key: cord-0732192-xzvdb29j
authors: Wedzicha, Jadwiga A.
title: Chapter 67 Acute Exacerbations of COPD
date: 2009-12-31
journal: Asthma and COPD
DOI: 10.1016/b978-0-12-374001-4.00067-5
sha: ffba5b8973e172b263428504d466156877eca422
doc_id: 732192
cord_uid: xzvdb29j

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.

Acute Exacerbations of COPD

Th ere 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 infl ammatory 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] .

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 fl ow readings, who were asked to report exacerbations as soon as possible after symptomatic onset [2] . Th e diagnosis of COPD exacerbation was based on criteria modifi ed 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 ). Th e 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 diff erences 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. Th ese patients have high levels of anxiety and depression and may accept their situation [6, 7] . Th e 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.

Using the median number of exacerbations as a cutoff point, COPD patients in the East London Study were classifi ed as frequent and infrequent exacerbators. Quality of life scores measured using a validated disease-specifi c scale, the St. George's Respiratory Questionnaire (SGRQ), was signifi cantly worse in all of its three component scores (symptoms, activities, and impacts) in the frequent, compared to the infrequent exacerbators. Th is 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 of colds, and longer recovery time from exacerbations. Symptoms of dyspnoea, common colds, sore throat, and cough increased signifi cantly during the prodromal phase, and this suggests that respiratory viruses may have early eff ects at exacerbations. Th e median time to recovery of peak expiratory fl ow was 6 days and 7 days for symptoms, but at 35 days peak expiratory fl ow 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. Th e 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] .

Th e reasons for the incomplete recovery of symptoms and lung function are not clear, but may involve inadequate treatment or persistence of the causative agent. Th e 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 ϳ30% 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 fi rst (index) exacerbation, and this event can be separated discretely from the index exacerbation [13] . Th us, exacerbations are complex events and careful follow-up is essential to ensure complete recovery.

Th e 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.

COPD exacerbations are associated with rises in airway (upper and lower airway) and systemic infl ammation [2, 14] . Increases in systemic markers seen at exacerbations are most likely driven by increases in airway infl ammation with exacerbation as the changes in airway and systemic infl ammation at exacerbation are directly related [14] . Obviously, biopsy studies are diffi cult 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, Tlymphocytes (CD3), and TNF-α ϩ cells, while there were no Ozone 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 signifi cant peak expiratory fl ow changes [9] . Falls in peak expiratory fl ow and FEV 1 at exacerbation were generally small and not useful in predicting exacerbations, but larger falls in peak expiratory fl ow were associated with symptoms of dyspnoea, presence Greater airway inflammation 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 diffi cult to interpret. Oxidative stress also plays an important role in the development of airway infl ammation 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 infl ammatory markers at exacerbation have been performed using sputum samples, either spontaneous or induced. Sputum infl ammatory 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 infl ammatory markers may persist for some time, suggesting incomplete recovery of exacerbations. Perera and colleagues also showed that systemic infl ammation 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 infl ammation in the stable state, compared to patients with infrequent exacerbations [2, 18] .

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 signifi cant 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 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 infl ammatory changes at exacerbation [22] . Th ey 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 infl ammation at exacerbation. Th is fi nding 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), infl uenza, parainfl uenza, and adenovirus can all trigger exacerbations. Infl uenza 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 infl uenza 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] .

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 . Th ese include Haemophilus Infl uenzae, 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] . Th e 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 fi rst-line therapy in such exacerbations. Anthonisen and colleagues in a classical paper investigating the benefi t 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 benefi t from antibiotic therapy. A meta-analysis of trials of antibiotic therapy in COPD has concluded that antibiotic therapy off ered a small but signifi cant benefi t 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 infl ammatory response has been reported in those exacerbations associated with both H. infl uenzae 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] . Th is has been confi rmed 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 confl icting and these infective agents may interact with other bacteria and viruses in the airways [33, 34] .

In patients with moderate and severe COPD, the mechanical performance of the respiratory muscles is reduced. Th e airfl ow obstruction leads to hyperinfl ation, with the respiratory muscles acting at a mechanical disadvantage and generating reduced inspiratory pressures. Th e load on the respiratory muscles is also increased in patients with airfl ow obstruction by the presence of intrinsic positive end-expiratory pressure (PEEP). With an exacerbation of COPD, the increase in airfl ow obstruction will further increase the load on the respiratory muscles and increase the work of breathing, precipitating respiratory failure in more severe cases. Th e minute ventilation may be normal, but the respiratory pattern will be irregular with increased frequency and decreased tidal volume. Th e 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. Th is causes increase in pulmonary artery pressure, which can lead to salt and water retention and the development of edema. Th e 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.

Beta 2 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 benefi t can be obtained with bronchodilator therapy in COPD, even without signifi cant changes in spirometry. Th is is probably due to a reduction in dynamic hyperinfl ation 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 β 2 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 diff erences between agents used and no signifi cant additive eff ect of the combination therapy, even though combination of anticholinergic and bronchodilator has benefi ts in the stable state [37, 38] . Th is diff erence in eff ect 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 eff ect.

Methylxanthines such as theophylline are sometimes used in the management of acute exacerbations of COPD. Th ere is some evidence that theophyllines are useful in COPD, though the main limiting factor is the frequency of toxic side eff ects. Th e 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 signifi cant benefi cial eff ect over and above conventional therapy [39, 40] . Th ere are some reports of benefi cial eff ects of methylxanthines upon diaphragmatic and cardiac function, though these mechanisms require further study in patients with COPD exacerbations.

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 eff ect on airway infl ammatory markers in patients with COPD [42, 43] . A number of early studies have investigated the eff ects 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 postbronchodilator FEV 1 when patients were treated for the fi rst 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 eff ect 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] .

Th ompson 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 steroidtreated group showed a more rapid improvement in PaO 2 , alveolar-arterial oxygen gradient, FEV 1 , peak expiratory fl ow 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 eff ect 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 fl ow. Th e treated exacerbations also had a longer recovery time to baseline for symptoms and peak expiratory fl ow. However, the rate of peak expiratory fl ow recovery was faster in the prednisolone-treated group, though not the rate of symptom score recovery. An interesting fi nding in this study was that steroids signifi cantly 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 eff ect 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 FEV 1 rose faster until day 5, when a plateau was observed in the steroidtreated group. Changes in the pre-bronchodilator and postbronchodilator FEV 1 were similar suggesting that this is not just an eff ect on bronchomotor tone, but involves faster resolution of airway infl ammatory changes or airway wall edema with exacerbation. Length of hospital stay analysis showed that patients treated with prednisolone had a signifi cantly shorter length of stay. Six weeks later, there were no diff erences in spirometry between the patient groups, and health status was similar to that measured at 5 days after admission. Th us, the benefi ts of steroid therapy at exacerbation are most obvious in the early course of the exacerbation. A similar proportion of the patients, ϳ32% 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] . Th e primary end point was a fi rst treatment failure, including death, need for intubation, readmission, or intensifi cation of therapy. Th ere was no diff erence in the results using the 2 or 8 week treatment protocol. Th e 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 FEV 1 improved faster in the prednisolone-treated group, though there were no diff erences 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. Th us, steroids should be used at COPD exacerbation in short courses of no more than 2 weeks duration to avoid risk of complications.

Acute exacerbations of COPD often present with increased sputum purulence and volume, and antibiotics have traditionally been used as fi rst-line therapy in such exacerbations. However, viral infections may be the triggers in a signifi cant 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] .

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 signifi cant increases in carbon dioxide tension at relatively modest oxygen fl ow rates. However, in the vast majority of cases, the administration of supplemental oxygen increases arterial oxygen tension suffi ciently without clinically significant rises in carbon dioxide. It is suggested that supplemental oxygen is delivered at an initial fl ow 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. Th e most commonly used is doxapram, which acts centrally to increase respiratory drive and respiratory muscle activity. Th e eff ect is probably only appreciable for 24 to 48 h; the main factor limiting use being side eff ects which can lead to agitation and are often not tolerated by the patient. Th ere are only a few studies of the clinical effi cacy 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.

Th e 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] . Th is 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. Th us, 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. Th e 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. Th e main advantage of the use of NIPPV is the avoidance of tracheal intubation and the ability to off er 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 benefi t 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 signifi cant 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 signifi cantly reduced from 29% in the conventionally treated group to 9% in the NIPPV group [56] . Complications, which were specifi cally associated with the use of mechanical ventilation, were also reduced. Th e diff erence in mortality disappeared after adjustment for intubation, suggesting that the benefi ts with NIPPV are due to fewer patients requiring intubation. Th is was also the fi rst 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] .

Th ese 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 eff ect 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] . Identifi cation of patients with a potentially poor outcome is important as delay in intubation can have serious consequences for the patient.

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 diffi cult, 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 fi rst 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. Th e patient's wishes and those of any close relatives should be considered in any decision to institute or withhold life supporting therapy.

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 diff erent 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 diff erences in mortality or readmission rates between the two groups [61] . Th ere 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 diff erences in readmission rates, no diff erences in visits to primary care physicians and health status measured 8 weeks after discharge was similar in the two groups. Th e authors also demonstrated that there were signifi cant 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 benefi ts may be seasonal, as COPD admissions are a particular problem in the winter. Further work is required on the diff erent models of supported discharge available and the cost eff ectiveness of these programmes.

Th ere has been much recent emphasis on prevention of exacerbations in patients with COPD. As respiratory tract infections are common factors in causing exacerbation, infl uenza, and pneumococcal vaccinations are recommended for all patients with signifi cant COPD. A study that reviewed the outcome of infl uenza vaccination in a cohort of elderly patients with chronic lung disease found that infl uenza vaccinaiton is associated with signifi cant health benefi ts 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 benefi t. However with the advent of novel and more specifi c antibiotics against airway organisms, the topic of long-term antibiotic therapy in COPD is currently being revisited and results of the fi rst trials are awaited. Recently there has been a report of the eff ects 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 benefi t are not clear, and further studies on the eff ects 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-infl ammatory activity [70] , and it is likely that tiotropium reduces exacerbations by reducing dynamic hyperinfl ation 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/fl uticasone (SFC) combination in the recently reported INSPIRE study in moderate-to-severe COPD patients showed that both interventions had an equal eff ect 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] . Th is for the fi rst time, it has been shown that different interventions have diff erent eff ects on exacerbations.

Th e Optimal study recently evaluated the combination of tiotropium with inhaled LABA (salmeterol) and inhaled steroids (fl luticasone) [72] . Th e 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 signifi cance due to the relatively small size of the study and the high dropout rate. Triple therapy may be more eff ective than other therapies and further studies of these combinations are now required with adequately powered studies.

COPD exacerbations: Defi ning their cause and prevention

Eff ect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease

Relation of sputum infl ammatory markers to symptoms and physiological changes at COPD exacerbations

Eff ect of environmental temperature on symptoms, lung function and mortality in COPD patients

Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease

Quality of life in patients with COPD and severe hypoxaemia

Home assessment of activities of daily living in patients with severe chronic obstructive pulmonary disease on long term oxygen therapy

Acute infective exacerbations of chronic bronchitis

Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease

Diff erences between asthma exacerbations and poor asthma control

Exacerbations of asthma

Clinical audit indicators of outcome following admission to hospital with acute exacerbation of chronic obstructive pulmonary disease

Infl ammatory changes and recurrence at COPD exacerbations

Systemic and upper and lower airway infl ammation at exacerbation of chronic obstructive pulmonary disease

Airway eosinophilia in chronic bronchitis during exacerbations

Biopsy neutrophilia, neutrophil chemokin and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease

Increased leukotriene B4 and 8-isprostane in exhaled breath condensate of patients with exacerbations of COPD

Airway and systemic infl ammation and decline in lung function, in chronic obstructive pulmonary disease

Respiratory viruses, symptoms and infl ammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease

Health eff ects of an air pollution episode in London

Personal exposure to nitrogen dioxide and risk of airfl ow obstruction in asthmatic children with upper respiratory infection

Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease

Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: A case-control study

Respiratory viral infections in adults with and without chronic obstructive pulmonary disease

Community study of the role of viral infections in exacerbations of asthma in 9-11 year old children

Detection of respiratory syncytial virus in adults with chronic obstructive pulmonary disease

Respiratory syncytial virus, airway infl ammation and FEV1 decline in patients with COPD

Interactions between lower airway bacterial and rhinoviral infection at exacerbations of chronic obstructive pulmonary disease

Antibiotics for exacerbations of chronic obstructive pulmonary disease . Cochrane Database Syst Rev

New strains of bacteria and exacerbations of chronic obstructive pulmonary disease

Infections and airway infl ammation in chronic obstructive pulmonary disease severe exacerbations

Pneumoniae and chronic bronchitis: Association with severity and bacterial clearance following treatment

Pneumoniae and COPD exacerbation

Inhaled bronchodilators reduce dynamic hyperinfl ation during exercise in patients with chronic obstructive pulmonary disease

A comparison of the eff ect of ipratropium and albuterol in the treatment of chronic obstructive airway disease

In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more eff ective than either agent alone

Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial

Intravenous aminophylline in patients admitted to hospital with nonacidotic exacerbations of chronic obstructive pulmonary disease: A prospective randomised controlled trial

Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: A metaanalysis

Eff ects of inhaled and oral glucocorticoids on infl ammatory indices in asthma and COPD

Eff ects of high dose inhaled steroids on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease

Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insuffi ciency

Eff ron D . A randomised controlled trial of methylprednisolone in the emergency treatment of acute exacerbations of chronic obstructive pulmonary disease

Early corticosteroid use in acute exacerbations of chronic airfl ow limitation

Intravenous and oral corticosteroids for the prevention of relapse after treatment of decompensated COPD

Controlled trial of oral prednisolone in outpatients with acute COPD exacerbation

Oral corticosteroids in patients admitted to hospital with exacerbations of chronnic obstructive pulmonary disease: A prospective randomised controlled trial

Eff ect of systemic glucocorticoids on exacerbations of chronic obstuctive pulmonary disease

Changes in symptoms, peak expiratory fl ow and sputum fl ora during treatment with antibiotics of exacerbations in patients with chronic obstructive pulmonary disease in general practice

Respiratory stimulation with intravenous doxapram in respiratory failure

Comparison of the acute eff ects on gas exchange of nasal ventilation and doxapram in exacerbations of chronic obstructive pulmonary disease

Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease

Randomized prospective trial of noninvasive positive pressure ventilation in acute respiratory failure

Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease

A multicentre randomised controlled trial of the early use of non-invasive ventilation foracute exacerbations of chronic obstructive pulmonary disease on general respiratory wards

Noninvasive mechanical ventilation in acute respiratory failure due to chronic obstructive pulmonary disease: Correlates for success

Outcome of nasal intermittent positive pressure ventilation when used for acute-on-chronic respiratory failure on a general respiratory ward

Incidence and causes of noninvasive mechanical ventilation failure after initial success

Home treatment of exacerbations of COPD by an acute respiratory assessment service

Early discharge for patients with exacerbations of COPD: A randomised controlled trial

A randomised controlled trial of supported discharge in patients with exacerbations of COPD

Relation between infl uenza vaccination and out patient visits, hospitalisation and mortality in elderly patients with chronic lung disease

Eff ect of an immunostimulating agent on acute exacerbations and hospitalization in COPD patients

Salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease

Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium

A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease

Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once daily inhaled anticholinergic bronchodilator: A randomised trial

Eff ect of tiotropium on infl ammation and exacerbations in chronic obstructive pulmonary disease

Th e Prevention of Chronic Obstructive Pulmonary Disease Exacerbations by Salmeterol/ Fluticasone Propionate or Tiotropium Bromide

Tiotropium in combination with placebo, salmeterol, or fl uticasone-salmeterol for treatment of chronic obstructive pulmonary disease: A randomized trial