Are you one of those clinicians who frequently finds himself frustrated with asthma patients who improve to a point but not enough to discharge home? Even though this has to be a common problem, no one seems to talk or write much about it. I was feeling deeply frustrated about these patients, and it led me to serious clinical introspection. Why does everyone write about the crashing asthma patient, but hardly anyone addresses the problematic patient with improving but recalcitrant bronchospasm?
Most articles typically cover every available therapeutic option, including the proverbial “kitchen sink” for managing severe asthma emergencies. Kitchen-sink recommendations generally include continuous albuterol nebulization, intravenous magnesium sulfate, intramuscular epinephrine or terbutaline, noninvasive (NIV) positive pressure ventilation, helium-oxygen administration, and ultimately intubation and ventilation using ketamine. It is time, however, to give “out-the-door” asthma management a little respect and attention.
Typically, emergency department asthma protocols will include repeated albuterol treatments with at least two of those treatments combined with nebulized ipratropium bromide. Corticosteroids are also administered orally or intravenously. When these initial interventions fail, most practitioners continue to treat the bronchospasm with additional doses of albuterol and ultimately continuous nebulization of the β2 agonist.
This is where logic seems to fade. Continuing to hammer the patient with the same medication and the same receptors seems a little illogical. Wouldn’t it make more sense to switch to other medications that target different pulmonary smooth muscle receptors and the inflammatory factors associated with the bronchoconstriction? Nevertheless, most clinicians maintain a relatively limited number of therapeutic tools in their toolbox when it comes to routinely managing asthma. Consequently, many patients are ultimately admitted to the hospital for ongoing management when some of them could have been discharged home.
What other options do we have? Truthfully, a lot of new magic bullets don’t really exist for acutely managing asthma. What about looking again at some of the older, proven interventions that have been benched for the newer, shinier treatments? Maybe we should be treating the known common inflammatory factors associated with asthma more aggressively. The following treatment options seem to be working anecdotally, especially for my pediatric asthma patients. Beginning with the strongest evidence first, these tools for your asthma tool box may help you get a few more patients home.
One of the best supported asthma management options is inhaled corticosteroids. The literature is consistently positive, and appears to support nebulized steroids in addition to other systemic corticosteroids. In our pediatric emergency department, we typically give one dose of oral dexamethasone (0.6 mg/kg) up to a maximum of 16 mg for asthma exacerbations that have been ongoing for one to two days and are resistant to home management. Other options are effective, but my choice for an inhaled or nebulized corticosteroid is 0.5 mg of budesonide. A review article and a Cochrane review of the benefits of inhaled corticosteroids provide supporting evidence for routinely adding this intervention for patients with recalcitrant bronchospasm. (Respir Med 2007;101:685; Cochrane Database Syst Rev 2012;12:CD002308.)
Intramuscular or Nebulized Epinephrine
Epinephrine, of course, has always worked for bronchospasm. Older clinicians will remember when subcutaneous epinephrine administered every 20 minutes was one of the few treatment options available. Despite the tears caused by the painful injections, it worked. In fact, many older papers described injected and nebulized epinephrine as being therapeutically similar to agents such as terbutaline or albuterol. (Ann Allergy 1983;50:398; Clin Pharm 1983;2:45.) Besides having a few more side effects, epinephrine, a nonselective β2 agonist, also fell to the wayside because it was far easier and less objectionable to nebulize medications than give painful injections to children and adults. If they use it at all, most clinicians reserve epinephrine for the patient presenting with severe and status asthma.
Nebulized epinephrine, however, probably works just as well as intramuscular epinephrine, and possibly delivers a greater quantity of epinephrine with minimal side effects. Both regular epinephrine (5 mg maximum) and racemic epinephrine (11.25 mg maximum) can be nebulized to treat asthma and croup. It seems to be much easier to use the commercially supplied preparations of racemic epinephrine for nebulization current available. Again, there is good evidence for the effectiveness of nebulized racemic epinephrine to treat asthma. (CJEM 2007;9:304; Acad Emerg Med 2000;7:1097; Am J Emerg Med 2006;24:217; J Crit Care 2004;19:99; Allergy 1980;35:605.) When the effectiveness of nebulized albuterol seems to have petered out and you sense a need for something else, consider a trial of nebulized racemic epinephrine.
The triggers of an asthma exacerbation are commonly divided into allergic and nonallergic etiologies. In fact, it is possible that allergies trigger asthma attacks in 60 to 90 percent of children and 50 percent of adults. (Medscape. April 13, 2017; http://bit.ly/2oXKp4s
.) Mite and cockroach antigens are known to increase asthma morbidity, and are commonly found in the environment. (J Allergy Clin Immunol
2015;136:38.) Histamine is a known inflammatory mediator in the pathophysiology of asthma. IgE binds to high-affinity receptors on the surface of mast cells and basophils, leading to mast cell and basophil degranulation. Mast cell mediators, histamine, pro-inflammatory cytokines, and proteases are released, leading to an early allergic response.
Consequently, it seems intuitive that antihistamines could play a role in treating asthma. Unfortunately, evidence for the benefit of first-generation antihistamines in asthma is relatively limited. This may be secondary to the fact that antihistamines were avoided in asthma for many years. Clinicians were taught to avoid antihistamines out of concerns for possible drying and inspissation of airway secretions. Current research on second-generation antihistamines suggests benefit, however. (Am J Med 2002;113[Suppl 9A]:2S; Curr Opin Allergy Clin Immunol 2002;2:53; Treat Respir Med 2006;5:149; J Allergy Clin Immunol 2003;112[4 Suppl]:S96.) Clinical studies have shown mixed results, but no detrimental effects were noted. Despite weaker evidence, the addition of intravenous or oral antihistamines during an acute asthma event seems safe, reasonable, and disease mechanism-based. And it is possible that antihistamines could prove to be synergistic with other anti-inflammatory interventions.
Ibuprofen or NSAIDs
Another even more controversial option is the use of the anti-inflammatory drug, ibuprofen, in asthma. Ibuprofen is a nonselective inhibitor of the enzyme cyclooxygenase (COX), which is required for the synthesis of prostaglandins via the arachidonic acid pathway. This pathway is active in the pathogenesis of asthma. (Pharmacotherapy 1997;17[1 Pt 2]:3S.) (Figure 1.)
Figure 1. Stylized cell depicting the mechanism of action of ibuprofen. (Pharmacogenet Genomics 2015;25:96.) Pharmacodynamics ©PharmGKB. Reprinted with permission from PharmGKB and Stanford University.
Ibuprofen is often immediately rejected as a therapeutic intervention for asthma because of concerns about exacerbating asthma in the context of aspirin sensitivity. Literature analysis seems to indicate that the use of ibuprofen in the pediatric population does not exacerbate asthma morbidity. (Paediatr Drugs 2004;6:267; Clin Ther 2007;29:2716.) As stated by one author: "Given the infrequent occurrence of aspirin/NSAID sensitivity in children with asthma, it seems reasonable to allow the use of ibuprofen in this population unless there is a personal or family history of aspirin-induced asthma. In addition, the inflammatory pathogenesis of asthma, anti-inflammatory effect of ibuprofen, and evidence suggesting ibuprofen may reduce morbidity in children with asthma raises the intriguing possibility that ibuprofen might actually have therapeutic benefit for at least some children with asthma." (Paediatr Drugs 2004;6:267.)
A paper by Lesko, et al., stated that rather than supporting the hypothesis that ibuprofen increases asthma morbidity among children who are not known to be sensitive to aspirin, their study suggested that compared with acetaminophen, ibuprofen may reduce such risks. (Pediatrics 2002;109:E20.) Finally, another study recommended that ibuprofen be withheld for at least 24 hours prior to investigations utilizing allergen bronchoprovocation because a single dose of ibuprofen was found to inhibit early and late asthmatic responses to allergen bronchoprovocation. (Allergy Asthma Clin Immunol 2016;12:24.) The evidence is limited, but ibuprofen should theoretically decrease the inflammatory factors causing bronchospasm in asthma through its actions on the arachidonic acid pathway.
If you find yourself regularly frustrated with asthma patients who only partially improve, consider putting back into the game some or all of these older, previously benched bronchodilators and anti-inflammatory treatment modalities.