Acute exacerbation of chronic obstructive pulmonary disease

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ACUTE

at presentation

1st line – short-acting bronchodilator

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Short-acting bronchodilators include short-acting beta-2 agonists (SABAs) and short-acting muscarinic antagonists (SAMAs). These medications are considered first-line therapy and are delivered either by nebulization or by metered-dose inhaler.[149][151] 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.[1] Initial therapy with SABAs may lead to a transient reduction in partial pressure of oxygen (PaO2).[152] If the initial dose of SABA does not provide sufficient benefit, the frequency of dosing may be increased and a SAMA may be added.[153] 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 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).[154]

It is not clear whether the combination of a SABA plus a SAMA provides additional benefit.[155][156] 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.[1]

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.[151][157] 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.[1] 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.[1][145]

There is insufficient evidence to determine whether MDIs or the aerosol nebulizer technique is the optimal method of delivering bronchodilators to adults with COPD exacerbations who are receiving mechanical ventilation via endotracheal tube.[248]

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.[1] 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.[1]

Optimal dosing of bronchodilators in acute exacerbations of COPD has not been established. Adjust dose according to clinical symptoms and adverse effects. Higher or more frequent dosing may be required.

Primary options

albuterol inhaled: consult specialist for guidance on dose

levalbuterol inhaled: consult specialist for guidance on dose

-- AND / OR --

ipratropium bromide inhaled: consult specialist for guidance on dose

Consider – systemic corticosteroid

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Treatment recommended for SOME patients in selected patient group

Systemic (oral or intravenous) corticosteroids should be considered after initial treatment with short-acting inhaled bronchodilators.[1] For patients able to take oral medications, intravenous corticosteroids do not appear to provide any significant benefit over those taken orally.[158][159][160][161] However, some patients may require intravenous administration if they cannot tolerate oral therapy (e.g., if they are vomiting).

Systemic corticosteroids 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.[1][158][159][162][163][164] However, there is no evidence that the use of corticosteroids has an effect on rates of mortality.[158] In addition, corticosteroids are associated with increased risk of pneumonia, sepsis, and death.[165] They should only be used in patients with significant exacerbations.[1]

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.[166] 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).[167] [ ] This 5-day regimen is recommended by the Global Initiative for Chronic Obstructive Lung Disease guidelines.[1] 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.[168]

One systematic review found no difference in risk of treatment failure or relapse, likelihood of an adverse event, length of hospital stay, or lung function, at the end of short (approximately 5 days) and longer (10-14 days) courses of systemic corticosteroids.[158]

The balance of risks and benefits of corticosteroids for people with milder exacerbations is uncertain. The eosinophil count may prove to be useful in determining who should receive corticosteroids for acute exacerbations of COPD; systemic corticosteroids may be less effective for acute exacerbations of COPD among patients with lower blood eosinophil levels.[1][120][121][122][123]

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 intensive care unit (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.[169]

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.

Diabetes is common in patients with COPD, and the need for treatment of hyperglycemia is more frequently encountered when patients receive systemic corticosteroids.[158][163]

Primary options

prednisone: 30-40 mg orally once daily

methylprednisolone: 40-60 mg/day orally given once daily or in 2 divided doses

methylprednisolone sodium succinate: 0.5 to 2 mg/kg intravenously every 6 hours for up to 72 hours, followed by taper or change to oral dosing

Consider – airway clearance techniques

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Treatment recommended for SOME patients in selected patient group

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.[173] [ ] However, they are not uniformly helpful.[174] Other clearance techniques, such as manual chest wall percussion, are also either not routinely helpful or may have detrimental effects.[175][176][177] 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.[173] [ ]

Consider – oxygen

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Treatment recommended for SOME patients in selected patient group

Oxygen therapy is recommended for patients with acute exacerbations who are hypoxemic (partial pressure of oxygen [PaO2] <60 mmHg, oxygen saturation [SaO2] <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.[1][129] 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.[1][129] 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.[178]

Oxygen is best administered in a controlled fashion via a high-flow Venturi mask to deliver 24% to 28% oxygen.[129]

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.[1][179] Nasally-delivered high-flow oxygen may be a suitable alternative to noninvasive mechanical ventilation for some patients with severe COPD exacerbations in the intensive care unit setting.[1]

Oxygen therapy may be discontinued when the patient is able to maintain their target oxygen saturation on room air.[129] 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.

Consider – supportive care

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Treatment recommended for SOME patients in selected patient group

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); thromboprophylaxis; nutritional supplements; smoking cessation (e.g., nicotine replacement therapy).[1]

suspected bacterial etiology (exacerbation of lesser severity)

Consider – narrow-spectrum antibiotic

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Treatment recommended for SOME patients in selected patient group

International guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend antibiotics for people with acute exacerbations of COPD and an increase in sputum purulence, plus an increase in sputum volume, and/or increased dyspnea.[1]

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).[147]

Some patients with COPD may keep antibiotics at home for use in an exacerbation as part of their self-management plan.[147]

Patients who receive antibiotics are at increased risk for antibiotic-associated diarrhea, compared with placebo, although the difference is not statistically significant.[187] [ ]

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.[188][189][190] When indicated, GOLD recommends that the duration of antibiotic therapy should be 5 to 7 days, but local guidelines should be consulted.[1] More recent guidance from the American College of Physicians recommends limiting antibiotic treatment to 5 days in patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection.[191]

Oral antibiotics should be given first-line if possible, and if the severity of the exacerbation does not necessitate intravenous antibiotics.[1][147] If the patient’s dyspnea and/or sputum purulence improve, this suggests that the antibiotic is effective.[1]

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.[147]

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.[147]

Primary options

amoxicillin: 500 mg orally three times daily

doxycycline: 100 mg orally twice daily

sulfamethoxazole/trimethoprim: 160 mg orally twice daily

azithromycin: 500 mg orally once daily on day 1, followed by 250 mg once daily for 4 days

Secondary options

cefuroxime axetil: 250-500 mg orally twice daily

amoxicillin/clavulanate: 875 mg orally twice daily

clarithromycin: 500 mg orally twice daily

suspected bacterial etiology (exacerbation of greater severity)

Consider – broad-spectrum antibiotic

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Treatment recommended for SOME patients in selected patient group

Some patients with COPD may keep antibiotics at home for use in an exacerbation as part of their self-management plan.[147]

Patients with more severe exacerbations, particularly those requiring treatment in the intensive care unit (ICU), have been shown to derive greater benefit from antibiotic therapy.[77][187] [ ] International guidelines from GOLD recommend that antibiotics should be given to patients with severe exacerbations requiring mechanical ventilation (invasive or noninvasive).[1]

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).[75] 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.[75] Agents with activity against Pseudomonas aeruginosa are also indicated for people at risk of this infection.[37] 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.[1][37] 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.[75]

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.[1]

Patients who receive antibiotics are at increased risk for antibiotic-associated diarrhea, compared with placebo, although the difference is not statistically significant.[187] [ ]

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.[1][144] The most common bacterial pathogens include: Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.[32][37] When indicated, GOLD recommends that the duration of antibiotic therapy should be 5 to 7 days, but local guidelines should be consulted.[1] More recent guidance from the American College of Physicians recommends limiting antibiotic treatment to 5 days in patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection.[191]

If the patient's dyspnea and/or sputum purulence improve, this suggests that the antibiotic is effective.[1] 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.[147]

Fluoroquinolones should be used only when it is considered inappropriate or impossible to use other antibacterial agents that are commonly recommended for the treatment of these infections, due to the risk of serious, disabling, and potentially irreversible adverse effects including tendonitis, tendon rupture, arthralgia, neuropathies, and other musculoskeletal or nervous system effects.[200][201][202] Coadministration of a fluoroquinolone and a corticosteroid should be avoided when possible due to a higher risk of tendon damage.[200]

Primary options

ampicillin/sulbactam: 1.5 to 3 g intravenously every 6 hours

piperacillin/tazobactam: 3.375 g intravenously every 6 hours

vancomycin: 500-1000 mg intravenously every 12 hours

Secondary options

levofloxacin: 500 mg orally/intravenously once daily

ciprofloxacin: 500-750 mg orally twice daily; 400 mg intravenously every 8-12 hours

moxifloxacin: 400 mg orally/intravenously once daily

respiratory insufficiency

Consider – noninvasive mechanical ventilation

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Treatment recommended for SOME patients in selected patient group

Severity depends on the patient's prior status and any changes to previous baseline investigation (based on symptoms, examination, lung function, ABG). 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.[1]

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.[1][112][205][206][207][208][209] [ ] [Evidence B] 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 of 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.[1]

Improvements in the patient's level of dyspnea and physiologic state are typically seen within 1 to 4 hours.[210] The Global Initiative for Chronic Obstructive Lung Disease report recommends that if patients improve and can breathe unassisted for at least 4 hours, then NIV can be stopped.[1]

However, NIV is not successful for all patients, and clinicians should discuss the risks and benefits of invasive mechanical ventilation with patients receiving NIV to determine their desired course of treatment.

Consider – invasive mechanical ventilation

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Treatment recommended for SOME patients in selected patient group

Noninvasive mechanical ventilation (NIV) may fail. 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). [211]

Tracheal intubation: animated demonstration

Bag-valve-mask ventilation: animated demonstration

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.[1][212]

The risk for mortality is significant (11% to 49%) for people with severe disease in whom invasive mechanical ventilation is indicated.[12][213] Complications of mechanical ventilation include ventilator-associated pneumonia and barotrauma.

Weaning patients with severe COPD from mechanical ventilation can be difficult.[211] Use of NIV to assist weaning from mechanical ventilation can reduce weaning failure and nosocomial pneumonia, and may reduce mortality.[214][215]

ONGOING

after stabilization

1st line – pulmonary rehabilitation and disease-management programs

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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.[220][221]

A systematic review that included 13 randomized controlled trials reported reduced mortality and number of readmissions among patients who had pulmonary rehabilitation initiated during hospitalization or within 4 weeks of discharge. Long-term effects on mortality were not statistically significant, but improvements in health-related quality of life and exercise capacity appeared to be maintained for at least 12 months.[1][222] These results have been corroborated by real world evidence in which pulmonary rehabilitation within 90 days of discharge was significantly associated with a lower risk of mortality and fewer rehospitalizations at one year.[1][223][224]

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).[225][226]

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 each patient.

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.[227][228][229]

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.[230][231][232][233][234][235][236][237]

Comprehensive supervised pulmonary rehabilitation in the outpatient setting in the post-exacerbation period also decreases the risk for future hospitalization.[226][233][234][238] Participation in pulmonary rehabilitation within 90 days of discharge following hospitalization for COPD exacerbation is associated with a significant decrease in mortality risk.[224] Unsupervised, home-based exercise training following exacerbations does not appear to confer the same benefits.[239]

Disease management programs can be helpful, but 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, as compared with control patients who were receiving guideline-based routine medical care.[225][240][241][242][243] 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.[239]

Some data is emerging that hospital-at-home care with support from respiratory nurses may be appropriate for selected people with moderate exacerbations of COPD.[244] [ ] 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.[96][245]

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.[246] 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.[247]

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Acute exacerbation of chronic obstructive pulmonary disease

Treatment algorithm

at presentation

Primary options

Primary options

suspected bacterial etiology (exacerbation of lesser severity)

Primary options

Secondary options

suspected bacterial etiology (exacerbation of greater severity)

Primary options

Secondary options

respiratory insufficiency

after stabilization

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