrophil chemokine expression [15]. However, intubated COPD patients may have secondary airway infection and thus results may be difficult to interpret. Oxidative stress also plays an important role in the development of airway inflammation at COPD exacerbation. Markers of oxidative stress have been shown to rise in the airways during exacerbations such as hydrogen peroxide and 8-isoprostane, and these markers may take some time to recover to baseline stable levels [16]. Patients with severe exacerbations associated with hospitalization-assisted ventilation showed evidence of increased oxidative stress [17].

Most studies on airway inflammatory markers at exacerbation have been performed using sputum samples, either spontaneous or induced. Sputum inflammatory markers such as IL-6, IL-8, and myeloperoxidase (MPO) rise at the start of the exacerbation and usually recover to normal by 14 days, though in some cases higher airway inflammatory markers may persist for some time, suggesting incomplete recovery of exacerbations. Perera and colleagues also showed that systemic inflammation may persist after the exacerbation and those patients with an elevated C-reactive protein (CRP), 2 weeks after the onset of an exacerbation were more likely to develop an early recurrent exacerbation [13]. Patients with a history of frequent exacerbations have also increased airway and systemic inflammation in the stable state, compared to patients with infrequent exacerbations 2., 18..

ETIOLOGY of COPD exacerbation

COPD exacerbations have been associated with a number of aetiological factors, including infection and pollution episodes (Table 67.1). COPD exacerbations are frequently triggered by upper respiratory tract infections [19], and these are commoner in the winter months, when there are more respiratory viral infections in the community. Patients may also be more prone to exacerbations in the winter months as lung function in COPD patients shows small but significant falls with reduction in outdoor temperature during the winter months [4]. COPD patients have been found to have increased hospital admissions, suggesting increased exacerbation when increasing environmental pollution occurs. During the December 1991 pollution episode in the UK, COPD mortality was increased together with an increase in hospital admission in elderly COPD patients [20]. However, common pollutants especially oxides of nitrogen and particulates may interact with viral infection to precipitate exacerbation rather than acting alone [21].

Viral infections

Viral infections are an important trigger for COPD exacerbations 19., 22., 23.. Studies have shown that at least one-third of COPD exacerbations were associated with viral infections, and that the majority of these were due to human rhinovirus, the cause of the common cold 19., 22., 23.. Viral exacerbations were associated with symptomatic colds and prolonged recovery of the exacerbation [9]. Using molecular techniques, Seemungal and colleagues also showed that rhinovirus can be recovered from induced sputum more frequently than from nasal aspirates at exacerbation, suggesting that wild-type rhinovirus can infect the lower airway and contribute to inflammatory changes at exacerbation [22]. They also found that exacerbations associated with the presence of rhinovirus in induced sputum had larger increases in airway IL-6 levels [22], suggesting that viruses increase the severity of airway inflammation at exacerbation. This finding is in agreement with the data that respiratory viruses produce longer and more severe exacerbations and have a major impact on health care utilization 9., 24.. Other viruses may trigger COPD exacerbation, though coronavirus was associated with only a small proportion of asthmatic exacerbations and is unlikely to play a major role in COPD [25]. RSV (respiratory syncytial virus), influenza, parainfluenza, and adenovirus can all trigger exacerbations. Influenza has become a less prominent cause of exacerbation with the introduction of immunization, though this is still likely to be an important factor at times of influenza epidemics. RSV infection has been found at COPD exacerbation [26], but it is not clear if RSV is a cause of COPD exacerbation as RSV can be frequently detected in the airways of COPD patients when stable [27].

Bacterial infection

Over the past years, the role of bacterial infection at COPD exacerbation has been somewhat controversial as airway bacterial colonization is found when patients are stable state and the same organisms are isolated exacerbations. These include Haemophilus Influenzae, Streptococcus Pneumoniae, Branhamella cattarhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. [28]. In a study in patients with moderate-to-severe COPD, bacteria were found in 48.2% of patients in the stable state and at exacerbation, bacterial detection rose to 69.6%, with an associated rise in airway bacterial load [29]. The case for involvement of bacteria has come from the studies of antibiotic therapy as exacerbations often present with increased sputum purulence and volume and antibiotics have traditionally been used as first-line therapy in such exacerbations. Anthonisen and colleagues in a classical paper investigating the benefit of antibiotics in over 300 acute exacerbations demonstrated a greater treatment success rate in patients treated with antibiotics, especially if their initial presentation was with the symptoms of increased dyspnoea, sputum volume, and purulence [5]. Patients with mild COPD obtained less benefit from antibiotic therapy. A meta-analysis of trials of antibiotic therapy in COPD has concluded that antibiotic therapy offered a small but significant benefit in outcome in exacerbations [30]. Sethi and colleagues have suggested that isolation of a new bacterial strain in COPD patients who were regularly sampled was associated with an increased risk of exacerbation [31], though this also does not conclusively prove that bacteria are direct causes of exacerbations as not all exacerbations were associated with strain change, and not all strain changes resulted in exacerbation.

At COPD exacerbations both respiratory viruses and bacteria may be isolated. A greater systemic inflammatory response has been reported in those exacerbations associated with both H. influenzae and rhinovirus isolations, and if the isolation of Haemophilus was associated with new or worsening coryzal symptoms (a surrogate of viral infection) such infections were more severe as assessed by changes in symptoms and lung function at exacerbation onset [29]. This has been confirmed in a further study demonstrating greater lung function impairment and longer hospitalizatons in exacerbations associated with viral and bacterial co-infection [32]. It has also been suggested that atypical micro-organisms such as chlamydia and mycoplasma may cause COPD exacerbations, though evidence on their role is conflicting and these infective agents may interact with other bacteria and viruses in the airways 33., 34..

Pathophysiological Changes at COPD Exacerbation

In patients with moderate and severe COPD, the mechanical performance of the respiratory muscles is reduced. The airflow obstruction leads to hyperinflation, with the respiratory muscles acting at a mechanical disadvantage and generating reduced inspiratory pressures. The load on the respiratory muscles is also increased in patients with airflow obstruction by the presence of intrinsic positive end-expiratory pressure (PEEP). With an exacerbation of COPD, the increase in airflow obstruction will further increase the load on the respiratory muscles and increase the work of breathing, precipitating respiratory failure in more severe cases. The minute ventilation may be normal, but the respiratory pattern will be irregular with increased frequency and decreased tidal volume. The resultant hypercapnia and acidosis will then reduce inspiratory muscle function, contributing to further deterioration of the respiratory failure.

Hypoxaemia in COPD usually occurs due to a combination of ventilation–perfusion mismatch and hypoventilation, although arterio-venous shunting can also contribute in the acute setting. This causes increase in pulmonary artery pressure, which can lead to salt and water retention and the development of edema. The degree of the ventilation perfusion abnormalities increases during acute exacerbations and then resolves over the following few weeks. Acidosis is an important prognostic factor in survival from respiratory failure during COPD exacerbation, and thus early correction of acidosis is an essential goal of therapy.

Treatment

Inhaled bronchodilator therapy

Beta₂ agonists and anti-cholinergic agents are the inhaled bronchodilators most frequently used in the treatment of acute exacerbations of COPD. In patients with stable COPD, symptomatic benefit can be obtained with bronchodilator therapy in COPD, even without significant changes in spirometry. This is probably due to a reduction in dynamic hyperinflation that is characteristic of COPD and hence leads to a decrease in the sensation of dyspnoea especially during exertion [35]. In stable COPD greater bronchodilatation has been demonstrated with anti-cholinergic agents than with β₂ agonists, which may be due to the excessive cholinergic neuronal bronchoconstrictor tone [36]. However, studies investigating bronchodilator responses in acute exacerbations of COPD have shown no differences between agents used and no significant additive effect of the combination therapy, even though combination of anticholinergic and bronchodilator has benefits in the stable state 37., 38.. This difference in effect between the acute and stable states may be due to the fact that the larger doses of drug delivered in the acute setting produce maximal bronchodilatation, whereas the smaller doses administered in the stable condition may be having a sub-maximal effect.

Methylxanthines such as theophylline are sometimes used in the management of acute exacerbations of COPD. There is some evidence that theophyllines are useful in COPD, though the main limiting factor is the frequency of toxic side effects. The therapeutic action of theophylline is thought to be due to its inhibition of phosphodiesterase that breaks down cyclic 3’5’ adenosine monophosphate (AMP), an intracellular messenger, thus facilitating bronchodilatation. However studies of intravenous aminophylline therapy in acute exacerbations of COPD have shown no significant beneficial effect over and above conventional therapy 39., 40.. There are some reports of beneficial effects of methylxanthines upon diaphragmatic and cardiac function, though these mechanisms require further study in patients with COPD exacerbations.

Corticosteroids

Only about 10% to 15% of patients with stable COPD show a spirometric response to oral corticosteroids [41] and, unlike the situation in asthma, steroids have little effect on airway inflammatory markers in patients with COPD 42., 43.. A number of early studies have investigated the effects of corticosteroid therapy at COPD exacerbation. In an early controlled trial in patients with COPD exacerbations and acute respiratory failure, Albert and co-workers found that there were larger improvements in pre- and post-bronchodilator FEV₁ when patients were treated for the first 3 days of the hospital admission with intravenous methylprednislone than those treated with placebo [44]. Another trial found that a single dose of methylprednisolone given within 30 min of arrival in the accident and emergency department produced no improvement after 5 h in spirometry, and also had no effect on hospital admission, though another study reduced readmission 45., 46.. A retrospective study comparing patients treated with steroids at exacerbation compared to those not treated showed that the steroid group had a reduced chance of relapse after therapy [47].

Thompson and colleagues gave a 9 day course of prednisolone or placebo in a randomized manner to out-patients presenting with acute exacerbations of COPD [48]. Unlike the previous studies, these patients were either recruited from out-patients or from a group that were pre-enrolled and self reported the exacerbation to the study team. In this study patients with exacerbations associated with acidosis or pneumonia were excluded, so exacerbations of moderate severity were generally included. Patients in the steroid-treated group showed a more rapid improvement in PaO₂, alveolar–arterial oxygen gradient, FEV₁, peak expiratory flow rate, and a trend toward a more rapid improvement in dyspnoea in the steroid-treated group.

In a recent cohort study by Seemungal and colleagues, the effect of therapy with prednisolone on COPD exacerbations diagnosed and treated in the community was studied [9]. Exacerbations treated with steroids were more severe and associated with larger falls in peak expiratory flow. The treated exacerbations also had a longer recovery time to baseline for symptoms and peak expiratory flow. However, the rate of peak expiratory flow recovery was faster in the prednisolone-treated group, though not the rate of symptom score recovery. An interesting finding in this study was that steroids significantly prolonged the median time from the day of onset of the initial exacerbation to the next exacerbation from 60 days in the group not treated with prednisolone to 84 days in the patients treated with prednisolone. In contrast, antibiotic therapy had no effect on the time to the next exacerbation. If short course oral steroid therapy at exacerbation does prolong the time to the next exacerbation, then this could be an important way to reduce exacerbation frequency in COPD patients, which is an important determinant of health status [2].

Davies and colleagues randomized patients admitted to hospital with COPD exacerbations to prednisolone or placebo [49]. In the prednisolone group, the FEV₁ rose faster until day 5, when a plateau was observed in the steroid-treated group. Changes in the pre-bronchodilator and post-bronchodilator FEV₁ were similar suggesting that this is not just an effect on bronchomotor tone, but involves faster resolution of airway inflammatory changes or airway wall edema with exacerbation. Length of hospital stay analysis showed that patients treated with prednisolone had a significantly shorter length of stay. Six weeks later, there were no differences in spirometry between the patient groups, and health status was similar to that measured at 5 days after admission. Thus, the benefits of steroid therapy at exacerbation are most obvious in the early course of the exacerbation. A similar proportion of the patients, 32% in both study groups required further treatment for exacerbations within 6 weeks of follow-up, emphasizing the high exacerbation frequency in these patients.

Niewoehner and colleagues performed a randomized controlled trial of either a 2-week or an 8-week prednisolone course at exacerbation compared to placebo, in addition to other exacerbation therapy [50]. The primary end point was a first treatment failure, including death, need for intubation, readmission, or intensification of therapy. There was no difference in the results using the 2 or 8 week treatment protocol. The rates of treatment failure were higher in the placebo group at 30 days, compared to the combined 2 and 8 week prednislone groups. As in the study by Davies and colleagues, the FEV₁ improved faster in the prednisolone-treated group, though there were no differences by 2 weeks. In contrast, Niewoehner and colleagues performed a detailed evaluation of steroid complications and found considerable evidence of hyperglycaemia in the steroid-treated patients. Thus, steroids should be used at COPD exacerbation in short courses of no more than 2 weeks duration to avoid risk of complications.

Antibiotics

Acute exacerbations of COPD often present with increased sputum purulence and volume, and antibiotics have traditionally been used as first-line therapy in such exacerbations. However, viral infections may be the triggers in a significant proportion of acute infective exacerbations in COPD and antibiotics used for the consequences of secondary infection. As discussed previously, antibiotic therapy at exacerbations is most useful if patients present with symptoms of increased dyspnoea, sputum volume, and purulence [30]. A randomized placebo-controlled study investigating the value of antibiotics in patients with mild obstructive lung disease in the community concluded that antibiotic therapy did not accelerate recovery or reduce the number of relapses, though patients had mixed pathologies [51].

Management of respiratory failure

Hypoxaemia occurs with more severe exacerbations and usually requires hospital admission. Caution should always be taken in providing supplemental oxygen to patients with COPD, particularly during acute exacerbations, when respiratory drive and muscle strength can be impaired leading to significant increases in carbon dioxide tension at relatively modest oxygen flow rates. However, in the vast majority of cases, the administration of supplemental oxygen increases arterial oxygen tension sufficiently without clinically significant rises in carbon dioxide. It is suggested that supplemental oxygen is delivered at an initial flow rate of 1–2 l/min via nasal cannulae or 24–28% inspired oxygen via Venturi mask, with repeat blood gas analysis after 30–45 min of oxygen therapy.

Hypercapnia during COPD exacerbations may be managed initially with the use of respiratory stimulants. The most commonly used is doxapram, which acts centrally to increase respiratory drive and respiratory muscle activity. The effect is probably only appreciable for 24 to 48 h; the main factor limiting use being side effects which can lead to agitation and are often not tolerated by the patient. There are only a few studies of the clinical efficacy of doxapram and short-term investigations suggest that improvements in acidosis and arterial carbon dioxide tension can be attained [52]. A small study comparing doxapram with non-invasive ventilation (NPPV) in acute exacerbations of COPD suggested that NPPV was superior with regard to correction of blood gases during the initial treatment phase [53]. Increases in pulmonary artery pressure during acute exacerbations of COPD can result in right-sided cardiac dysfunction and development of peripheral edema. Diuretic therapy may thus be necessary if there is edema or a rise in jugular venous pressure.

Ventilatory support

Non-invasive ventilation

The introduction of noninvasive positive pressure ventilation (NPPV) using nasal or face masks has had a major impact on the management of acute exacerbations and has enabled acidosis to be corrected at an early stage. Studies have shown that NIPPV can produce improvements in pH relatively rapidly, at 1 h after instituting ventilation 54., 55.. This will allow time for other conventional therapy to work, such as oxygen therapy, bronchodilators, steroids, and antibiotics and thus reverse the progression of respiratory failure and reduce mortality. With NIPPV, there are improvements in minute ventilation, reductions in respiratory rate and in transdiaphragmatic activity. Thus, NIPPV can improve gas exchange and allows respiratory muscle rest in respiratory failure.

With the use of NIPPV patient comfort is improved; there is also no requirement for sedation with preservation of speech and swallowing. The technique can be applied in a general ward, though a high-dependency area is preferable and intensive care is unnecessary. Patient cooperation is important in application of NIPPV. The main advantage of the use of NIPPV is the avoidance of tracheal intubation and the ability to offer ventilatory support to patients with respiratory failure due to severe COPD, who would be considered unsuitable for intubation. A lower incidence of nosocomial penumonia has also been reported with the use of NPPV compared with conventional intubation and ventilation.

Following a number of uncontrolled studies, randomized controlled trials have shown benefit of NIPPV in acute COPD exacerbations. A UK study showed that with the use of NIPPV in exacerbations of respiratory failure, earlier correction of pH can be achieved, together with reduction in breathlessness over the initial 3 days of ventilation, compared with a control standard therapy group [54]. A study from the United States showed a significant reduction in intubation rates with NIPPV from 67% in a group receiving conventional therapy to 9% in the NIPPV group [55]. A third study showed convincingly that in patients with exacerbations of respiratory failure, the use of NIPPV with pressure supports ventilation, reduces the need for intubation and mortality is significantly reduced from 29% in the conventionally treated group to 9% in the NIPPV group [56]. Complications, which were specifically associated with the use of mechanical ventilation, were also reduced. The difference in mortality disappeared after adjustment for intubation, suggesting that the benefits with NIPPV are due to fewer patients requiring intubation. This was also the first study to show that hospital length of stay can be reduced with use of NIPPV. A recent study showed that NPPV can be applied on general wards, though patients with more severe acidosis had a worse outcome [57].

These studies have treated patients where the pH was below 7.35, rather than just below 7.26, when the prognosis of COPD worsens. A number of these patients may have improved without NIPPV, though it seems that the major effect of NIPPV is the earlier correction of acidosis and thus avoidance of tracheal intubation, with all its associated complications. Studies have shown that NIPPV can be successfully implemented in up to 80% of cases 58., 59.. NIPPV is less successful in patients who have worse blood gases at baseline before ventilation, are underweight, have a higher incidence of pneumonia, have a greater level of neurological deterioration, and where compliance with the ventilation is poor [58]. Moretti and colleagues have recently shown that “late treatment failure” (after an initial 48 h of therapy with NPPV) is up to 20% and that patients with late failure were more likely to have severe functional and clinical disease with more complications at the time of admission [60]. Identification of patients with a potentially poor outcome is important as delay in intubation can have serious consequences for the patient.

Indications for invasive ventilation

If NIPPV fails, or is unavailable in the hospital, invasive ventilation may be required in the presence of increasing acidosis. It may be considered in any patient when the pH falls below 7.26. Decisions to ventilate these patients may be difficult, though with improved modes of invasive ventilatory support and better weaning techniques, the outlook for the COPD patient is better.

Patients will be suitable for tracheal intubation if this is the first presentation of COPD exacerbation or respiratory failure, or there is a treatable cause of respiratory failure, such as pneumonia. Information will be required on the history and quality of life, especially the ability to perform daily activities. Patients with severe disabling and progressive COPD may be less suitable, but it is important that adequate and appropriate therapy has been used in these patients, with documented disease progression. The patient’s wishes and those of any close relatives should be considered in any decision to institute or withhold life supporting therapy.

Supported discharge

Many hospital admissions are related to exacerbations of COPD and thus reductions of admissions especially during the winter months when they are most frequent is particularly desirable. Over the last few years a number of different models of supported discharge have been developed and some evaluated 61., 62., 63.. Patients have been discharged early with an appropriate package of care organized, including domiciliary visits made to these patients after discharge by trained respiratory nurses.

Cotton and colleagues randomized patients to discharge on the next day or usual management and found that there were no differences in mortality or readmission rates between the two groups [61]. There was a reduction in hospital stay from a mean of 6.1 days to 3.2 days. In another larger study by Skwarska and colleagues, patients were randomized to discharge on the day of assessment or conventional management [62]. Again there were no differences in readmission rates, no differences in visits to primary care physicians and health status measured 8 weeks after discharge was similar in the two groups. The authors also demonstrated that there were significant cost savings of around 50% for the home support group, compared to the admitted group. However, other considerations need to be taken into account in organizing an assisted discharge service in that resources have to be released for the nurses to follow the patients and the benefits may be seasonal, as COPD admissions are a particular problem in the winter. Further work is required on the different models of supported discharge available and the cost effectiveness of these programmes.

Prevention of COPD Exacerbation

There has been much recent emphasis on prevention of exacerbations in patients with COPD. As respiratory tract infections are common factors in causing exacerbation, influenza, and pneumococcal vaccinations are recommended for all patients with significant COPD. A study that reviewed the outcome of influenza vaccination in a cohort of elderly patients with chronic lung disease found that influenza vaccinaiton is associated with significant health benefits with fewer outpatient visits, fewer hospitalizations, and a reduced mortality [64].

Long-term antibiotic therapy has been used in the past in patients with very frequent exacerbations, though the evidence was not strong for benefit. However with the advent of novel and more specific antibiotics against airway organisms, the topic of long-term antibiotic therapy in COPD is currently being revisited and results of the first trials are awaited. Recently there has been a report of the effects of an immunostimulatory agent in patients with COPD exacerbations, with reduction in severe complications and hospital admissions in the actively treated group [65]. However, the mechanisms of benefit are not clear, and further studies on the effects of these agents in the prevention of COPD exacerbation are required.

Long-acting bronchodilators (LABA) have been shown to reduce exacerbations. In the recently reported TORCH (Towards a Revolution in COPD Health) study, salmeterol, a long-acting beta agonist, reduced the frequency of exacerbations [66], while a number of other studies have shown that the long-acting anticholinergic tiotropium reduces the exacerbation rate and also a trend to reduction in hospital admission 67., 68., 69.. However, there is no good evidence at present that long-acting anticholinergic agents possess anti-inflammatory activity [70], and it is likely that tiotropium reduces exacerbations by reducing dynamic hyperinflation and thus dyspnoea. Combinations of long-acting beta agonists and inhaled corticosteroids have been also evaluated and reduced exacerbations more than the individual components [66]. A direct comparison of inhaled tiotropium with the salmeterol/fluticasone (SFC) combination in the recently reported INSPIRE studyin moderate-to-severe COPD patients showed that both interventions had an equal effect on exacerbation rates [71]. However, patients taking tiotropium required more courses of oral corticosteroids with exacerbations whereas patients on the SFC combination required more courses of antibiotics [71]. This for the first time, it has been shown that different interventions have different effects on exacerbations.

The Optimal study recently evaluated the combination of tiotropium with inhaled LABA (salmeterol) and inhaled steroids (flluticasone) [72]. The triple combination reduced hospitalization as a result of exacerbation, but not the total number of exacerbations. In addition a trend was observed in the reduction of the number of exacerbations with the triple combination, which did not reach statistical significance due to the relatively small size of the study and the high dropout rate. Triple therapy may be more effective than other therapies and further studies of these combinations are now required with adequately powered studies.