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The overall goals of therapy are to alleviate the patient's symptoms of dyspnea, to stabilize and improve respiratory status, and where possible, to remove the ongoing trigger. Many patients with an acute exacerbation of COPD are stable enough to be managed in the outpatient setting. Key pharmacologic therapies include short-acting bronchodilators, systemic corticosteroids, and antibiotics. Oxygen may also be needed. Patients with more severe exacerbations may need to be admitted to hospital and may require ventilatory support.
The World Health Organization has specified a minimum set of interventions for the management of exacerbations of COPD.
COPD patients and their exacerbations are highly heterogeneous. Some patients with mild exacerbations may be able to manage their symptoms at home using their self-management plan. While many aspects of care are amenable to protocols, those who may require hospitalization, those who may benefit from pulmonary rehabilitation, or those who have a less versus more severe acute exacerbation, will vary according to the comorbidities and other characteristics of each patient.
Hospitalization should be considered for people with:
Sudden worsening of resting dyspnea
High respiratory rate (>30 breaths/minute)
Acute respiratory failure
Decreased oxygen saturation (SaO₂): SaO₂ <90% on air or deteriorating SaO₂ in patients with known hypoxemia (i.e., those on long-term oxygen therapy)
Confusion or drowsiness
Change in or onset of new signs, such as cyanosis or worsening peripheral edema
Failure to respond to initial management
Serious comorbidities that would affect recovery or impact treatment, such as heart failure, atrial fibrillation, or other cardiorespiratory conditions
Insufficient support at home or in the community treatment setting.
The patient should be reassessed if their condition worsens rapidly or significantly. In particular, physicians should be alert for symptoms and signs of pneumonia, cardiorespiratory failure, and sepsis.
Patients who meet any of the following criteria require immediate admission to the intensive care unit (ICU), or a respiratory care unit that is equipped to identify and manage acute respiratory failure:
Severe dyspnea that does not respond adequately to initial treatment
Changes in mental status (e.g., confusion, lethargy, coma)
Hypoxemia that persists or worsens (partial pressure of oxygen [PaO2] <5.3kPa or <40mmHg) and/or respiratory acidosis that is severe or worsening (pH <7.25), despite supplemental oxygen therapy and noninvasive ventilation
Invasive mechanical ventilation is needed
Hemodynamic instability (vasopressors are needed).
ICU admission should also be considered for those who newly require noninvasive ventilation and/or acute respiratory acidosis; this may depend on local hospital resources and policy.
Short-acting bronchodilators include beta-2 agonists (SABAs) and short-acting muscarinic antagonists (SAMAs). SABAs and SAMAs both reduce symptoms of dyspnea and also improve airflow, possibly by decreasing lung hyperinflation. These medications are considered first-line therapy, and are delivered either by nebulization or by metered-dose inhaler (MDI). SABAs and SAMAs may provide benefit within 15 and 30 minutes, respectively. Optimal dosing of bronchodilators in acute exacerbations of COPD has not yet been determined; however, guidelines generally recommend increasing the dose or frequency of administration if the patient remains symptomatic. After clinical improvement, the time between doses may be increased as tolerated.
SABAs are typically favored as they have a faster onset of action than SAMAs. International guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend SABAs, with or without SAMAs, as the initial bronchodilators to treat an acute exacerbation of COPD. Initial therapy with SABAs may lead to a transient reduction in PaO2. If the initial dose of SABA does not provide sufficient benefit, the frequency of dosing may be increased and a SAMA may be added. Nebulized ipratropium (a SAMA) may be given in combination with nebulized albuterol (a SABA). Ipratropium may be used in lieu of albuterol for patients developing significant adverse effects due to SABA use. Levalbuterol may also be used in lieu of racemic albuterol, and it may be possible to provide levalbuterol less frequently than racemic albuterol in patients with exacerbations. Levalbuterol may be best considered for patients who have adverse cardiovascular effects from albuterol (e.g., tachycardia/tachyarrhythmia).
It is not clear whether the combination of a SABA plus a SAMA provides additional benefit. While there is no definitive evidence that the combination improves outcomes, patients may derive symptomatic benefit, plus additional bronchodilation, because these agents work by different mechanisms. Combination therapy is generally recommended for patients who are not improving promptly on a SABA alone.
One systematic review did not find significant differences in FEV1 when short-acting bronchodilators were delivered by a nebulizer, compared with an MDI (with or without a spacer device), in patients with an acute exacerbation of COPD. Patients with severe dyspnea and low inspiratory flow rates may have difficulty achieving proper technique and medication delivery with MDIs; nebulizer treatment may be easier to use for such patients. Technique with MDIs should be observed and a spacer should be used.
Guidelines from GOLD recommend that patients do not receive continuous nebulization, but rather, take 1 or 2 puffs every hour from an MDI (plus spacer) for two or three doses, and then every 2 to 4 hours based on response. If a nebulizer is used to deliver the inhaled drugs, then it should be driven by air, not oxygen, in order to avoid the risk of worsening hypercarbia that may be caused by oxygen-driven nebulization.
There are as yet no clinical trials to clearly guide whether or not long-acting bronchodilators should be continued during acute COPD exacerbations. Although discontinuation of a maintenance therapy might potentially contribute to worsening symptoms and/or lung function, regular frequent administration of short-acting bronchodilators, in addition to long-acting bronchodilators of the same class, has the potential to increase the risk of medication-related adverse effects, such as arrhythmia, urinary retention, and constipation. The current GOLD report recommends continuing inhaled long-acting bronchodilators during an exacerbation, or starting them as soon as possible before discharge from hospital. Clinical judgement should dictate whether or not to continue long-acting bronchodilators during acute hospitalizations for COPD when patients are receiving short-acting bronchodilators four or more times per day. Consideration should be made as to whether adjustments to pre-hospitalization drug regimens are needed, based on recommendations for step-up therapy to reduce future risk of exacerbations.
Systemic (oral or intravenous) corticosteroids should be considered after initial treatment with short-acting inhaled bronchodilators. For patients able to take oral medications, intravenous corticosteroids do not appear to provide any significant benefit over those taken orally. However, some patients may require intravenous administration if they cannot tolerate oral therapy (e.g., if they are vomiting).
Systemic corticosteroids decrease airway inflammation and have been shown to be beneficial for patients with acute exacerbations of COPD. They have been associated with greater early (within 3 days) improvement in FEV1, improved oxygenation, faster recovery time, decreased duration of hospitalization, and decreased rate of treatment failure and relapsed disease. However, there is no evidence that the use of corticosteroids has an effect on rates of mortality. In addition, corticosteroids are associated with increased risk of pneumonia, sepsis, and death. They should only be used in patients with significant exacerbations.
Studies examining the role of systemic corticosteroids have been primarily performed among people presenting to emergency rooms and those who are hospitalized, and have used a range of dose amounts and treatment durations.
Previous national and international guidelines recommended that patients receive prednisone, or equivalent, for 7 to 14 days. It is not known whether tapering systemic corticosteroids provides any clinical benefit apart from likely avoidance of adrenal insufficiency. One randomized controlled trial showed that 5 days’ treatment of prednisone was noninferior to 14 days’ treatment with regard to the risk of exacerbations in the subsequent 6 months. One Cochrane systematic review concluded that five days of oral corticosteroids is likely to be sufficient for acute exacerbations of COPD, and that it is unlikely that shorter courses of systemic corticosteroids (of around five days) lead to worse outcomes than longer courses (10 to 14 days). [ ] This 5-day regimen is recommended by the GOLD guidelines. The Department of Veterans’ Affairs recommends prednisone for 5 to 7 days. An equivalent oral dose of methylprednisolone may be used. Joint guidelines from the European Respiratory Society and American Thoracic Society recommend a short course (≤14 days) of oral corticosteroids for ambulatory patients with an exacerbation of COPD.
The balance of risks and benefits of corticosteroids for people with milder exacerbations is uncertain. Eosinophil count may prove to be useful in determining who should receive corticosteroids for acute exacerbations of COPD; corticosteroids may be less effective for acute exacerbations of COPD among patients with lower blood eosinophil levels.
The benefit of systemic corticosteroid therapy for people with acute exacerbations of COPD with associated respiratory failure requiring mechanical ventilatory support is also unclear. One randomized controlled trial found no difference in ICU mortality, duration of mechanical ventilation, or ICU length of stay between patients who received prednisone versus the control group who did not, yet those who received prednisone had a higher risk of hyperglycemia.
The presence of pneumonia as a cause of respiratory decompensation in a patient with COPD does not necessarily imply the presence of a COPD exacerbation per se (i.e., the presence of worsened airflow limitation related to airways inflammation and/or bronchoconstriction), and as such, careful consideration should be given as to whether systemic corticosteroids are warranted in such patients.
Nebulized corticosteroids have been used with some success, but their utility in acute exacerbations of COPD and relative efficacy compared with systemic corticosteroids is not fully clear. Nebulized budesonide may be suitable in some patients, providing similar clinical outcomes to intravenous methylprednisolone, although local costs and availability may vary.
Corticosteroids may pose a risk of development and/or worsening of tracheobronchomalacia, which may mimic COPD exacerbations.
Airway clearance techniques
Selected airway clearance techniques, such as mechanical vibration and nonoscillating positive expiratory pressure devices, may improve sputum clearance in some patients with copious secretions, or concurrent bronchiectasis, and may slightly reduce short-term risk of need for ventilatory assistance. [ ] However, they are not uniformly helpful. Other clearance techniques, such as manual chest wall percussion, are also either not routinely helpful or may have detrimental effects. There is as yet no proven benefit of airway clearance techniques on long-term outcomes following COPD exacerbation, such as reduction in subsequent exacerbation risk. [ ]
Oxygen therapy is recommended for patients with acute exacerbations who are hypoxemic (PaO2 <60 mmHg, oxygen saturation <90%). Oxygen should be applied with caution to prevent further hypercarbia. Arterial blood gas and pulse oximetry should be checked on presentation, and then after 30 to 60 minutes, to ensure satisfactory oxygenation and to check for carbon dioxide retention and/or respiratory acidosis. Controlled oxygen should be titrated to a target saturation of 88% to 92% as COPD patients are considered at risk for hypercarbic (type 2) respiratory failure. Careful titration of supplemental oxygen, even in the prehospital setting (e.g., en route to the hospital), is important to prevent worsening respiratory acidosis, which may increase mortality.
Oxygen is best administered in a controlled fashion via a high-flow Venturi mask to deliver 24% to 28% oxygen.
Excessive oxygen therapy may lead to worsening hypercarbia, acidosis, and respiratory failure, due to worsening V/Q mismatch and decreased CO2-carrying capacity of oxygenated erythrocytes (Haldane effect). For this reason, oxygen delivery via a high-flow Venturi mask is favored over nasal prongs, as nasal prongs are less accurate and deliver higher inspired oxygen concentrations. High-flow oxygen (HFO) therapy may be an alternative to standard oxygen therapy or noninvasive mechanical ventilation in patients with acute hypoxemic respiratory failure. HFO involves the delivery of heated, humidified oxygen at up to 60 L/min in adults via special nasal cannulae. However, there is currently insufficient evidence to recommend the use of HFO in acute hypoxemic/hypercarbic respiratory failure in patients with COPD.
Oxygen therapy may be discontinued when the patient is able to maintain their target oxygen saturation on room air. Oxygen saturation should be checked at rest, with exertion, and during sleep (if possible) prior to discharge for hospitalized patients, in order to determine if supplemental oxygen will be newly needed in the home, or if changes to prior oxygen prescription are necessary.
While methylxanthine medications, such as theophylline or aminophylline, may provide benefit to some people with COPD, this class of medications has a narrow therapeutic window and there does not appear to be a role for use in patients with acute exacerbations of COPD.
The use of mucolytics, expectorants, and/or physical mucus-clearing techniques does not appear to provide any clear proven benefit during exacerbations, although some patients do experience symptomatic relief.
Exacerbations with suspected bacterial etiology
Bacterial infections are thought to be a common trigger of exacerbations. Interactions between host factors, bacteria, viruses, and changes in air quality are also thought to cause, or contribute toward, exacerbations. Many exacerbations are not caused by bacterial infections, so will not respond to antibiotics.
Multiple, randomized placebo-controlled trials have shown that antibiotics are beneficial for the treatment of patients with acute exacerbations of COPD. However, one updated Cochrane review concluded that the effects of antibiotics for non-ICU patients are small, are inconsistent for some outcomes (treatment failure), and absent for other outcomes (mortality and length of hospital stay). When this Cochrane review restricted its analysis to four studies that assessed the currently used antibiotics of non-ICU inpatients, a beneficial effect in terms of treatment failure was found but it was not statistically significant (risk ratio 0.65, 95% CI 0.38 to 1.12). For outpatients, currently used antibiotics statistically significantly reduced the risk for treatment failure (risk ratio 0.72, 95% CI 0.56 to 0.94).
International guidelines from GOLD recommend antibiotics for people with acute exacerbations of COPD and:
increased sputum purulence, plus
increased sputum volume, and/or
Some patients with COPD may keep antibiotics at home for use in an exacerbation as part of their self-management plan.
Patients with more severe exacerbations, particularly those requiring treatment in the ICU, have been shown to derive greater benefit from antibiotic therapy. [ ] International guidelines from GOLD recommend that antibiotics should be given to patients with severe exacerbations requiring mechanical ventilation (invasive or noninvasive).
Antibiotic choice and duration of therapy is an unresolved issue, but in general should be based on local resistance patterns and patient characteristics, including any previous culture results for the patient. The most common bacterial pathogens include: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.
It has been shown that short courses of antibiotics (e.g., 5 days) are equally effective as longer courses (e.g., >5 days) for patients with mild to moderate exacerbations of COPD. When indicated, GOLD recommends that the duration of antibiotic therapy should be 5 to 7 days, but local guidelines should be consulted.
Oral antibiotics should be given first-line if possible, and if the severity of the exacerbation does not necessitate intravenous antibiotics. If the patient’s dyspnea and/or sputum purulence improve, this suggests that the antibiotic is effective. Guidelines from the National Institute for Health and Care Excellence (NICE) recommend that, if intravenous antibiotics are given, they should be reviewed within 48 hours and stepped down to oral antibiotics where possible. Antibiotic-resistant bacteria should be considered, and a sputum sample sent for microscopy, culture, and Gram stain if symptoms have not improved following antibiotic treatment, and if these tests have not been done already.
It has been recommended that more narrow-spectrum antibiotics (e.g., amoxicillin, amoxicillin/clavulanate, doxycycline, second-generation cephalosporins, macrolides, trimethoprim/sulfamethoxazole) be considered for patients at less risk for a poor outcome and with an exacerbation of lesser severity. The severity depends on the patient's prior status and any changes to previous baseline investigation (based on symptoms, examination, lung function, ABG).
Patients with more severe underlying COPD, and those with greater exacerbation severity, are more often colonized with gram-negative bacteria such as Pseudomonas aeruginosa or other enteric gram-negative organisms and/or Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus). Therefore, broad-spectrum antibiotics such as ampicillin/sulbactam, piperacillin/tazobactam, vancomycin, and fluoroquinolones are considered for patients at greater risk for a poor outcome, or with an episode of greater severity. Agents with activity against Pseudomonas aeruginosa are also indicated for people at risk of this infection. The choice of antibiotic should also be based in part on local bacterial resistance patterns.
Sputum cultures or endotracheal aspirates (in patients who are intubated) are recommended for assessment of bacterial infection in patients with severe lung function impairment, those with a history of frequent exacerbations, and/or in patients hospitalized with COPD exacerbations or who require mechanical ventilation, as gram-negative bacteria (such as Pseudomonas species) or resistant pathogens may be present. Consideration may also be given to obtaining a sputum culture in patients who have bronchiectasis and suspected infectious exacerbations as a feature of their COPD.
Risk factors for a poor outcome include recent history of antibiotic use, more severe baseline COPD, need for hospitalization, treatment failure, prior antibiotic resistance, or risk factors for healthcare-associated infections. Critically ill patients in the ICU are also at higher risk.
Use of accessory muscles of respiration, paradoxical respirations, cyanosis, new peripheral edema, hemodynamic instability, and worsened mental status (e.g., confusion, lethargy, coma) are important indicators of a more severe exacerbation.
Specialist advice may be needed if symptoms do not improve after repeated courses of antibiotics, or with a bacterial infection resistant to oral antibiotics, or for patients who cannot take oral medications.
Studies have suggested that the use of a respiratory fluoroquinolone, amoxicillin/clavulanate, second- or third-generation cephalosporins, or macrolides may be associated with fewer treatment failures or recurrent exacerbations. One meta-analysis of randomized controlled trials found that there were no differences between patients with acute exacerbation of chronic bronchitis receiving semisynthetic penicillins (e.g., amoxicillin, ampicillin), and those receiving trimethoprim-based regimens (e.g., trimethoprim, trimethoprim/sulfamethoxazole), in terms of treatment success and number of drug-related adverse events in general. One randomized controlled trial has shown that three months of azithromycin for an infectious exacerbation of COPD that requires hospitalization may reduce treatment failure during the highest-risk period.
In November 2018, the European Medicines Agency (EMA) completed a review of serious, disabling, and potentially irreversible adverse effects associated with systemic and inhaled fluoroquinolone antibiotics. These adverse effects include tendonitis, tendon rupture, arthralgia, neuropathies, and other musculoskeletal or nervous system effects. As a consequence of this review, the EMA now recommends that fluoroquinolone antibiotics be restricted for use in serious, life-threatening bacterial infections only. Furthermore, they recommend that fluoroquinolones should not be used for mild to moderate infections, unless other appropriate antibiotics for the specific infection cannot be used, and should not be used in nonsevere, nonbacterial, or self-limiting infections. Patients who are older, have renal impairment, or have had a solid organ transplant, and those being treated with a corticosteroid, are at a higher risk of tendon damage. Coadministration of a fluoroquinolone and a corticosteroid should be avoided where possible. The UK-based Medicines and Healthcare products Regulatory Agency (MHRA) support these recommendations. The Food and Drug Administration (FDA) issued a similar safety communication in 2016, restricting the use of fluoroquinolones in acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections. In addition to these restrictions, the FDA has issued warnings about the increased risk of aortic dissection, significant hypoglycemia, and mental health adverse effects in patients taking fluoroquinolones. Therefore, fluoroquinolones should be used only when it is considered inappropriate, or when it is impossible to use other antibacterial agents that are commonly recommended for the treatment of these infections.
There is currently insufficient evidence to guide use of antibiotics based on serum procalcitonin levels in patients with COPD. Importantly, procalcitonin-guided antibiotic use is not recommended for COPD exacerbations in the ICU setting, as this has been associated with increased mortality. C-reactive protein (CRP) is also being investigated as a potential biomarker to guide the use of antibiotics during exacerbations of COPD. A decision to withhold antibiotics based on low CRP levels at the point of care has been associated with reduced antibiotic prescriptions, without worse clinical outcomes.
Respiratory failure is often seen in patients with severe acute exacerbations of COPD. Patients with severe exacerbations who do not appear to respond sufficiently to initial interventions should be considered for noninvasive mechanical ventilation (NIV). The use of NIV has been shown to improve gas exchange, reduce dyspnea, decrease the need for endotracheal intubation, reduce complications such as pneumonia, and decrease length of hospitalization and mortality in these patients. [ ] Where possible, NIV should be used in preference to invasive mechanical ventilation for respiratory failure associated with COPD exacerbation.
NIV use should be considered for patients with one or more of the following:
Respiratory acidosis (partial pressure of carbon dioxide [PaCO2] ≥6.0 kPa or 45 mmHg and arterial pH ≤7.35)
Severe dyspnea with signs that suggest fatigue of respiratory muscles, or increased work or breathing, or both, such as the use of accessory muscles of respiration, paradoxical movement of the abdomen, or retraction of the intercostal spaces
Persistent hypoxemia while on supplemental oxygen.
Improvements in patients' level of dyspnea and their physiologic state are typically seen within 1 to 4 hours. The GOLD report recommends that if patients improve, and can breathe unassisted for at least 4 hours, then NIV can be stopped.
However, NIV is not successful for all patients. Clinicians should discuss the risks and benefits of invasive mechanical ventilation with patients receiving NIV to determine their desired course of treatment.
Invasive mechanical ventilation should be considered for patients with outright respiratory or cardiac arrest, who are in, or have signs of, impending acute respiratory failure despite NIV, have impaired mental status or cardiovascular instability, are at high risk for aspiration, or for whom NIV cannot be appropriately applied (e.g., craniofacial trauma, recent gastroesophageal surgery, copious secretions, anxiety disorder, facial discomfort, or severe skin breakdown).
Physiologic criteria for invasive mechanical ventilation include the following: life-threatening hypoxemia in patients unable to tolerate NIV, inability to tolerate NIV or failure of NIV, respiratory or cardiac arrest, irregular breathing with gasping or loss of consciousness, massive aspiration or persistent vomiting, inability to clear respiratory secretions, heart rate <50 beats per minute with diminished alertness, severe hemodynamic instability not responsive to medical treatment, or severe ventricular or supraventricular arrhythmias.
The risk for mortality is significant (11% to 49%) for people with severe disease in whom invasive mechanical ventilation is indicated. Complications of mechanical ventilation include ventilator-associated pneumonia and barotrauma. Weaning patients with severe COPD from mechanical ventilation can be difficult. Use of NIV to assist weaning from mechanical ventilation can reduce weaning failure and nosocomial pneumonia, and may reduce mortality.
Tracheal intubation: animated demonstration
Bag-valve-mask ventilation: animated demonstration
Depending on the patient’s clinical condition, the following may also need to be addressed:
Monitoring and correction of fluid balance (e.g., in patients with heart failure)
Treatment of any comorbidities (e.g., lung cancer, cardiovascular disease, osteoporosis, depression)
Smoking cessation (e.g., nicotine replacement therapy).
Pulmonary rehabilitation and disease management programs
Patients with COPD who experience acute exacerbations of COPD often have skeletal muscle dysfunction (potentially due to limited physical activity), nutritional disturbances, corticosteroid use, and/or systemic inflammatory factors.
Pulmonary rehabilitation is a multidisciplinary program of care that involves physical rehabilitation as well as guidance on disease management, nutrition, and other lifestyle issues (e.g., smoking cessation, medication adherence and inhaler technique, supplemental oxygen, and maintenance of physical activity). As COPD patients and their exacerbations are highly heterogeneous, determining who may benefit from respiratory rehabilitation varies greatly according to the comorbidities and other characteristics of individual patients.
Selected forms of exercise rehabilitation initiated during a hospitalization for COPD exacerbation, including resistance strength training and transcutaneous electrical muscle stimulation, are well tolerated and can prevent muscle function decline and hasten functional status recovery.
Pulmonary rehabilitation initiated early during the recovery phase of an exacerbation is safe and effective, and leads to improvements in exercise tolerance, physical abilities, the degree of symptoms due to COPD, and quality of life.
Comprehensive supervised pulmonary rehabilitation in the outpatient setting in the post-exacerbation period decreases the risk for future hospitalization. Participation in pulmonary rehabilitation within 90 days of discharge following hospitalization for COPD exacerbation is associated with a significant decrease in mortality risk. Unsupervised, home-based exercise training following exacerbations does not appear to confer the same benefits.
Disease management programs can be helpful. However, their use remains controversial given that a randomized controlled trial had to be stopped early due to a noted increase in mortality in the comprehensive care management group, compared with the control patients who were receiving guideline-based routine medical care. Another study involving unsupervised home-based exercise training following hospitalization for acute COPD exacerbation also showed a mortality signal at the 6-month, post-hospitalization time point.
Some data are emerging that hospital-at-home care, with support from respiratory nurses, may be appropriate for selected people with moderate exacerbations of COPD. [ ] However, this approach is not yet considered the standard of care, and people with unstable vital signs, decompensated gas exchange, acute respiratory acidosis, worsened hypoxemia, change in mental status, or significant comorbid illness are not suitable for this approach.
A randomized controlled trial has suggested that the use of nurse-centered tele-assistance may decrease the occurrence of exacerbations of COPD and hospitalization. The use of such programs may be cost-saving. However, another randomized controlled trial demonstrated that tele-monitoring integrated into existing clinical services did not reduce hospital admissions or improve patients’ quality of life.
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