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CE: Swati; COPE-D-17-00008; Total nos of Pages: 6;



OPINION Management of acute asthma exacerbations
Erin K. Stenson a, Michael J. Tchou b, and Derek S. Wheeler a,c

Purpose of review
Herein, we review the current guidelines for the management of children with an acute asthma
exacerbation. We focus on management in the emergency department, inpatient, and ICU settings.
Recent findings
The most recent statistics show that the prevalence of asthma during childhood has decreased in certain
demographic subgroups and plateaued in other subgroups. However, acute asthma accounts for significant
healthcare expenditures. Although there are few, if any, newer therapeutic agents available for
management of acute asthma exacerbations, several reports leveraging quality improvement science have
shown significant reductions in costs of care as well as improvements in outcome.
Asthma is one of the most common chronic conditions in children and the most common reason that
children are admitted to the hospital. Nevertheless, the evidence to support specific agents in the
management of acute asthma exacerbations is surprisingly limited. The management of acute
exacerbations focuses on reversal of bronchospasm, correction of hypoxia, and prevention of relapse and
recurrence. Second-tier and third-tier agents are infrequently used outside of the ICU setting. Reducing the
variation in treatment is likely to lead to lower costs and better outcomes.
acute asthma, ICU, inpatient, quality improvement, status asthmaticus

INTRODUCTION statistics, there is a clear opportunity for utilizing
Asthma is the most common chronic disease of quality improvement science to reduce variation,
childhood and one of the most common reasons minimize costs, and improve outcomes. Herein, we
that children are admitted to the hospital [1]. will focus on the management of acute asthma
Although several epidemiologic studies reported exacerbations and highlight some of these oppor-
an increase in the prevalence of childhood asthma tunities for the care of these children.
in the waning years of the 20th century, recent
statistics suggest that the prevalence is decreasing
in a number of demographic groups. More impor-
tantly, disparities between racial subgroups appear
to have plateaued [2]. Regardless, asthma affects Currently, the key priorities for managing children
more than 7 million children (9.6% of all children) with an acute asthma exacerbation are to reverse
in the United States of America alone, and more airflow obstruction with short-acting beta agonists
than half of these children will suffer from at least (SABAs), correct hypoxia with supplemental oxy-
one acute exacerbation every year [3]. Asthma costs gen, minimize the risk of relapse with the use of
the US healthcare system over $56 billion per year, systemic corticosteroids, and prevent future exacer-
with acute exacerbations accounting for more than bations with the use of controller medications, such
50% of total expenditures [4]. Acute asthma exacer-
bations are largely preventable. Indeed, the United a
Divisions of Critical Care Medicine, bHospital Medicine, Cincinnati
States of America has the highest rate of asthma-
Children’s Hospital Medical Center and cDepartment of Pediatrics,
related hospitalizations and mortality among all of University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
the highest income peer nations in the Organisation Correspondence to Derek S. Wheeler, MD, MMM, MBA, Chief of Staff,
for Economic Co-operation and Development [5]. A Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue,
&& && & &
number of studies [6 ,7 ,8 ,9 ] have documented Cincinnati, OH 45229-3039, USA. Tel: +1 513 803 1422;
significant variation in the care of these patients, e-mail:
which likely increases the cost of care and poten- Curr Opin Pediatr 2017, 29:000–000
tially worsens outcome. Given these sobering DOI:10.1097/MOP.0000000000000480

1040-8703 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Aerosolized albu. there is significant variation in care in the Steroids act through anti-inflammatory mechan- emergency department. Unauthorized reproduction of this article is prohibited. For example. and prednisolone [15 ]. bronchospasm by acting as a surrogate for calcium Mild hypoxemia is common in children with an and causing smooth muscle relaxation. and ICU settings. molecular markers of preferred. and effectiveness] between dexamethasone & outcomes.CE: Swati. inpatient. in a study comparing albuterol with research has investigated the potential for increased levalbuterol. a recently published study hospital was 93  5% [13]. but there was no net benefit analysis concluded that there was no improvement & in prevention of hospitalization [11 ]. Severe hypoxemia is & [23 ] showed that continuous infusions of MgSO4 in uncommon and should prompt evaluation for the ED led to shorter LOSs. prescribing ICS albuterol in the ED setting to maximize bronchodi. most studies have not found significant benefit to ADJUNCTIVE TREATMENTS FOR ACUTE the use of anticholinergics in the acute management ASTHMA of asthma outside the ED setting and never as the Intravenous magnesium sulfate (MgSO4) relieves sole agent. however. and for this of acute management of asthma exacerbation. They can be admin- istered in oral or intravenous forms and should be  A stepwise approach to acute asthma exacerbations is warranted. oxygen titrated to maintain an oxygen saturation These findings are supported by pharmacologic data of 93–95% appears to balance the need for treating indicating that the pharmacokinetic effects of 2 www. tinuous fashion (again. A stepwise methasone has a higher cost than prednisolone. depending upon the severity ICS are a mainstay of outpatient treatment for of the presentation) is the preferred agent of choice. and no adverse events. or dexamethasone. Inc. Finally.  The evidence to support the management of acute Systemic corticosteroids are the other mainstay asthma exacerbations in children is whereas the oxygen saturation in those majority of reports involve the use of intermittent or children who were subsequently admitted to the one-time doses of MgSO4. and prevention lines recommend either prednisone/prednisolone of relapse and recurrence. prevention of asthma exacerbations. There is currently interest in the use of setting may be a cost-effective approach to minimiz- tiotropium for the management of moderate ing the risk of recurrent asthma exacerbations [20]. however cholinergic medications such as ipratropium bro. adverse acute asthma exacerbations will minimize variations in care. Volume 29  Number 00  Month 2017 Copyright © 2017 Wolters Kluwer Health. which decreases worsening of intrapulmonary shunt as a result of cytosolic calcium and thus smooth muscle cell con- beta-agonist-mediated reversal of normal hypoxic tractility. Although the was 95  4%. ations. Although dexa- as inhaled corticosteroids (ICS) [10]. reason. Supplemental discharges home at 24 h. asthma exacerbations in children [12]. It mitigates acute asthma exacerbation. & phenotypes [18 ]. controlled trials failed to show any meaningful  A quality improvement approach to management of difference in outcomes [length of stay (LOS). A recent meta- asthma exacerbations.22]. Current guide- bronchospasm. at the time of discharge from the emergency care lation. A meta-analysis of 18 random- ized. has been shown to be more predictive than clinical terol administration in either a repetitive or con. However. COPE-D-17-00008. Given recommendations to use ICS as con- mide are also frequently used in conjunction with troller therapy for persistent asthma. Inhaled anti. higher proportion of pneumonia or pneumothorax. approach to management based upon an objective less-frequent dosing leads to a simpler regimen for assessment of the severity of the exacerbation is providers and families. primarily as a result of both entry of extracellular calcium and release of ventilation–perfusion mismatch and at times due to calcium from intracellular stores. & [19 ]. the use of IV MgSO4 in the ED led to fewer hospitaliz- mean oxygen saturation of over 1000 children pre. more recent stud- ies have demonstrated that dexamethasone has comparable results with a shorter LOS [16] and is & noninferior to prednisolone [17 ]. although the available studies were hindered senting to the ED with an acute asthma exacerbation & by their small sample size [21 . some For example. SABAs act to rapidly reverse airflow inflammation may be a useful tool in the future for obstruction through smooth muscle relaxation predicting steroid responsiveness of patients and and resulting bronchodilation. . COPE-D-17-00008 Pulmonology hypoxia and avoiding the aggravation of venti- KEY POINTS lation–perfusion mismatch [14]. correction of hypoxia. in admission rates with double-dose ICS. leading to lower costs of care and better events. there was some benefit in prevention dosing of ICS to prevent ED visits and hospital of emergency department (ED) visits during acute admissions and improve outcomes. Total nos of Pages: 6. with a principal focus on reversal of initiated promptly in exacerbations. A recent Cochrane review found that the pulmonary vasoconstriction. isms that reduce airway edema.

and/or terbutaline. than 20 mg/ml. A systematic review of ketamine in status starting terbutaline therapy. Early use of tial for cardiac toxicity (primarily due to myocardial continuous positive airway pressure in asthmatics ischemia).. Despite these analysis. patients who received low-dose theophyl- results. terol. given the poten.e. several centers. particu- commonly) SABA that enhances ventilation by larly in those critically ill children who are refractory dilating constricted airways to reach lung segments to first-tier agents. Total nos of Pages: 6. In addition. patients receiving standard of care with those receiv- & xanthine derivative that acts as a phosphodiesterase ing NIPPV [35 ]. and titrating based on levels did not improve & of systemic side effects (primarily hypotension) and safety or efficacy [30 ]. The higher intrathoracic pressures associated there is no difference in outcomes between children with dynamic hyperinflation create a scenario in 1040-8703 Copyright ß 2017 Wolters Kluwer Health. or invasive positive pressure ventilation. albuterol) and the need trials are necessary. uated two randomized control trials compared Theophylline (or aminophylline) is a methyl. Terbutaline has the potential to cause acute respiratory failure secondary to status asthma- worsening tachycardia and hypotension. However. IV MgSO4. It is also the induction agent of choice half-life and must be administered by continuous for tracheal intubation in critically ill children with infusion. Inc. In a recent randomized theophylline may be explained by theophylline’s trial. though The safety of terbutaline was recently examined. only a small percentage The additional benefit of ketamine lies in its required inotropic support. several ideal levels with ‘supratherapeutic’ levels of more recent studies have investigated the effects of nebu. NIPPV was beneficial. both showed which tachycardia may not be as well tolerated. were unable to confirm or reject the hypothesis that theophylline has fallen out of favor due to avail. and the vast majority of sedative properties (mentioned above) to improve those patients were also receiving mechanical venti. Of interest. Inc. A recent Cochrane review that eval- of terbutaline to the ICU setting. that are not being adequately ventilated and thereby Ketamine also has potent bronchodilatory not ‘seeing’ inhaled beta agonist. Another systematic review found a lized MgSO4 in the ED setting. compliance of children requiring either noninvasive & latory support [28 ]. In addition. COPE-D-17-00008 Management of acute asthma exacerbations Stenson et al. Nebulized MgSO4 is lack of evidence for dosing guidelines of aminophyl- particularly attractive given the theoretical absence line. COPE-D-17-00008. spread use of ketamine. line in addition to standard of care had significantly trolled trial of nonresponders to standard of care shorter LOS. More work is needed to than 10 mg/ml [29 ]. may be beneficial. . a associated with increased airway resistance and the recent review published in the last year that consequent effects of dynamic hyperinflation (auto- included 10 randomized control trials showed that PEEP). All rights reserved. Clearly. Similar effects are effects in addition to the benefit of providing seda- observed with intramuscular epinephrine and intra. when ketamine 3 Copyright © 2017 Wolters Kluwer Health. both SBP and DBP. and there. tion to improve compliance in those patients requir- venous salmeterol (not currently available in the ing noninvasive positive pressure ventilation United States of America). including our own. and reduced costs [31 ].co-pediatrics. ticus. There is little evidence to support the wide- fore some clinicians may limit the use of this medi. other mechanism of action. larger randomized ability of better agents (i. Theophylline may ard of care did not show any improvement in time improve responsiveness to steroids by restoring to discharge. histone deacetylase-2 activity. Of these. to follow levels closely given its narrow therapeutic NIPPV appears to improve the work of breathing range and variable pharmacokinetics. Nonetheless.CE: Swati. there was no differ- determine optimum dosing and validate the initial ence in the rate of adverse effects when comparing & findings of this study [25 ]. especially in the adolescent age group in was compared with aminophylline. but their heart rates asthmaticus concluded that it is a reasonable option improved to below baseline once terbutaline was in severe asthma management given its safety pro- & discontinued. time to space albu- & & is currently being planned [27 ]. magnesium are short-lived and that the effective with ‘ideal’ therapeutic levels of 10–20 mg/ml com- doses may be higher than what are most commonly pared with children with subtherapeutic levels less & & used in the ED setting [24 ]. the addition of nebulized magnesium to stand. Historically. they ing ventilation–perfusion matching. than 100 patients and had a high risk of bias. all patients had sinus tachycardia after [32 ]. Given that these trials included less inhibitor to cause bronchodilation without affect. there was a decrease in file and potential benefits [33 ]. In a retrospective & analysis of four available studies [26 ]. there was no comparison with a placebo group & In this study. Unauthorized reproduction of this article is prohibited. similar improvement in asthma scores. This finding was replicated in a meta. however. even when initiated in the ED & monitor serial cardiac troponins and limit the use setting [34 ]. www. Terbutaline has a short (NIPPV). time to discharge. Further studies of Terbutaline is a parenterally administered (most theophylline would appear to be warranted. However. The lack of clinical difference easier route of administration (which obviates the between subtherapeutic and therapeutic levels of need for vascular access). an additional randomized con.

LOS in the ED and fewer admissions [40 ]. likely as a result to generate airflow. Even by simply implementing ating the use of Extracorporeal Membrane Oxygen. Unauthorized reproduction of this article is prohibited. readmissions by improving processes around dis- istration of ketamine). On a larger scale. and reduced readmission rates && with these modalities. There is no recent literature evalu. a tertiary hospital and its 16 patients treated over 4 years with ECMO showed surrounding community hospitals all implemented 100% survival without neurologic sequelae and had one clinical practice guideline to standardize care significant improvement in oxygenation. NIPPV. standardizing admission criteria can also treating physician [1]. . ing of tracheal intubation in these patients. In addition. and the incidence of hospital readmissions. && OPPORTUNITIES FOR IMPROVEMENT At the time of discharge.CE: Swati. In addition. the way 4 www. there is a significant also improve airway resistance. Total nos of Pages: 6. and The ‘stenting’ effect of NIPPV on the airways may perhaps most importantly. In the adult population. Inhaled anesthetics as lead to reduced LOS in the ED for admitted patients & adjunctive therapy for critically ill children with [41 ]. a case report of rate [44]. Creating partnerships between hospitals and are more likely to receive blood tests (e. Finally. blood local pharmacies to facilitate this ‘meds-in-hand’ gas). Variation in care leads to excessive pressure. improved adherence to evidence-based guidelines ACUTE ASTHMA EXACERBATIONS: has decreased hospital LOS [7 ]. quality measures. [45 ]. This effect is even seen in the ED setting. In the ED. It is still There are a number of ongoing efforts focused generally accepted that patients in cardiac arrest. especially by providing simple. All seven patients in this study had sig. and improve compliance with previously published and hypercarbia [37]. LOS for asthmatics improved ation (ECMO) for asthma treatment in the pediatric by an average of 8 h. reports. In bation must be made on a case-by-case basis by the addition.g. For already in hand (vs. handing patients a prescription) & Volume 29  Number 00  Month 2017 Copyright © 2017 Wolters Kluwer Health. and decreased use of respirat- & parameters [36]. there was a thetics and/or ECMO likely require transfer to a sustained improvement in compliance with guide- tertiary or quarternary care facility with experience lines. the odds of returning to A number of studies have documented significant the ED within the next 30 days can be lowered variation in the management of children with acute simply by discharging patients with medications asthma exacerbations in the ED setting. the need for hospital- be tracheally intubated. asthmatic patients are well known and include car. ipratropium. There is also discharging patients with albuterol in hand led to & significant variation in the testing. NIPPV reduces of the lack of evidence for most of the therapies the need for these drastic changes in intrapleural discussed above. EDs chest radiographs (presumably to rule out pneu. COPE-D-17-00008. as protocol has been shown to improve adherence to well as barotrauma and ongoing difficulties with NIH guidelines and improved timeliness of admin- ventilation due to severe obstruction during the istration of beta-agonists. one study showed a reduction in nificant improvement in pCO2 and other clinical costs. Even after the initial implementation. decreased LOS. This could potentially lead to shorter & indications. Theoretically. on these and other issues with the goal of preventing coma. even in pediatric lization of emergency and inpatient services [47 ]. and reduced reutilization [48 ]. Inc. in which & monia) are likely overutilized [9 ]. Beyond these absolute steroids [39 ]. reduced LOS. and antibiotics than those seen in initiative is an effective intervention to reduce reuti- && & pediatric EDs [6 ]. inhaled anes. fine- refractory status asthmaticus and acute respiratory tuning and reevaluating these pathways can lead to & failure have been described in a number of case sustained improvement [42 ]. materials that meet the needs of patients with a there are no specific recommendations for the tim. Unfortunately.. Obviously. acidosis. tracheal intubation in children with severe bron. children evaluated in nonpediatric EDs [46 ]. with no change in readmission population. may prevent the need for charge (either from the ED or inpatient setting).co-pediatrics. The most recent involved a case series of Several quality initiatives have also focused on seven pediatric patients who required sevoflurane improving care after admission to the hospital. COPE-D-17-00008 Pulmonology which the spontaneously breathing patient must adherence to guidelines in the inpatient acute care && & generate a greater change in intrapleural pressure [7 ] and intensive care settings [8 ]. wide range of medical literacy [38]. ory treatments [43 ]. the decision on timing of tracheal intu. After implementation. by implementing order sets and asthma therapies. The risks of intubation in ization. and cortico- & passive expiratory phase. thereby relieving the work of breathing. implementation of a standardized asthma diovascular collapse at the time of intubation. if opportunity to reduce the incidence of hospital applied early (facilitated by the concomitant admin. and/or impending respiratory arrest should acute asthma exacerbations. For inhalation after exhausting all other conventional example. clinical pathways. As such. treatment. radiography. costs and potentially worse outcomes. easy-to-read chospasm and respiratory failure. Across the United States of America. a discharge criterion.

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COPE-D-17-00008. Even though all patients had 45. there was improved adherence to evidence-based treatment guidelines. albuterol inhalers to patients discharged home from the ED. Hendaus M.wiley. et al. and decreased cost in sium in addition to standard of care. UK: John Wiley This Cochrane review evaluated the use of noninvasive positive pressure ventila- & Sons. There were only two studies included. 111:967–970. http://doi. This study evaluated the effect of asthma ordersets and an asthma pathway and This article outlines the plan for randomized controlled trial of nebulized magne. Sevoflurane therapy for life- department. children with acute asthma in the emergency department. et al. Migita R. 9:183–189. et al. Early use of noninvasive positive pressure ventilation for Those patients who had an ED visit of hospitalization in the preceding 6 months or asthmatic patients is potentially beneficial. overall LOS in patients who were treated with high-dose infusion of IV magne. Chichester. Pediatr Crit Care Med 2016. The effect of implementation of standardized. Jakobsen JC. Inc. 52:192–196. They found that the use of IV magnesium led to fewer hospitalizations. 47. et al. Kew KM. it is a reasonable option in severe asthma 78. 27. Atkins RC. & reduce length of stay in a pediatric emergency department. Kew KM.CD011050. cessed 23 December 2016] 34. 137:e20150039–e20150039. Zwitserloot AM. Cabral H. readmission rates. Cochrane database of systematic reviews. Rower JE. Emerg Care 2016. Moses J. Aminophylline dosage in asthma exacerbations discharge. This article evaluated pharmacokinetic of magnesium and concluded that the This quality improvement study achieved decreased time to first inhaled short- effective dose of magnesium is likely higher that what is typically used. 60:1759– magnesium. Anti-inflammatory dosing of theophylline in & prevent pediatric asthma reutilization in a satellite hospital. CD012067. 17:261. UK: 21. boration. [Ac- exacerbations. The absence of side effects with supratherapeutic levels as well as the & sion at discharge for patients with asthma: the meds-in-hand project. percentage needed intervention. Local pharmacy partnership to 31. oral corticosteroid use after initial discharge were at higher rates of readmission. Prifti E. Korang SK. Pediatr Emerg Care 2016.pub2. Pediatr & asthma pathway improves evidence-based. Bair-Merritt M. so the authors pub2. 5:624–629. 180:163–169. Increasing medication posses- therapy. & oral corticosteroid prescription fills and readmission in children with asthma. Paediatr Respir Rev 32:157–163. Kenyon C. 51:737–742. 1–6. Br J Anaesth 2013. This article evaluated the safety profile of terbutaline. [Epub ahead of print] patients when comparing aminophylline and ketamine. Respiratory support for children in the emergency 50. 136:e1602–e1610. Pediatrics 2015. In: The Cochrane Collaboration. Yu T. Ocakci AF. Hawcutt D. 2016 . main hesitancy for using theophylline. Quality improvement methods 35. Yu T. only a small && across multiple hospitals. & albuterol dispensing with pediatric asthma revisits and readmissions. Rower JE. Acad Emerg Med 2016. Pineda LC. Paredes F. They 2016. 27:70– and is relatively well tolerated. Griffiths B. 23:279–287. 2017. Hatoun J. acting beta agonist treatment. & acute asthma in the emergency department. Association between postdischarge & department: respiratory support for children. & the treatment of status asthmaticus in children. Keeney GE. Unmet needs at the time of 23. Volume 29  Number 00  Month 2017 Copyright © 2017 Wolters Kluwer Health. Griffiths B. PLoS One 2016. Hosp Pediatr 2015. 2016 . 26. Sinha I. Andrews AL. Doymaz S. Rhodes K. et al. Normansell R. Li R. hospital. Eur J Clin Pharmacol & acute asthma in a pediatric emergency department. & adherence to evidence-based guidelines for pediatric subjects with status This study was the first to evaluate high-dose infusion vs. Irazuzta JE.wiley. Criteria led discharge reduces length of & pediatric asthma.wiley. Pediatrics 2016. editor. et al. Wetterslev J.CE: Swati. et al. Titus MO. et al. et al. Breslin ME. Association of emergency department & children: a randomized. 138:e20153339–e20153339. J Asthma 2016.. Lucia AD. Improving pediatric asthma care and outcomes sinus tachycardia and lower blood pressures after initiating terbutaline. Jat KR. Intravenous and nebulized magnesium sulfate for treating 42. Pediatrics 2016. Ltd. Modification of an established pediatric & acute asthma in children: a systematic review and meta-analysis. decreased ED LOS. Ekim Is ketamine a lifesaving agent in decrease in ED reutilization for patients receiving albuterol inhalers for home use & childhood acute severe asthma? Ther Clin Risk Manag 2016. tory distress in the ED. 49. Clinical pharmacokinetics of magnesium sulfate in 40. Ketamine versus aminophylline for acute asthma in 48. 11:e0159965. PLoS One 2016. Intravenous magnesium sulfate for treating support for life-threatening acute severe status asthmaticus. although there was no This retrospective cohort study evaluated the effect of direct dispensing of placebo group included. 11:283. 53:1–1. controlled trial. Tiwari A. Unauthorized reproduction of this article is prohibited. demonstrated decreased LOS. Dayal the QI team was able to lower the rate of representing to the ED within 30 This systematic review found a lack of evidence for titrating aminophylline based on days. and decreased hospitalization 25. & based order sets on efficiency and quality measures for pediatric respiratory tric asthma (MagNUM PA) trial: study protocol for a randomized controlled illnesses in a community hospital. Total nos of Pages: 6. 73:325–331. 1. J This article showed that there was similar improvements in asthma scores in Asthma 2016. small bolus dosing of IV asthmaticus in the emergency department. Bickel S. et al.