Acute severe asthma and near fatal asthma are the modern terms for what was once known as status asthmaticus. While the change in nomenclature may be trivial, the goals of therapy remain the same: improve oxygenation, relieve airflow obstruction, reduce airway edema and mucus plugs, and support ventilation. In order to achieve these therapeutic goals, there are numerous drug therapies, as well as non-pharmacologic therapies that should be used. In this chapter we will focus on the drugs that should be administered in the first hour of presentation to the emergency department to patients suffering from acute severe asthma and near fatal asthma. I will refer to these conditions simply as asthma for the remainder of this chapter. Additionally, PFTs are rarely done in the ED, so for simplicity sake I won’t use these markers to guide therapy.
A 22 year old female is brought in by ambulance for shortness of breath. In the ED, she is anxious, diaphoretic, sitting up in the stretcher and with audible wheezes. On the monitor, she is tachycardic (120s), normotensive, tachypnic (40 bpm), hypoxic 85% on room air and afebrile. As the team is getting access and completing the physical exam, the physician asks for 3 “duonebs” and 125 mg of methylprednisolone IV.
Short acting beta-2 agonists
Inhaled short acting beta-2 agonists (SABA) are the initial bronchodilators of choice in asthma. There are two SABA agents available in the USA; albuterol and levalbuterol. A close look at the pharmacology reveals important pharmacologic and pathophysiologic concepts in asthma.
SABAs exert their bronchodilatory through direct and indirect mechanisms.[2,3] The direct bronchodilatory effects occur by acting as beta-2 receptor agonists. This adrenergic stimulation activates adenylyl cyclase, increasing cAMP and phosphokinase A. The resulting activation of intracellular phosphorylation pathways that leads to smooth muscle relaxation. Indirect bronchodilation occurs through reducing the release of numerous bronchoconstrictors (mast-cells, histamine, leukotriene), anti inflammatory actions and reduction in reduction in cholinergic activation through reduction in presynaptic acetylcholine release from presynaptic beta-2 receptors. The direct effects of SABA agents contribute the bronchodilatory actions in the acute setting, where long term benefits may be a result of indirect effects.
However, the anti-inflammatory effects of SABA agents are only theoretically beneficial in acute asthma and have no effect on chronic asthma.[2-4] The inhibition of mast-cell degranulation and subsequent microvascular leakage not only provides bronchodilation, but also acute anti-inflammatory benefits. However, these effects do not appear to persist for longer than an hour or two since long acting-beta-2 agonists do not demonstrate this benefit. The role of anti-inflammatory hero is played by systemic corticosteroids (see below).
These beneficial effects of the SABA albuterol (aka salbutamol outside the USA) are mediated by it’s (R)-enantiomer. The (S)-albuterol enantiomer has no beta-2 agonist activity of any benefit. In fact, it is likely pro-inflammatory, may worsen existing airway hyperreactivity, and its longer duration of action would allow these negative effects to exist without counterbalance from the (R)-albuterol action. This was the rationale for development of levalbuterol, which is just (R)-albuterol. However, levalbuterol does not reduce the incidence of tachycardia at doses given for asthma in the ED nor does it improve any patient-oriented outcomes. While the difference between albuterol and levalbuterol does not seem to be clinically significant, the current acquisition cost of levalbuterol restricts its use.
The beta-2 agonist activity of SABA agents extend to extrapulmonary actions. Although SABAs can stimulate gluconeogenesis, insulin secretion, lactate production (metabolic shift to free-fatty acid oxidation), tremors and intracellular shifting of potassium, the most notable effect is tachycardia. As described above, levalbuterol does not reduce the incidence of these effects at normal therapeutic dosing for the ED, nor at doses required for patients with acute life threatening asthma. However, the effects of catecholamine SABAs on metabolism are fascinating and shed light on why beta-2 agonists and insulin are abused for athletic performance.
Beta agonists (including beta-2 agonists) may potentially cause a type B-2 lactic acidosis – where lactate is produced despite having sufficient tissue oxygen delivery. This occurs through activation of gluconeogenesis and glycogenolysis in the liver and glycogenolysis in skeletal muscle, enhancing insulin secretion and glucose uptake into cells. However, simultaneous increases in fatty-acid oxidation causes an inhibition of pyruvate dehydrogenase shunting the metabolism of pyruvate to lactate, instead of into the citric acid cycle. From a athletic enhancement perspective, this can improve performance in short-burst anaerobic activities like sprinting or power weight lifting, and not really beneficial for say marathon running. Furthermore, the excess insulin secretion can have effects on human growth hormone as well as other desirable hormones for muscle growth (IGF-1). Take a stroll down a supplement aisle at GNC and observe how many products claim to have action on this pathway. In most patients with asthma, this action is beneficial, since cellular energy production can continue while ventilation issues are resolved and supported since these effects of lactate production are transient. However, if their buffering capacity is limited, or have underlying insulin deficiency/resistance (diabetes), these metabolic effects could lead to the development of acidemia.
With chronic use of SABAs, tachyphylaxis develops to both the therapeutic effects of SABAs and these toxicities. Occuring within a week of chronic use, a down regulation of beta-2 receptors occurs as well as decreased binding affinity. So chronic asthma patients that are taking SABA and long acting beta-2 agonists (LABA) agents at home, as dose increases, there should not be excessive adverse events. At the same time, however, a given dose has less bronchodilatory effects as tolerance develops (this partially explains the black box warning with LABA agents). Similarly in the ED, patients receiving high dose albuterol benefit from the bronchodilatory effects yet have few intolerable adverse effects. Tachyphylaxis is blunted by systemic (not inhaled steroids), one of the primary rationale for administration of systemic steroids early in the course of asthma in the ED despite its long onset of action.
Albuterol for severe asthma in the ED is almost always administered via nebulization. There is no difference between continuous vs intermittent (q20min x 3 doses), as long as the same dose is administered. However, for patients with life-threatening or near fatal asthma, continuous albuterol is recommended. As far as the dose to administer is a matter of empiricism rather than evidence guided. But, it’s worked well thus far. It is important to recognize that the severity of airway constriction reduces the dose-responsiveness of albuterol. So the more severe the asthma is, the more albuterol is required to achieve a given response. Therefore, dosing is on the higher spectrum in severe asthma. Between 15 and 20 mg continuous nebulization of albuterol, is considered appropriate dosing in the ED. For pediatric patients, fixed doses of 2.5 mg (to a maximum of 10 mg per hour) are usually used. The rationale for these relatively high doses is that the amount of albuterol reaching the lung is lower and risk of therapeutic failure is high.
Although not pharmacologically a pure beta-2 agonist, racemic epinephrine is often used as a short acting bronchodilator in the emergency department. Racemic epinephrine is somewhat of a misnomer, like saying ATM machine. We don’t routinely say racemic albuterol, we simply say albuterol. So to reduce any confusion that racemic epinephrine is any different any other form of the drug, I will refer to is as should be, ‘epinephrine.’ The use of nebulized epinephrine in asthma, is limited to pediatrics. In the pediatric realm, while epinephrine has not demonstrated any benefit over albuterol, there is a benefit of epinephrine for bronchiolitis.[11,12] So in the hyperacute setting, where the cause of respiratory distress is still undifferentiated, nebulized epinephrine is a reasonable choice. However, the use of parenteral epinephrine or terbutaline is controversial.
SABA agents are first-line for acute asthma. Continuous nebulization is a reliable route and the dose can be up to 20 mg in the first hour. Racemic epinephrine, or just simply nebulized epinephrine doesn’t offer any benefit over albuterol for asthma.
The patient’s already tachycardic and the patient’s family wants to know if it’s necessary to keep giving so much albuterol. Can she just have atrovent, it’s worked in the past?
Short acting antimuscarinic agents (SAMAs)
The pharmacology of the SAMA agents as a class are analogous to SABAs in that there is a prototypical agent that has undesirable effects with newer products that optimize efficacy and limit toxicity. In the case of SAMAs, atropine is the prototypical agent.[2-4] Atropine is not used for asthma as a result of it’s tertiary amine structure contributing to its ability to penetrate the CNS. CNS penetration in asthma is not desirable, and can cause unwanted delirium. The only SAMA agent used in acute asthma in the ED is ipratropium, a quaternary muscarinic agonist. Long acting muscarinic agonists have been developed for asthma and include tiotropium, glycopyrrolate, umeclidinium, and aclidinium.
Ipratropium exerts its activity on the M1 and M3 receptors. Ipratropium is a competitive antagonist of acetylcholine at the M3 receptor, leading to intracellular signaling ultimately reducing intracellular calcium and thus, smooth muscle relaxation. Additionally, through these antimuscarinic effects, mucus secretion is reduced. Unlike tiotropium which only inhibits these two receptors (M1 and M3), ipratropium also has activity on the M2 receptor. Unfortunately, M2 is a presynaptic, feedback receptor and it’s inhibition can potentially lead to increased acetylcholine and worsen respiratory effects. A paradoxical bronchoconstriction is possible, although fortunately, these effects appear to be theoretical and more marketing material than therapeutic considerations in acute asthma.
For acute asthma, ipratropium should be administered via nebulization at a dose of mg every 20 minutes for three doses. While the onset of ipratropium is relatively prolonged, about 30 minutes, it’s duration of action is 6 to 8 hours. This relatively long duration provides a protective effect at reducing the risk of relapsing airway reactivity. However, as the mechanism above describes, antimuscarinic agents only provide bronchodilation from acetylcholine-mediated bronchoconstriction and have no impact on other bronchoconstrictors such as mast-cells, histamine and leukotrienes. Therefore, this lack of immediate onset and targeted bronchodilatory effect is why ipratropium should only be used in addition to albuterol in the ED.
Fortunately, toxicity from ipratropium is rare. Systemic antimuscarinic effects outside of the pulmonary system rare occur. However, if the mask used for nebulization is not tight or the vapor contacts the patient’s eyes, can produce pupillary dilation and poor accommodation to light.[2-4] This can complicate HEENT exam if the provider is unaware of this effect.
Ipratropium should be given for three doses concurrently with albuterol in the ED for asthma. It’s short term benefits are not necessarily what we’re after, but rather, the long term (6-8 hours) effects that can prevent a relapse of symptoms. Don’t get thrown off by the blown pupil(s) since it’s likely ipratropium leaking from the neb mask – but always look into for more concerning causes.
The asthma patient we’ve been caring for in the ED is receiving albuterol+ipratropium via continuous nebulization on a non-rebreather mask. She can only speak in single words still and still anxious. There is an order for IV methylprednisolone, but does it seems like a good opportunity for an IV to PO intervention?
Roids- Systemic corticosteroids
Systemic corticosteroids offer a shotgun approach to anti inflammation, and offer numerous additional benefits. As mentioned previously, chronic use of SABA agents can lead to downregulation and desensitization of beta-2 receptors. Steroids can actually improve both of these effects by upregulating beta-2 receptor expression with 4 hours of administration and sensitivity to stimulation within 2 hours. Furthermore, steroids can reduce mucus secretion and airway edema.
The benefits of systemic corticosteroids are dose and duration dependent, however, the adverse effects of steroids also increases.[2-4] Inhaled corticosteroids are used to reduce these toxicities for management of chronic asthma, however, only systemic steroids have a role in acute management of asthma. Similar to vaptan therapy for heart failure, when corticosteroid therapy is removed in asthma, the underlying pathophysiology takes back over, without and disease modification.[2-4] Therefore, noncompliance, interruption or discontinuation can be a cause of acute asthma exacerbation.
While there is no difference between the efficacy of parenteral versus enteral steroids, the administration of oral steroids in acute asthma in the ED is often limited by patient specific factors. Non-invasive ventilation masks in place, continuous nebulization, or just a fatigued/panicked patient makes oral administration challenging. While the antimuscarinic effects of ipratropium on GI motility are probably not clinically significant, it is theoretically plausible. Therefore, if a patient already has IV access, they should get systemic corticosteroids via this route in the ED. If the patient is experiencing near-fatal asthma, IV corticosteroids are preferred. But as soon as the patient can tolerate PO meds, everything should be converted to the oral route.
The systemic steroids that could be given include hydrocortisone, dexamethasone, prednisone and methylprednisolone. While any could be given, methylprednisolone and prednisone are more frequently used in the ED due to their desirable balance of corticosteroid/mineralocorticoid effects. The commonly accepted, non evidence based dose of prednisone is 40 to 60 mg for adults and methylprednisolone IV is similarly dosed at 40 to 80 mg. Some references cite methylprednisolone 125 mg IV for near-fatal asthma.
After 3 duonebs and a dose of steroids, the patient has improved her oxygenation, but still is tachypneic, and borderline hypoxic. The physician is asking for magnesium but unsure of whether she needs it IV or via neb.
The addition of intravenous magnesium sulfate to the above standard treatment for acute asthma offers additional bronchodilation and potential anti inflammatory effects.[1, 13] Magnesium’s bronchodilatory effects are mediated via reductions in cytosolic calcium by increasing calcium uptake back into the sarcoplasmic reticulum. To confer these benefits, the evidence supports magnesium given by the IV route, but conflicting evidence suggest nebulized magnesium may have some benefit as well.
For patients with acute asthma, magnesium sulfate should be given at a dose of 2 grams IV. It is important to administer the magnesium rapidly, rather than slowly as most CPOE systems default to slow rates. Since we’re not trying to replace electrolytes, magnesium sulfate 2g IV should be given over 10-20 minutes. This dose can be repeated twice. Some references cite administration rates of up to 1 gram per minute. Infusion rates this rapid may increase the risk of adverse event, namely flushing and hypotension. While also possible, other concerning adverse events rarely happen in doses this low including loss of deep tendon reflexes, hypothermia, CNS depression and bradycardia. These effects are more commonly observed when administration or dosing errors occur in the OB setting (eclampsia dosing of magnesium).
The asthma guidelines recommend IV magnesium to reduce hospital admissions in patients with severe asthma, and patients who have persistent hypoxemia after standard treatment. It is not unreasonable to consider magnesium therapy for any patient in the ED for asthma related complaints considering it’s risk/benefit ratio.
Give magnesium IV if nebs are not achieving desired clinical outcomes. Heck, give magnesium anyways. Nebulized magnesium is no sure bet.
Despite all the interventions thrown at the patient, the team feels she is headed towards being intubated. But before intubation, the nurse suggests trying IV epinephrine since it’s something he saw years ago working at another ED. How much epinephrine should be given IV?
Parenteral beta-agonists are somewhat controversial in their use, the guidelines generally do not recommend them. In the emergency department setting, they are often used when nebulized beta agonists are not achieving desired clinical outcomes, or there is such a severe case that patient is not moving any air at all where the nebulized drugs are simply not reaching the sites of action. A crashing asthma patient, either adult or pediatric is really the only situation where the two agents (epinephrine and terbutaline) may play a role.
The evidence supporting these therapies is unarguably weak, however it gives some assurances that epinephrine or terbutaline are at least not making things worse. This literature mostly compares parenteral epinephrine/terbutaline to SABA agents other than albuterol, and is doing so with the intent of demonstrating nebulized SABAs can improve asthma without pain/systemic effects from parenteral agents. There is no high quality literature describing the impact of these agent as adjuncts to modern severe asthma (drugs described above plus non-invasive ventilation therapies).
Nevertheless, should epinephrine be selected as the adjunct agent, the dosing is similar to that of anaphylaxis. Epinephrine 1mg/mL should be given IM at a dose of 0.3-0.5 mg every 15-20 minutes. Most references use subcutaneous as the route for epinephrine, however, in a crashing patient who is likely hyperadrenergic, there may be limited absorption from the subcutaneous space (just like with anaphylaxis). Therefore, IM is a more desirable location for administration. Epinephrine could also be administered IV in this situation, should IM/SQ administration be a significant concern. In this scenario, push dose-epinephrine dosing would be appropriate (starting with 10 mcg). However, extreme caution should be taken since this is fraught with drug administration/dosing errors. Furthermore, patients over the age of 40 may be at higher risk of adverse cardiovascular effects.
Terbutaline should only be administered subcutaneously. It’s duration of action is much longer than epinephrine (about 4 hours), theoretically could prevent recurrence. The dose of terbutaline is 0.25 mg SQ. Similar adverse events should be expected with terbutaline as with epinephrine. However, since terbutaline is a beta-2 agonist, the effects are more likely to be tremor and tachycardia.
IV LT4 inhibitors
- National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma (EPR-3). July 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma.
- Barnes PJ. Pulmonary Pharmacology. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=172481165. Accessed December 28, 2018.
- Galanter JM, Boushey HA. Drugs Used in Asthma. In: Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2249§ionid=175218493. Accessed December 28, 2018.
- Sorkness CA, Blake KV. Asthma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146058008. Accessed December 28, 2018.
- Kelly HW. Risk versus benefit considerations for the beta(2)-agonists. Pharmacotherapy 2006;26:164S–174S. [PubMed: 16945063]
- Jat KR, Khairwa A. Levalbuterol versus albuterol for acute asthma: A systematic review and meta-analysis. Pulm Pharmacol Ther 2013;26:239–248. [PubMed: 23207739]
- Schatz M, Kazzi AAN, Brenner B, et al. American Thoracic Society documents: Joint task force report: Supplemental recommendations for the management and follow-up of asthma exacerbations. Proc Am Thorac Soc 2009;6:353–393. [PubMed: 19681235]
- Rodrigo GJ. Advances in acute asthma. Curr Opin Pulm Med 2015;21:22–26. [PubMed: 25405669]
- Saugy M, et al.Human growth hormone doping in sport. Br J Sports Med. 2006 Jul; 40(Suppl 1): i35–i39.PMID: 16799101
- Stratakos G, et al.Transient Lactic Acidosis as a Side Effect of Inhaled Salbutamol. Chest, July 2002;122(1):385–386
- Plint AC, Osmond MH, Klassen TP.The efficacy of nebulized racemic epinephrine in children with acute asthma: a randomized, double-blind trial.Acad Emerg Med. 2000 Oct;7(10):1097-103.
- Langley JM, Smith MB, LeBlanc JC, Joudrey H, Ojah CR, Pianosi P.Racemic epinephrine compared to salbutamol in hospitalized young children with bronchiolitis; a randomized controlled clinical trial [ISRCTN46561076].BMC Pediatr. 2005 May 5;5(1):7.
- Nowak RM, Tokarski GF. Asthma. In: Rosen’s Emergency Medicine: Concepts and Clinical Practice, 9th Edition. Elsevier, May 2017
- Aaron SD. The use of ipratropium bromide for the management of acute asthma exacerbation in adults and children: a systematic review.J Asthma. 2001 Oct;38(7):521-30.
- Firszt R, Kraft M. Pharmacotherapy of severe asthma. Curr Opin Pharmacol. 2010;10(3):266-71.
- Goodacre S, et al. The 3Mg trial: a randomised controlled trial of intravenous or nebulised magnesium sulphate versus placebo in adults with acute severe asthma. Health technology assessment (Winchester, England), no. 22. doi:10.3310/hta18220. http://www.ncbi.nlm.nih.gov/pubmed/24731521.
- Travers AH, Milan SJ, Jones AP, Camargo CA Jr, Rowe BH. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. Dec 12, 2012;12:CD010179.