Medication Summary
Medicines available for ED treatment of chronic obstructive pulmonary disease (COPD) include beta2-adrenoceptor agonists, anticholinergics, oxygen, methylxanthines, corticosteroids, some newer experimental classes of medication, and, possibly magnesium.
Terbutaline can be considered for patients with such significant exacerbations that they are not moving enough air to take full advantage of nebulizer therapy.
Beta2-adrenoceptor agonists
These agents are first-line therapy for COPD, both for acute exacerbations and for acute treatment. [11] Bronchodilators are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. [2] Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are better for day-to-day mitigation of the disease. The longer-acting agent, indacaterol, is now approved and allows once-daily dosing. [12]
Combinations of bronchodilators may improve efficacy and reduce risk of adverse effects rather than increasing the dose of a single agent. Keep in mind that, based on several studies, the acute response to short-acting agents does not predict the future response to long-acting agents.
Most of the beta-agonists used are racemic compounds that contain both the R and S enantiomers of the agonist. Much of the pharmacologic activity seems to reside in the R enantiomer, with the S thought to induce the negative side effects. Recently, the R enantiomer of both the short-acting agent albuterol (levalbuterol) and the long-acting agent formoterol (aformoterol) were approved for use in COPD. However, the cost effectiveness of these agents, in light of marginal observed clinical differences, remains controversial and needs further exploration.
Although the major action of beta2-agonists is relaxation of airway smooth muscles, they have also been shown to have several other potential effects. They seem to inhibit airway smooth muscle proliferation and inflammatory mediator release, as well as stimulation of mucociliary transport, cytoprotection of the mucosa, and attenuation of neutrophil recruitment and activation.
Multiple studies have demonstrated enhanced benefits of action when coadministered with inhaled anticholinergics and with corticosteroids.
The greatest single problem that persists in the acute phase is the under dosing of beta-agonists and the nonutilization of anticholinergics. Although only a small subset of patients respond to beta-agonists, a reasonable dose approaches continuous nebulization, as is seen in current asthma treatment.Keep in mind that with larger doses and continuous nebulization, elevated lactate levels are possible (see Workup).
Note that, in mild or moderate exacerbations, the use of MDIs with an aerosol chamber in higher doses (6-12 puffs) can achieve equivalent bronchodilation as the use of a nebulizer. This is particularly important in the office and prehospital setting.
Epinephrine or terbutaline can be administered subcutaneously when intravenous access is not possible or the patient is moving so little air that nebulizer therapy is ineffective. Terbutaline is thought to be safer in older patients, and it has shown to be more efficacious than epinephrine.
Anticholinergics
Anticholinergics have an important role in the acute treatment of COPD exacerbations. The anticholinergics reduce airway tone and improve expiratory flow limitation, primarily by blocking parasympathetic activity in the large and medium-sized airways. They also block the release of acetylcholine, which has been linked to increased bronchial smooth muscle tone and mucus hypersecretion.
These are not as effective as beta-agonists in acute attacks, but they have synergistic properties with the beta-agonists, and the combination of both agents is superior to either by themselves. They act by antagonizing the vagal innervation of the tracheobronchial tree. Vagal tone can be increased by as much as 50% in patients with COPD.
Anticholinergic agents include short-acting agents appropriate for management of acute exacerbations (eg, ipratropium) and long-acting agents (eg, tiotropium, aclidinium, and umeclidinium).
Methylxanthines
These agents (eg, theophylline) increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Despite this, many questions exist as to their true efficacy, and they have no real role in the acute exacerbation of COPD, except to increase the risk of adverse effects. [13] Patients may subjectively feel better, but no data suggest any real change in measureable outcomes or disease progression.
In general, if the patient is already on theophylline and has a subtherapeutic level, a mini-loading dose could be considered but is certainly not considered first-line therapy. If the patient is not on theophylline, the delay before benefit of the oral form makes it not worth using. Intravenous aminophylline has a propensity to cause arrhythmias, especially in a population that already has cholinergic excess coupled with coronary disease.
Phosphodiesterase-4 (PDE-4) inhibitors
Selective PDE-4 inhibitors increase intracellular cyclic adenosine monophosphate (cAMP) and result in bronchodilation. Additionally, they may improve diaphragm muscle contractility and stimulate the respiratory center. Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use as an adjunctive agent.
Antibiotics
These patients are almost uniformly heavily colonized with Haemophilus influenzae, streptococcal pneumonia, and others [3] ; however, researchers have not proven these organisms to be the cause of the exacerbation. In fact, viruses are thought to be the instigating factor in as many as half of the cases.
The particular antibiotic chosen seems to have much less effect on outcome than the particular host factors of the patient in some studies, with other studies suggesting fluoroquinolones are the best strategy. This may really be a factor of the severity of the exacerbation and whether antibiotics are really indicated for minor exacerbations. [14] However, in a retrospective study of 84,621 hospitalized patients, improved outcomes were seen for all patients with COPD with early antibiotic treatment regardless of disease severity. [15]
If antibiotics are given, the choice should provide coverage against pneumococcus, H influenzae,Legionella species, and gram-negative enterics.
Daniels et al conducted a randomized, placebo-controlled trial that compared the addition of doxycycline to corticosteroids on clinical outcome in patients hospitalized with acute exacerbation of COPD (n=223). [16] In addition to clinical outcome, other parameters were measured, including microbiological outcome, lung function, and systemic inflammation. The 223 patients enrolled in the study represented 265 COPD exacerbations. In addition to systemic corticosteroids, patients received either doxycycline 200 mg or placebo for 7 days. Results at 30 days were similar between the 2 groups. At 10 days, the doxycycline group showed superiority for clinical success compared with placebo in the intention-to-treat arm but not in the per-protocol arm. Also at day 10, doxycycline was superior for clinical cure, microbiological outcome, use of open label antibiotics, and symptoms.
In cases of severe acute exacerbations of chronic bronchitis (AECB), guidelines suggest using fluoroquinolone antibiotics as first-line therapy. [17, 18] This suggestion is based on level I evidence from several trials that show clinical and microbial superiority of these agents.
Use of fluoroquinolones has also been shown to shorten hospital stay, reduce recurrences, and lower costs.
Fortunately, resistance to these agents is still very low, and reserving them for use in populations at risk should preserve their effectiveness for some time. Be aware of the potential for complications with Clostridium difficile colitis, QT prolongation, and musculoskeletal damage from fluoroquinolones, especially in this patient group.
Magnesium
Though controversial, administration of magnesium is thought to produce bronchodilation through the counteraction of calcium-mediated smooth muscle constriction. The addition of intravenous magnesium is now considered to have class B evidence supporting its use in difficult and life-threatening exacerbations.
Heliox
Heliox usually is a 60:40 mixture of helium and oxygen. Helium is a smaller particle than oxygen and in small airways promotes laminar flow and facilitates both oxygen transport and carbon dioxide diffusion. Many patients who seem to breathe better on Heliox return to a worsened respiratory state when removed from Heliox.
Because of helium's low density, some class B evidence now exists for its use as the medium to drive nebulizer therapy. In theory, a mixture of helium and oxygen could improve gas exchange in patients who have an airway obstruction. In the realm of COPD exacerbations, however, the evidence is more slight, and more investigation is needed.
Leukotriene receptor antagonists
Intravenous leukotriene receptor antagonists have been shown to have benefit in asthma in limited studies, but, at this time, they have no role in COPD exacerbations.
Corticosteroids
These also have bronchodilatory properties, although they primarily act by decreasing inflammation in the tracheobronchial tree. Although 8-12 hours are required for full effect, corticosteroids should be administered in the ED, as some mild improvements may be noted much earlier.
Bronchodilators
Class Summary
These agents act to decrease muscle tone in both small and large airways in the lungs, thus increasing ventilation. The category includes beta2-adrenergic agonists, methylxanthines, and cholinergic/muscarinic antagonists. Note that only 10-15% of all patients with COPD have a true reversible (ie, bronchospastic) component; however, because predicting response is impossible on presentation, all patients should be treated with aggressive bronchodilator therapy.
Terbutaline (Brethaire, Bricanyl)
Terbutaline acts directly on beta2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Albuterol (Proventil)
Albuterol is a beta-agonist useful in the treatment of bronchospasm. This drug selectively stimulates the beta2-adrenergic receptors of lungs. Bronchodilation results from relaxation of bronchial smooth muscle, which relieves bronchospasm and reduces airway resistance. Note that prior use of long-acting agents, such as salmeterol, does not seem to compromise the response to albuterol during acute attacks.
Use a 5-mg/mL solution for nebulization; it is usually underdosed in acute settings. Many studies have demonstrated that high-dose therapy is most efficacious. The goal is continuous therapy in the initial treatment phase. Note that a properly used MDI with a spacer is equal in effectiveness to nebulized therapy.
Theophylline (Theo-Dur, Slo-bid, Theo-24)
Theophylline acts to increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. It acts partly by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle.
However, clinical efficacy is controversial, especially in the acute setting. This author advocates this medicine only if the patient was taking medicine already and had a subtherapeutic level. Do not give the intravenous form (aminophylline) because it can precipitate arrhythmias, especially in patients such as these who are already in an excess-catecholamine state. Measure the serum level to adjust the dose.
Note that most recent meta-analyses and other literature have failed to show a benefit from the use of methylxanthines in acute exacerbations.
Ipratropium bromide (Atrovent)
The ipratropium bromide dose can (and should) be mixed with the first beta-agonist nebulizer because it can take up to 20 minutes to begin having an effect. Controversy exists regarding the efficacy of ipratropium, but it still should be part of the total treatment picture. It is available as a nebulized solution and a metered-dose inhaler. It is an anticholinergic medication that appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, specifically with the muscarinic receptor on bronchial smooth muscle. Vagal tone can be increased by as much as 50% in patients with COPD, so this can have a profound effect.
Albuterol/ipratropium (Combivent Respimat)
Ipratropium is chemically related to atropine. It elicits antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.
Albuterol is a beta2-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.
Tiotropium (Spiriva)
Tiotropium is not a rescue inhaler. It is indicated as maintenance treatment for COPD. Tiotropium is a long-acting, once-daily quaternary ammonium compound. It elicits anticholinergic/antimuscarinic effects with inhibitory effects on M3receptors on airway smooth muscles, leading to bronchodilation. It is available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. It helps patients with COPD by dilating narrowed airways and keeping them open for 24 hours.
Aclidinium (Tudorza Pressair)
Aclidinium is not a rescue inhaler. Aclidinium is a twice-daily, long-acting selective muscarinic (M3) antagonist (anticholinergic) indicated for long-term maintenance of COPD including bronchitis and emphysema. It is available as breath-activated, dry powder metered-dose inhaler.
Salmeterol (Serevent Diskus)
Salmeterol is not a rescue inhaler. It is indicated as maintenance treatment for COPD. It is a long-acting beta2-agonist. By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasms. Its effect also may facilitate expectoration.
Salmeterol has been shown to improve symptoms and morning peak flows. It may be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents.
When administered at high or more frequent doses than recommended, the incidence of adverse effects is higher. The bronchodilating effect lasts more than 12 hours. It is used on a fixed schedule in addition to regular use of anticholinergic agents.
Indacaterol, inhaled (Arcapta Neohaler)
Inhaled indacaterol is not a rescue inhaler. It is a long-acting beta2-agonist (LABA) indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. LABAs act locally in the lungs as bronchodilators. It stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle. It is not for use as initial therapy in patients with acute deteriorating COPD.
Umeclidinium bromide/vilanterol inhaled (Anoro Ellipta)
Umeclidinium bromide and vilanterol is a long-acting muscarinic antagonist (LAMA) and LABA inhalation powder. It is the first once-daily dual bronchodilator approved. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema.
Indacaterol, inhaled/glycopyrrolate inhaled (Utibron Neohaler)
This agent contains glycopyrronium, which is a LAMA that produces bronchodilation by inhibiting acetylcholine’s effect on the muscarinic receptor in the airway smooth muscle. It also contains indacaterol, a LABA that stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP, and thereby relaxes bronchial smooth muscle. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema.
Glycopyrrolate inhaled (Breztri, Lonhala Magnair, Seebri Neohaler)
This agent contains glycopyrronium, which is a LAMA that produces bronchodilation by inhibiting acetylcholine’s effect on the muscarinic receptor in the airway smooth muscle. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Seebri Neohaler is available as an encapsulated powder for inhalation that is used with the Neohaler device. Lonhala Magnair is available as a solution for nebulization used with the Magnair device.
Corticosteroids
Class Summary
These agents have been shown to be effective in accelerating recovery from acute COPD exacerbations. Although they may not make a clinical difference in the ED, they have some effect by 6-8 hous into therapy; therefore, early dosing is critical.
Some newer studies are suggesting that inhaled corticosteroids (eg, nebulized budesonide) may be equally effective as intravenous or oral steroids in the mild-to-moderate exacerbation. In addition, level B evidence suggests that the addition of inhaled corticosteroids to oral agents at discharge may be very beneficial.
Methylprednisolone (Solu-Medrol, Medrol)
Methylprednisolone is usually given in intravenous form in the ED for initiation of corticosteroid therapy, although the oral form theoretically is equally efficacious. The two forms are equal in potency, time of onset, and adverse effects. Inhaled corticosteroids are probably equally efficacious and have fewer adverse effects for patients discharged from ED.
Phosphodiesterase-4 Inhibitors
Class Summary
Selective phosphodiesterase-4 (PDE-4) inhibitors reduce exacerbations, improve dyspnea, and increase lung function in patients with severe COPD.
Roflumilast (Daliresp)
Roflumilast is a selective phosphodiesterase-4 (PDE-4) inhibitor. The specific mechanism of action is not well defined but is thought to be related to the effects of increased intracellular cyclic AMP in lung cells. It is indicated to decrease the frequency of exacerbations or the worsening of symptoms from severe COPD.
Electrolyte supplements
Class Summary
Magnesium is used to replenish stores that become depleted in periods of adrenergic excess such as asthma attacks, COPD exacerbations, and diuretic use.
Magnesium sulfate
Magnesium sulfate is thought to produce bronchodilation through the counteraction of calcium-mediated smooth muscle constriction. Again, for every study showing a positive finding, probably another shows no benefit, but given properly, magnesium is safe and may have some benefit.
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Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.
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Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered view).
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Posteroanterior (PA) and lateral chest radiograph in a patient with severe chronic obstructive pulmonary disease (COPD). Hyperinflation, depressed diaphragms, increased retrosternal space, and hypovascularity of lung parenchyma is demonstrated.
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Chronic obstructive pulmonary disease (COPD). A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on lateral chest radiograph.
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Chronic obstructive pulmonary disease (COPD). A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on posteroanterior chest radiograph.
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Subcutaneous emphysema and pneumothorax.
