Asthma Nursing CE Course for RNs and LPNs Part 3: The Assessment and Pharmacological Treatment of Mild-to-Moderate Asthma Nursing CE Course

ICS is the primary controller medication used in both algorithms for persistent asthma. They function by reducing bronchial inflammation, preventing exacerbations, and often relieve cough (Bostantzoglou et al., 2015). They were first developed in 1973 due to the significant side effects seen with systemic steroids (de Groot et al., 2015). They are traditionally dosed daily or BID regardless of symptoms. Thrush is a common side effect of ICS, but the risk of thrush can be reduced significantly with diligent oral hygiene after medication administration and the use of a spacer or chamber (see Figure 1 below), which also helps with medication delivery when using a metered-dose inhaler (MDI) (NHLBI, n.d.). In older patients, ICS may also increase the rate of bone mineral loss and cause skin thinning, bruising, and adrenal suppression (Bostantzoglou et al., 2015). GINA guidelines recommend a lower dose of ICS earlier, as opposed to a higher dose, with greater side effects, later. They indicate that an increase in FEV₁ should be seen within days of starting ICS and usually plateaus in roughly two months, while PEF readings usually increase to PB level after about two weeks of treatment, with variability diminishing after three months of treatment. They also list nasal spray corticosteroid as an alternative in patients with allergic rhinitis and a proven allergy in lieu of ICS (GINA, 2018). Eosinophilic asthmatics typically require a higher dose of ICS for inflammation management, regardless of what may seem like acceptable symptom control (Bostantzoglou et al., 2015). In some patients, because inflammation can affect the entire respiratory tract, ICS may be insufficient. Systemic steroids carry with them significantly greater adverse effects (de Groot et al., 2015). 

Intermittent ICS dosing is defined as varying in dose, frequency, or duration of administration, such as initiating a temporary course of ICS or temporarily increasing the dose. An executive summary in preparation for the upcoming update to EPR-3 regarding intermittent ICS use and LAMA use was published by Sobieraj et al. (2017) regarding the efficacy of intermittent ICS use by age group. In patients aged four and under with recurrent wheezing, they found intermittent ICS use with SABA (vs. SABA alone) reduced the risk of exacerbation requiring oral steroids based on moderate strength of evidence and improved QOL based on low strength of evidence. In these same patients, intermittent ICS was found to reduce the risk of exacerbation requiring oral steroids, hospitalization, or rescue medication use versus regularly scheduled ICS controller use. In patients age 5-11 with persistent asthma, they found intermittent ICS use did not affect QOL or rescue medication use versus ICS controller use based on low strength of evidence, and there was insufficient evidence to assess the effect on the other outcomes in this age group. In patients with persistent asthma aged 12 and older, they found that the use of intermittent ICS dosing, either alone or with ICS controller dosing, versus ICS controller dosing alone, was found not to affect the risk of exacerbation based on low strength of evidence. However, the use of intermittent and controller ICS versus controller dosing alone was found to decrease the number of asthma-related outpatient visits based on low strength of evidence (Sobieraj et al., 2017).

Typically, the second controller medication introduced in the third step of both algorithms discussed above is a LABA such as salmeterol (Serevent, Advair), vilanterol (Breo Ellipta) or formoterol (Perforomist, Symbicort, Dulera). These work as bronchodilators by relaxing the smooth muscles that surround the airway by selectively stimulating ß-2 adrenergic receptors. Vilanterol’s (Breo Ellipta) half-life is 16-21 hours (allowing once-daily dosing) with an onset of about 10 minutes, formoterol's (Perforomist, Symbicort, Dulera) half-life is 10 hours with an onset of fewer than five minutes, and salmeterol's (Serevent, Advair) half-life is just 5.5 hours with an onset of about 15 minutes.  They should not be used as monotherapy, but always in conjunction with ICS, and (other than formoterol) not for acute symptom relief. They work especially well in patients with a lot of wheezing, SOB, and nocturnal symptoms or those patients found to be in the non-eosinophilic clinical phenotype characterized by severe symptoms but minimal inflammation (Bostantzoglou et al., 2015; Lynn & Kushto-Reese, 2015; NHLBI, 2012). ICS/LABA, as the initial maintenance controller treatment, has been shown to reduce symptoms and improve lung function but does not reduce the risk of exacerbation and is more expensive than ICS alone (GINA, 2018). 

In 2018, the NEJM published a compilation study regarding the safety of LABA based on the four large prospective randomized controlled clinical trials mandated by the FDA. These trials compared ICS with a combination of ICS and LABA in over 36,000 patients. The combination of LABA and ICS was not found to increase the risk of hospitalization, intubation, or death, but did show a decreased relative risk for exacerbation. Unfortunately, this decrease in risk was not universal as it was not seen as strongly in adolescents, African Americans, or Asian Americans. Despite the lack of clear evidence that this combination is dangerous, there remains a Black Box warning on all ICS-LABA combination products that patients should be made aware of (Busse et al., 2018). 

In the GINA treatment guidelines (2018), low-dose ICS-formoterol (Symbicort, Dulera) is listed below steps 3-5 as an option for reliever medication. This method, they report, has been shown to reduce exacerbations and hospitalizations in patients over the age of 11 (and likewise in patients 4-11, but they remark that this practice is not approved for this age group in many countries) (GINA, 2018). This newer treatment concept that has emerged recently in asthma is termed single maintenance and reliever therapy (SMART) (Sobieraj et al., 2018b). It is also referred to as maintenance and reliever therapy (MART), dynamic dosing, or adjustable maintenance dosing (AMD) (Dinakar et al., 2014; Tang et al., 2018). The basic concept is as follows: the traditional instructions to asthma patients involve one or two inhalers for daily control/maintenance, and separate reliever medication in another inhaler to be used PRN. Alternatively, the SMART method instructs patients to utilize one inhaler, a combination of ICS and formoterol, which is a rapid-onset LABA, for both maintenance and PRN symptom control. Dinakar et al. (2014) discussed this concept as a recommended strategy in adult patients with mild to moderate asthma to both avoid and exit from a state of increased asthma symptoms, termed the "yellow zone". They recommended the use of a single inhaler, containing both ICS and a LABA, as they found this to be the most convenient for the patient as well as the most well-studied. They did not believe this would be advisable in children or severe asthmatics. They also pointed out that this method of dosing is currently considered off-label in the US (Dinakar et al., 2014). Sobieraj et al. (2017) discussed this strategy within the executive summary regarding intermittent ICS use and LAMA use. They found in patients age 5-11 with persistent asthma, the use of SMART versus ICS and LABA as controller medication versus a higher ICS controller dose reduced the risk of exacerbation. In patients with persistent asthma over the age of 11, when compared with regularly scheduled ICS controller dosing, they found that the use of SMART reduced the risk of exacerbation and improved spirometry results, as well as reducing the use of rescue medication. When SMART was compared with ICS controller medication at a higher dose, there was still a reduced risk of exacerbation in the SMART group. When SMART was compared with ICS plus LABA as controller medication, they found a reduced risk of exacerbation, improved asthma control scores, and reduced use of reliever medication. When SMART was compared with ICS plus LABA as controller medication at a higher ICS dose, they again found a reduced risk of exacerbations in the SMART group. Finally, when they compared the outcomes of patients using SMART versus the conventional best practices of ICS as a controller medication with or without LABA, they found a reduced risk of exacerbation, reduced use of reliever medication, and improved asthma control scores in the SMART group (Sobieraj et al., 2017).  

Tang et al. (2018) point out that while up to 70% of asthma patients are categorized as mild, between 40-50% of these are uncontrolled, and 25% have had a severe exacerbation in the last 12 months. They postulated that this is due to an overreliance on SABA, which is likely secondary to a combination of the comfort level of the patient's first medication and the quick symptom relief it provides. They found that if SMART therapy is utilized in mild asthma patients, it leads to fewer exacerbations, as well fewer hospitalizations and ED visits secondary to reduced inflammation (which SABAs do not affect), improved adherence, and overall less exposure to corticosteroids (Tang et al., 2018). Finally, a systematic review and meta-analysis of SMART therapy using budesonide/formoterol (Symbicort) in dry powder inhaler (DPI) All studies included the use of SABA as reliever medication in the control group. Amongst patients over the age of 11, they found a significantly reduced risk of exacerbation compared with ICS-LABA controller use, even when a higher dose of ICS was used in the control group. Similar results were seen when SMART was compared with ICS alone as a controller medication, either at the same or at higher doses. Amongst the 341 patients ages 5-11, they saw the same reduced risk of exacerbation but based on a smaller sample size (Sobieraj et al., 2018b). 

EPR-3 (NHLBI, 2012) and GINA (2018) guidelines both list leukotriene modifiers such as montelukast (Singulair), zafirlukast (Accolade), or zileuton (Zyflo) as alternative options for persistent asthma treatment in patients age five and above. They are available as once-daily oral tablets, and montelukast (Singulair) is also available in a granule packet. They work by blocking the leukotriene portion of the inflammatory cascade (NHLBI, n.d.). GINA specifies that these oral medications may be an appropriate daily controller choice in patients who experience intolerable adverse effects related to ICS or who may have concomitant allergic rhinitis as well as an alternative in EIB. It is an alternative adjunct with ICS but has been shown to be less effective than adding LABA. It can also be considered an optional adjunct therapy in patients with aspirin-sensitive asthma (GINA, 2018). EPR-3 (NHLBI, 2012) specifies that montelukast (Singulair) may be used in children as young as one year, while zafirlukast (Accolade) should not be used in patients under five and zileuton (Zyflo) should not be used in patients under 12. They further specify that both zafirlukast (Accolade) and zileuton (Zyflo) require liver function monitoring regularly. Zileuton (Zyflo) also has a slightly different mechanism of action, working as a 5-lipoxygenase inhibitor to interfere with leukotriene formation while montelukast (Singulair) and zafirlukast (Accolade) both function as selective leukotriene receptor antagonists (LTRAs). They also suggest LTRAs as an alternative in the treatment of EIB (NHLBI, 2012). 

Tiotropium bromide (Spiriva) was FDA approved in 2014 as the only LAMA for use in asthma patients over the age of 11 in the US (although others are approved for the treatment of COPD). It functions as an antagonist to acetylcholine receptors, causing bronchodilation, with a half-life of 25 hours. GINA states that in adolescent or adult patients with a history of exacerbations not well-controlled on low-dose ICS and LABA, the addition of tiotropium (Spiriva) can be considered as the fourth step (GINA, 2018). Sobieraj et al. (2017, 2018a) found that in patients over the age of 11 with uncontrolled persistent asthma, the addition of LAMA to ICS versus placebo decreased the risk of exacerbation and improved spirometry results, and results of LAMA combined with ICS was equivalent to doubling the dose of ICS or the combination of ICS and LABA. Finally, they reviewed what they termed "triple treatment", which included ICS, LABA, and LAMA and found that the addition of LAMA improved FEV₁ and asthma control or QOL scores but saw no significant effect on risk of exacerbation or hospitalization (Sobieraj et al., 2017, 2018a). 

Theophylline (Theo-24) is an oral medication that functions by antagonizing adenosine receptors and increasing cyclic adenosine monophosphate (cAMP), thereby causing bronchodilation. It can be especially helpful with nocturnal symptoms (Lynn & Kushto-Reese, 2015). It is limited in its utility by the necessity of checking serum drug levels periodically to ensure a therapeutically appropriate serum concentration (NHLBI, n.d.). EPR-3 (NHLBI, 2012) recommends theophylline (Theo-24) as an alternative or an adjunct treatment in steps 2-6. It is available in liquid, capsule, or sustained-release tablet form (NHLBI, 2012). GINA guidelines (2018) offer theophylline (Theo-24) as an alternative initial controller medication in adolescents and adults with initial presentation of asthma symptoms and/or SABA use more than twice weekly but note that this is typically less effective than low-dose ICS. They also mention the use of short-acting theophylline (Theo-24) as a reliever medication but note that it has a slower onset of action than most other SABAs and a higher risk of adverse effects. GINA guidelines do not recommend its use in children and warn that it may worsen GERD symptoms via relaxation of the lower esophageal sphincter (GINA, 2018). 

Cromolyn sodium (Intal) is an anti-inflammatory medication that is delivered via nebulizer, which functions as a mast cell stabilizer, blocking the cellular response to inhaled antigens that can trigger asthma exacerbations. A significant limitation of cromolyn (Intal) is the need for a nebulizer and the need to be dosed four times daily in order to be effective. It is listed in EPR-3 as an alternative controller medication in mild persistent asthmatics, but not recommended in children under two. It is also one of the options that may be used to pre-treat EIB prior to exercise (NHLBI, 2012). Notably, there was no mention of the use of cromolyn (Intal) or other mast cell stabilizers in GINA (2018).

Reliever Medications

Reliever or rescue medications are used to treat asthma exacerbations or sudden onset of symptoms on an as-needed basis. Albuterol (Pro-Air, Ventolin) and levalbuterol (Xopenex) are bronchodilators that selectively stimulate ß-2 adrenergic receptors, similar to the previously mentioned LABAs, relaxing the airway smooth muscles. Their half-life is 2.7-6 hours. Both are available as MDIs or can be used in nebulizers, and albuterol (Pro-Air, Ventolin) can also be found in oral tablet form, extended-release oral tablet, or liquid syrup. Terbutaline (Bricanyl) is a SABA that is available in tablet form as well as a subcutaneous injection with a half-life of three to four hours. It is approved for use in patients over the age of five up to three times per day. EPR-3 and GINA guidelines suggest the use of SABAs like albuterol (Pro-Air, Ventolin) on an as-needed basis in patients with mild intermittent asthma. Formoterol (Perforomist, Symbicort, Dulera), as mentioned above, is a quick-onset but long-acting ß-agonist with a 10-hour half-life. Ipratropium bromide (Atrovent) is a SAMA that creates bronchodilation by antagonizing acetylcholine receptors. It has a half-life of two hours and is available as a nebulizer solution that can be mixed with Albuterol (Pro-Air, Ventolin) or levalbuterol (Xopenex) or an MDI that can be used independently. Both guidelines suggest utilizing the patient’s report of reliever use frequency to help gauge the level of symptom control in asthma patients (GINA, 2018; NHLBI, 2012). 

Asthma Action Plan

A crucial component of comprehensive care, an AAP serves as a patient’s road map for the management of symptoms at home on a daily basis. In 2014, Dinakar et al. discussed the use of the AAP in the management of acute loss of control, termed the "yellow zone". AAPs utilize a traffic light analogy, and thus the yellow zone is a loss of control that is mild or moderate in nature and not severe enough to require an ED visit. An AAP helps the patient monitor their symptoms and their lung function to first identify where they are in the plan (green, yellow, or red zone) and the appropriate actions to take based on that self-assessment. They recommend that all asthma patients, regardless of age, be given a written or electronic AAP that is reviewed, and if needed, edited or updated at each follow-up visit. They define the green zone as less than two days per week of symptoms (cough, wheeze) or reliever medication use. They define the yellow zone as an increase in symptoms, increased use of reliever medication, a PEF reading that is decreased 15% from previous readings or less than 80% of PB, or the presence or increase in nocturnal symptoms. SABA use should be initiated if the patient finds themselves in the yellow zone at two to four puffs every four to six hours. If this persists longer than twelve hours, the patient should then contact their provider. If the patient is on a low-to-moderate daily dose of ICS, they could also be instructed on the AAP to increase their ICS dose up to four times per 24 hours. For pediatric patients under the age of six with recurrent wheezing and risk factors for subsequent asthma, they recommend considering initiation of high-dose ICS or montelukast (Singulair) at the first sign of wheezing illness to reduce the intensity. For patients with mild to moderate asthma, they recommend the symptom-driven use of a combination ICS-LABA inhaler to manage yellow zone symptoms, as described above in SMART therapy (Dinakar et al., 2014). GINA guidelines state that all adolescent and adult patients should be educated on and given an AAP (GINA, 2018, p.77). See Figure 2 below for a sample plan from the NHLBI, recommended by the EPR-3 guidelines: 

It is important to note that while current guidelines all recommend written AAPs, some studies question whether or not they improve outcomes in pediatric patients. A 2016 review by Kelso questions their effectiveness. His literature review found minimal evidence of improved outcomes, and in fact found a higher cost of care in AAP users secondary to increased medication and health care service usage. As an alternative, he suggests time spent educating patients and caregivers regarding the asthma diagnosis itself as well as goals of care and signs/symptoms that should prompt follow-up action. He also suggests reinforcing this with written information (Kelso, 2016).

References

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Busse, W. W., Bateman, E. D., Caplan, A. L., Kelly, H. W., O’Byrne, P. M., Rabe, K. F., & Chinchilli, V. M. (2018). Combined analysis of asthma safety trials of long-acting B2-agonists. New England Journal of Medicine, 378 (26), 2497-2505. https://doi.org/10.1056/NEJMoa1716868

de Groot, J. C., ten Brinke, A., & Bel, E. H. D. (2015). Management of the patient with eosinophilic asthma: A new era begins. ERJ Open Research, 1(1), 00024–02015. https://doi.org/10.1183/23120541.00024-2015

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Global Initiative for Asthma. (2018). Global strategy for asthma management and prevention. www.ginasthma.org

Hsu, J., Sircar, K., Herman, E., & Garbe, P. (2018). EXHALE: A technical package to control asthma. National Center for Environmental Health, The Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/pdfs/EXHALE_technical_package-508.pdf

Kelso, J. M. (2016). Do written asthma action plans improve outcomes? Pediatric Allergy, Immunology, and Pulmonology, 29(1), 2-5. https://doi.org/10.1089/ped.2016.0634

Lynn, S. J., & Kushto-Reese, K. (2015). Understanding asthma pathophysiology, diagnosis, and management. American Nurse Today, 10(7), 49–51. https://www.myamericannurse.com/wp-content/uploads/2015/07/ant7-Asthma-622.pdf

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National Heart, Lung, and Blood Institute. (2012). Asthma care quick reference: Diagnosing and managing asthma (NIH Publication No. 12-5075). https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthma_qrg_0_0.pdf

Sobieraj, D. M., Baker, W. L., Weeda, E. R., Nguyen, E., Coleman, C. I., White, C. M., Lazarus, S. C., Blake, K. V., & Lang, J. E. (2017). Intermittent inhaled corticosteroids and long-acting muscarinic antagonists for asthma. Agency for Healthcare Research and Quality. https://doi.org/10.23970/AHRQEPCCER194

Sobieraj, D. M., Baker, W. L., Nguyen, E., Weeda, E. R., Coleman, C. I., White, C. M., Lazarus, S. C., Blake, K. V., & Lang, J. E. (2018a). Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: A systematic review and meta-analysis. JAMA, 319(14), 1473–1484. https://doi.org/10.1001/jama.2018.2757

Sobieraj, D. M., Weeda, E. R., Nguyen, E., Coleman, C. I., White, C. M., Lazarus, S. C., Blake, K. V., Lang, J. E., & Baker, W. L. (2018b). Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: A systematic review and meta-analysis. JAMA, 319(14), 1485-96. https://doi.org/10.1001/jama.2018.2769

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US Food and Drug Administration. (2012). MDI with attached spacer device [image]. https://www.flickr.com/photos/fdaphotos/7349095984/in/photostream/

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