Chronic Obstructive Pulmonary Disease and Emphysema in Emergency Medicine Medication

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.^[6] Bronchodilators are given on an as-needed basis or on a regular basis to prevent or reduce symptoms.^[3] 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. Even longer-acting agents, which would allow once-daily dosing, are in development.
  • 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.
  • 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.
• 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.
  • Two anticholinergic agents are available at this time, a short-acting agent appropriate for management of acute exacerbations (ipratropium) and a long-acting agent (tiotropium).
• Methylxanthines: These agents 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.^[7]
• Phosphodiesterase inhibitors: In theory, phosphodiesterase inhibitors would work to selectively inhibit of phosphodiesterase to cause smooth muscle relaxation and anti-inflammatory effects. These agents would have a better safety profile than the methylxanthines, but they are all still in various stages of development.
• Antibiotics

  • These patients are almost uniformly heavily colonized with Haemophilus influenzae, streptococcal pneumonia, and others;^[2] 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.^[8] 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.^[9]
  • 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).^[10] 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.
• 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: 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.

Class Summary

These agents act to decrease muscle tone in both small and large airways in the lungs, thus increasing ventilation. Category includes subcutaneous medications, beta-adrenergic agonists, methylxanthines, and anticholinergics. 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)

Acts directly on beta2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.

Albuterol (Proventil)

Beta-agonist useful in treatment of bronchospasm. Drug selectively stimulates 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 response to albuterol during acute attacks.

Use 5 mg/mL solution for nebulization; usually underdosed in acute settings. Many studies have demonstrated that high-dose therapy is most efficacious. Goal is continuous therapy in initial treatment phase. Note that properly used MDI with spacer is equal in effectiveness to nebulized therapy.

Theophylline (Theo-Dur, Slo-bid, Theo-24)

Acts to increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Acts partly by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in bronchi, resulting in relaxation of smooth muscle.

However, clinical efficacy is controversial, especially in acute setting. Author advocates this medicine only if patient was taking medicine already and had subtherapeutic level. Do not give IV form (aminophylline) because it can precipitate arrhythmias, especially in patients such as these who are already in an excess catecholamine state. Measure serum level to adjust 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)

Anticholinergic medication that appears to inhibit vagally mediated reflexes by antagonizing action of acetylcholine specifically with 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.

Dose can (and should) be mixed with first beta-agonist nebulizer because it can take up to 20 min to begin having effect. Admitted controversy exists regarding efficacy of ipratropium, but it still should be part of total treatment picture.

Ipratropium and albuterol (Combivent)

Ipratropium is chemically related to atropine. Has anti-secretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa.

Albuterol is a beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Recommended to "test spray" 3 times before using the first time and in cases where the aerosol has not be used for >24 h.

Tiotropium (Spiriva)

A quaternary ammonium compound. Elicits anticholinergic/antimuscarinic effects with inhibitory effects on M₃ receptors on airway smooth muscles, leading to bronchodilation. Available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. Helps patients with COPD by dilating narrowed airways and keeping them open for 24 h.

Salmeterol (Serevent Diskus)

By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasms. Effect also may facilitate expectoration.

Shown to improve symptoms and morning peak flows. 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, incidence of adverse effects is higher. The bronchodilating effect lasts >12 h. Used on a fixed schedule in addition to regular use of anticholinergic agents.

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 h into therapy; therefore, early dosing is critical.

Some newer studies are suggesting that inhaled corticosteroids (eg, nebulized budesonide) may be equally effective as IV or PO 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)

Usually given in IV form in ED for initiation of corticosteroid therapy, although PO form theoretically equally efficacious. Two forms equal in potency, time of onset, and adverse effects. Inhaled corticosteroids probably equally efficacious and have fewer adverse effects for patients discharged from ED.

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

Thought to produce bronchodilation through counteraction of calcium-mediated smooth muscle constriction. Again, for every study showing positive finding, probably another shows no benefit, but given properly, magnesium is safe and may have some benefit.