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An Assessment of Therapeutic Regimens in the Treatment of Acute Exacerbations in Chronic Obstructive Pulmonary Disease and Asthma
Grant H. Skrepnek, PhD, RPh; and Stan V. Skrepnek, MD
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An Assessment of Therapeutic Regimens in the Treatment of Acute Exacerbations in Chronic Obstructive Pulmonary Disease and Asthma

Grant H. Skrepnek, PhD, RPh; and Stan V. Skrepnek, MD

Acute exacerbations in chronic obstructive pulmonary disease (COPD) and asthma are potentially life-threatening clinical events that may result in substantial morbidity and mortality. Treatment of these episodes requires the rapid reversal of airway obstruction by decreasing bronchoconstriction and inflammation. Consensus guidelines and recommendations build on stepwise approaches to care, with the mainstay of therapeutic interventions involving brochodilators and often including systemic corticosteroids, oxygen, and other treatments, depending on severity and setting. Future therapies that target inflammatory processes may offer improved efficacy and potential disease-modifying effects. The purpose of this article is to assess the treatment options for acute exacerbations in COPD and asthma within the scope of current consensus guidelines and recommendations (eg, Global Initiative for Chronic Obstructive Lung Disease, National Asthma Education and Prevention Program, Global Initiative for Asthma). Although bronchodilators and corticosteroids are the primary therapies discussed, antibiotics, oxygen, magnesium sulfate, noninvasive positive pressure ventilation, and helium/oxygen mixtures are also addressed. Preventive approaches for future exacerbations are considered in the overall approach to achieve optimal outcomes.

(Am J Manag Care. 2004;10:S139-S152)

Exacerbations in chronic obstructive pulmonary disease (COPD) and asthma account for a substantial clinical and economic burden and are often associated with events that ultimately result in morbidity and mortality.1 As such, guidelines in the overall treatment of both COPD and asthma offer specific recommendations for the management of these acute episodes. The more recent guidelines for the treatment of COPD published by the National Heart, Lung, and Blood Institute of the National Institutes of Health and the World Health Organization's (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD), the American College of Physicians-American Society of Internal Medicine, and the American College of Chest Physicians (ACCP) are based on expert panel consensus and empirical evidence.2,3 Although numerous other recommendations have been developed, more recent consensus guidelines for asthma have been developed by the National Asthma Education and Prevention Program (NAEPP) at the NHLBI and through collaborative efforts between NHLBI/WHO's Global Initiative for Asthma (GINA).4-9

Treatment regimens for acute exacerbations generally follow stepwise approaches to therapy with the goals of rapidly reducing airway obstruction and restoring or maintaining lung function. Achieving optimal clinical outcomes through therapeutic approaches requires the consideration of patient characteristics and risk factors, failure of initial treatment, treatment setting, and the severity of the exacerbation itself. Pharmacotherapeutic interventions emphasize the use of bronchodilators, although systemic corticosteroids, oxygen, and numerous other agents may be considered. Prevention and risk-factor modification remain of key importance in long-term care. Many therapies that target underlying inflammatory processes are in development and may offer disease-modifying strategies to reduce the number of substantially premature deaths and hospitalizations while improving quality of life in patients with COPD or asthma.

Given the importance of managing COPD and asthma, the purpose of this article is to assess the treatment options for exacerbations within the scope of current consensus guidelines and recommendations. Although an emphasis is placed on the management of these acute events, preventive approaches and future treatments are also highlighted. Providing important background for this discussion, the epidemiology, clinical and economic burden of illness, and clinical presentation of COPD and asthma have been discussed elsewhere in this supplement.1 The discussion offered herein establishes insight into relevant material; consensus recommendations and additional sources should guide clinical decision making. Many facets beyond exacerbations are important to the management of COPD and asthma, although these issues are beyond the scope of this article.

General Considerations of Acute Exacerbations in COPD and Asthma

Guidelines for COPD. Several factors must be considered before treating COPD exacerbations. The first is determining the appropriate setting to establish intervention (eg, outpatient, emergency department, hospital admission).10 Exacerbations are managed by improving airway obstruction by reducing inflammation and bronchoconstriction while promoting mucociliary clearance.11 Comorbid conditions or problems that may precipitate respiratory worsening or failure must also be addressed; if hypoxemia has manifested, it should be rectified.12 The severity of the exacerbation, treatment failures, comorbidities, and underlying disease characteristics will determine treatment options and the setting in which it is administered.13 Careful observation concerning underlying and evolving pulmonary function, particularly in response to therapy, is helpful in determining the need for hospital admission. Outpatient regimens may involve bronchodilators, systemic corticosteroids, and antibiotics; again, a stepwise approach is generally recommended.14-17 Guidelines for hospital care also consider oxygen therapy and potential mechanical ventilation.2 Establishing preventive measures to decrease the likelihood of future exacerbations is a final consideration.

Four aspects of COPD management offered by GOLD involve assessing and monitoring COPD, reducing risk factors, managing stable COPD, and managing exacerbations.2 The algorithm for treating acute exacerbations of COPD in outpatient settings appears in Figure 1; the Table outlines the general considerations of inpatient treatment.

Guidelines for Asthma. GINA recommends that asthma management involve establishing and maintaining control of symptoms, preventing exacerbations and adverse effects of medications, maintaining lung function and normal activity levels, and preventing irreversible airflow limitations and mortality.6 The restoration of lung function and the rapid improvement of both airway obstruction and hypoxia are critical treatment goals for acute exacerbations.6 Treatment approaches for these acute cases across guidelines follow stepwise approaches that add additional therapeutic measures when considering the severity of exacerbation; outpatient management emphasizes increasing short-acting β2-agonist use and monitoring the response to initial treatment.18 According to the NAEPP, GINA, and other experts, the primary management of exacerbations within inpatient settings involves increasing the frequency of inhaled short-acting β2-agonists, adding systemic corticosteroids, and using oxygen supplementation.4-6,19-21 In instances when exacerbations are resistant to initial treatment or are severe in nature, hospital- or emergency departmentóbased monitoring and treatment are recommended.6 NAEPP emphasizes the importance of early intervention in asthma exacerbations and directing special attention toward patients at high risk for asthma-related mortality.4 Consideration is also placed on reducing the probability of recurrent severe exacerbations and developing written plans to aid in guiding the early management of future exacerbations.

Although NAEPP and GINA generally coincide, clinicians should be aware that certain nuances exist between the 2 guidelines. Recommendations for outpatient management stipulate that the frequency of an inhaled short-acting β2-agonist be increased and that continued intensive treatment should be carried out for several days based on severity and response.5 Figure 2 presents the most recent guidelines from GINA on the home management of asthma exacerbations, whereas Figure 3 focuses on hospital management. More important, development of specific treatment algorithms in acute care settings has been shown to improve patient outcomes and decrease resource consumption.22 A caveat of care in acute asthma involves the use of sedatives; use of these agents is generally contraindicated because of potential respiratory depression and increased mortality.5,23,24 Clinicians treating severe cases that require mechanical ventilation and the use of sedatives are directed toward appropriate references for additional information for monitoring and intervention.5,6,25

Therapeutic Considerations in Management and Treatment

Bronchodilators. The primary therapy for overall COPD and related exacerbations is inhaled bronchodilator therapy.2,14,15,26 Bronchodilators recommended specifically for COPD exacerbations include short-acting β2-agonists (eg, albuterol, levalbuterol, bitolterol, pirbuterol) and anticholinergics (eg, ipratropium bromide). Outpatient management typically involves increasing the dose and/or frequency of agents prescribed to the patient, whereas inpatient therapy relies on short-acting β-agonists by GOLD standards.2 A meta-analysis indicated that no significant differences in improved forced expiratory volume in 1 second (FEV1) were noted in COPD exacerbations between the β2-agonists and ipratropium, although the β2-agonists that were included may have worsened the arterial blood gas profile in the hours immediately following initial patient presentation.27 Delivery via a metered dose inhaler (MDI) and spacer has been reported to produce similar effects as nebulization, although certain studies specific to asthma have noted that MDIs with a spacer may provide a more rapid onset to lessen time spent in emergency departments.28-30 The use of long-acting β2-agonists (eg, salmeterol, formoterol) is generally reserved for maintenance treatment of COPD.2,31,32 Taken from Bach and colleagues,33 the following was concluded in their review of 14 randomized trials concerning bronchodilator use in COPD:

"Short-acting β-agonistótype and anticholinergic-type inhaled bronchodilators have similar effects on spirometry and a greater effect than all parenterally administered bronchodilators (ie, parenteral methylxanthines and sympathomimetics); the toxicity profile of the methylxanthine agents makes them potentially harmful; and some patients may experience additional benefits when a second bronchodilating agent is administered after the maximal dose of the initial inhaled bronchodilator is reached."33

Tiotropium bromide, a long-acting muscarinic receptor M1- and M3-selective anticholinergic agent, has demonstrated in international clinical trials improved efficacy relative to ipratropium as well as salmeterol in the treatment of stable COPD.34-37 Decreases in exacerbations in COPD have been observed with the once-daily dosed medication.38,39 Given the long-acting nature of tiotropium, however, its use in the emergent care of acute exacerbations of either COPD or asthma has yet to be established. Currently, no newer short-acting anticholinergic agents are in an advanced development phase.40

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