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Home , Acute severe asthma, Asthma, Brittle asthma

Regimens for Managing

Diego J Maselli MD and Jay I Peters MD

Introduction Definition and Importance of Asthma Exacerbations Patients at Risk for Severe Asthma Exacerbations Diagnostic Considerations Pharmacotherapy for Asthma Exacerbations ␤ Short-Acting 2 Agonists Short-Acting Muscarinic Antagonists Systemic Methylxanthines Sulfate Helium- Therapy Patient-initiated Therapy Treatment in the Out-Patient Setting Therapy in the Management of Patients Admitted to the Hospital: Wards and ICU Care Management of Status Asthmaticus in the ICU Unproved Alternate Therapy in Status Asthmaticus Postdischarge Therapy and Importance of an Action Plan Summary

Asthma exacerbation is defined as a progressive increase in symptoms of , , or wheezing sufficient to require a change in therapy. After ruling out diagnoses that mimic an ␤ asthma exacerbation, therapy should be initiated. Short-acting 2 agonists and short-acting mus- carinic antagonists are effective as for asthma in the acute setting. Systemic cor- ticosteroids to reduce airway continue to be the mainstay therapy for asthma exac- erbations, and, unless there is a contraindication, the oral route is favored. Based on the current evidence, nebulized magnesium should not be routinely used in acute asthma. The evidence favors the use of intravenous in selected cases, particularly in severe exacerbations. Methylxanthines have a minimum role as therapy for asthma exacerbations but may be considered in refractory cases of status asthmaticus with careful monitoring of toxicity. Current guidelines recommend the use of helium-oxygen mixtures in patients who do not respond to standard therapies or those with severe disease. Key words: asthma exacerbation; asthma therapy; bronchodilators; severe asthma. [Respir Care 2018;63(6):783–796. © 2018 Daedalus Enterprises]

Introduction . Appropriate evidence-based therapy for exac- erbations is key in an attempt to reduce the burden of these Asthma is one of the most common chronic respiratory acute episodes and help in the rapid recovery of these conditions in children and adults, and is associated with patients. Over the past several decades, there has been an significant morbidity and health-care expenditure, which increase in the understanding of which therapies are ef- is driven in large part by asthma exacerbations. These fective in the management of acute asthma. Both systemic events have significant consequences in asthma quality of corticosteroids and bronchodilators continue to be the cor- life and reduced school and/or workdays, and in the cost of nerstone for therapy in acute asthma, but other therapies,

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 783 THERAPY FOR ACUTE ASTHMA such as magnesium sulfate and helium-oxygen mixtures, and frequent use of rescue are considered to have may have a role, particularly in severe asthma. Advances increased risk of severe asthma exacerbations and death. have been made in determining the best method of deliv- Patients with asthma and with these characteristics should ery and frequency of bronchodilators, and the implemen- be evaluated promptly and treated expeditiously. In addi- tation of patient-initiated therapy has been linked to im- tion, a minority of patients with asthma may experience a proved asthma control. The treatment for acute asthma significant decline in function without a change in varies from the out-patient setting to the ICU. In patients symptoms.3 These “under-perceivers” are at higher risk with severe or life-threatening exacerbations, various ther- for near-fatal exacerbations.4 This article focuses on the apeutic strategies have been studied to improve outcomes. approach to manage exacerbations of asthma. The purpose of this review is to describe the treatment options for acute asthma and the clinical evidence behind Diagnostic Considerations these interventions. Before initiating therapy for an exacerbation of asthma, Definition and Importance of Asthma Exacerbations it is important to exclude conditions that may mimic an acute deterioration of asthma.1 Patients with COPD may The long-term goals for management of asthma are to also have similar symptoms during a COPD exacerbation. achieve good control of symptoms, maintain normal ac- Patients with COPD are typically older and have a signif- tivity, and minimize the risk of asthma exacerbation.1 How- icant history of exposure. Congestive ever, even with optimal care, approximately 10% of pa- is a condition that is also encountered in older individuals tients with asthma will experience a major exacerbation and may present acutely with respiratory symptoms, such that requires oral corticosteroids, an emergency depart- as dyspnea and wheezing. Patients with congestive heart ment visit, or hospitalization once a year.2 failure often have a history of other cardiovascular dis- Exacerbations of asthma are defined as a progressive eases (eg, ), and may have signs and symp- increase in symptoms of shortness of breath, cough, or toms of volume overload, such as , lower ex- wheezing sufficient to require a change in therapy.1 Usu- tremity edema, and evidenced on chest ally exacerbations occur in patients with preexisting asthma radiograph. Other conditions that present with an acute but can be the first presentation of asthma. Most often, deterioration of respiratory status, including , asthma flares or asthma attacks occur as the result of a , , and acute myocar- viral upper respiratory , exposure to an , or dial infarction, should be considered in all patients. the result of poor to controller . Pharmacotherapy for Asthma Exacerbations Patients at Risk for Severe Asthma Exacerbations ␤ Short-Acting 2 Agonists Careful consideration should be carried out in patients with risk factors for severe asthma exacerbations. Patients The pathophysiology of asthma involves increased hy- with exacerbations that led to endotracheal intubation, pre- per-reactivity that results in airway inflammation and bron- vious admissions to the ICU, a history of multiple (Ն3) choconstriction. For this reason, a mainstay of therapy for hospitalizations in the past year or multiple (Ն3) emer- acute asthma involves bronchodilators. The most com- ␤ gency department visits in the past month, the need of monly used bronchodilators in asthma are inhaled 2 ago- ␤ chronic oral corticosteroids use, poor access to health care, nists. Activation of 2 receptor results in stimulation of the adenylyl cyclase, which results in closing of calcium chan- nels and subsequent relaxation of the The authors are affiliated with the Department of Medicine, Division of through inactivation of myosin light-chain kinase and ac- Pulmonary Diseases and Critical Care, UT Health, San Antonio, Texas. ␤ tivation myosin light-chain phosphatase. Inhaled 2 ago- The authors have disclosed no conflicts of interest. nists are classified based on the duration of their effect: ␤ ␤ short-acting 2 agonists and long-acting 2 agonists. Al- Dr Peters presented a version of this paper at the 56th RESPIRATORY CARE buterol, a short-acting ␤ agonist, is the most widely used Journal Conference, Respiratory Medications for COPD and Adult Asth- 2 ma: Pharmacologic Actions to Clinical Applications, held June 22–23, for the treatment of acute asthma. It has a 2017 in St Petersburg, Florida. half-life of 4–6 h and rapid onset of action. Typical ad- verse effects include , nervousness, tremors, Correspondence: Jay I Peters MD, Department of Medicine, Division of and chest pressure. Pulmonary Diseases and Critical Care, 7400 Merton Minter MC 111E, San Antonio, Texas, 78229. E-mail: [email protected]. Albuterol can be delivered via the inhaled route, admin- istered orally, or administered intravenously. During an DOI: 10.4187/respcare.05953 asthma exacerbation, the inhaled delivery form is favored

784 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 THERAPY FOR ACUTE ASTHMA over the other modalities. During this stage of treatment, Systemic Corticosteroids albuterol can be delivered through a pressurized metered- dose with a spacer (5 puffs followed by 3–5 puffs Corticosteroids have a pivotal role in the treatment of every 20 min) or via nebulization.5 Costs may vary from asthma by reducing airway inflammation. Although asthma institution to institution, with some institutions using neb- corticosteroids are routinely delivered by the ulizers more frequently in the initial stages. There is con- route for stable disease, during an exacerbation, systemic troversy regarding the benefits of continuous versus inter- corticosteroids are preferred. Systemic corticosteroids are mittent inhaled albuterol. A systematic review of 6 studies recommended for all but the mildest asthma exacerbations. that included 393 subjects found equivalence of continu- Despite considerable debate regarding the mode of deliv- ous compared with intermittent albuterol during an asthma ery, intravenous or intramuscular routes do not provide significant advantages over the oral route.14 The oral route exacerbation.6 Nevertheless, a subsequent meta-analysis is preferred if the patient is able to tolerate taking oral of 8 studies that totaled 461 subjects found that continuous medication and there are no concerns for abnormal intes- treatment with albuterol reduced hospital admissions in tinal absorption.1 The dose that is recommended for an subjects with severe asthma who presented to the emer- asthma exacerbation is 50 mg of (or predni- gency department and improved lung function compared sone) or its equivalent for 5–7 days.1 Longer-duration reg- 7 with intermittent delivery. For these reasons, it is recom- imens have not been found to be superior.15,16 mended that patients receive continuous therapy in the Early administration of systemic corticosteroids has been earlier stages of therapy, particularly for severe exacerba- associated with improved outcomes.17 Although written tions, with a change to intermittent dosing at the later asthma action plans may advocate doubling the dose of stages of therapy and after the patient’s symptoms im- inhaled corticosteroids during an exacerbation, a system- prove.1 The addition of intravenous albuterol to an inhaled atic review of 8 randomized controlled trials, which in- regimen has not consistently shown benefit and is cur- cluded 1,669 subjects with mild-to-moderate asthma, found rently not recommended.8,9 Oral preparations of short-act- no significant reduction in the odds of requiring oral cor- ␤ ing 2 agonists, such as , are not recommended ticosteroids after increasing the dose of inhaled corticoste- during an asthma exacerbation because the effects are not roids compared with a stable dose.18 Despite these find- superior to inhaled preparations, have a slower onset of ings, other studies found benefits of administering inhaled action, and have an increased incidence of adverse ef- corticosteroids during the initial presentation of an asthma fects.1,10 exacerbation in the emergency department.19 For milder exacerbations, early use of high-dose inhaled corticoste- roids may be an alternative for oral corticosteroids.19 Short-Acting Muscarinic Antagonists Methylxanthines Inhaled muscarinic antagonists are bronchodilators fre- quently used during asthma exacerbations. These medica- and , the most widely used tions block the action of acetylcholine on muscarinic re- methylxanthines in asthma, are nonselective phosphodies- ceptors and results in a decrease in cyclic guanosine terase inhibitors. Inhibition of this enzyme raises intracel- monophosphate and alterations in intracellular calcium con- lular cyclic monophosphate, activates protein centrations, with subsequent airway smooth-muscle relax- kinase A, and may have other immunomodulatory effects. In addition, this class of medications can activate, nonse- ation. Treatment with muscarinic antagonists results in lectively, adenosine receptors.20 Potential beneficial clin- bronchodilation and decreased mucus production. This ical effects include bronchodilation, improved mucociliary class of medications is classified into short-acting musca- transport, and enhanced diaphragmatic contractility.20 rinic antagonists and long-acting muscarinic antagonists. These properties make this class of medications an attrac- , a short-acting muscarinic antago- tive option for the treatment of asthma exacerbations. Am- nist, was shown to decrease hospitalizations in children inophylline, which is administered intravenously, has been 11,12 and adults with an asthma exacerbation. Combination studied more extensively in this setting. A meta-analysis ␤ therapy of ipratropium and a short-acting 2 agonist re- of 17 studies that explored the effects of adding intrave- sults in improvements in lung function compared with nous aminophylline to inhaled ␤ agonists for the treat- ␤ 2 short-acting 2 agonists alone, particularly during severe ment of asthma exacerbations found no benefit with regard exacerbations.11-13 It is recommended to add ipratropium to bronchodilation or the risk for hospital admission.21 to the bronchodilator regimen in patients with asthma with Importantly, compared with placebo, aminophylline was a moderate-to-severe exacerbation, especially in the initial associated with an increased incidence of and stages of treatment.1 or .21 The cardiac adverse effects

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 785 THERAPY FOR ACUTE ASTHMA have been linked to activation of adenosine receptors and Intravenous magnesium sulfate delivery was considered may be related to serum levels.20 Because of the safety superior to the nebulized form with regard to breathless- ␤ 29 profile and superior bronchodilation effects of inhaled 2 ness when measured by using a visual analog scale. agonists, intravenous aminophylline is not recommended Based on the current evidence, nebulized magnesium for the treatment of acute asthma.1 Aminophylline may should not be routinely used in acute asthma. There is have a role in refractory asthma, but patients with refrac- evidence that the use of intravenous magnesium sulfate is tory asthma should be closely monitored for adverse ef- favored in selected cases. In patients with a severe asthma ␤ fects. exacerbation with a poor initial response to inhaled 2 agonists, an infusion of2gofmagnesium sulfate delivered Magnesium Sulfate over 20 min may be considered.1

Magnesium sulfate interferes with calcium ion transport Helium-Oxygen Therapy in the membranes of smooth-muscle cells, which results in relaxation.22,23 Various studies explored the effects of both Helium-oxygen mixtures may increase the deposition of nebulized and intravenous magnesium sulfate for the treat- inhaled particles in the distal airways. Therefore, this mode ␤ ment of asthma exacerbations. A meta-analysis of 7 trials, of delivery of medications (ie, 2 agonists) is an attractive with a total of 668 subjects with asthma, investigated the alternative for the treatment of patients with asthma exac- effects of intravenous magnesium sulfate in acute asthma erbation. Various studies evaluated the efficacy of helium- and found no improvements in hospitalization rates or pul- oxygen mixtures in acute asthma. A systematic review, monary function.24 However, a subgroup analysis of those which included 10 studies and 697 subjects, showed that subjects with severe asthma exacerbations (varying defi- treatment with a helium-oxygen mixture was associated Ͻ 30 nitions at presentation: FEV1 25–30% predicted, peak with a significant improvement in PEF. Notably, a sub- expiratory flow (PEF) Ͻ 60% predicted, or poor initial group analysis revealed that the effect was more promi- ␤ response to inhaled 2 agonists), revealed improvements nent in subjects with severe and very-severe asthma. There in hospitalization rates and lung function with a number also was a reduced rate of hospitalizations associated with needed to treat of 5.24 the use of a helium-oxygen mixture.30 Current guidelines The studies of inhaled magnesium sulfate in asthma recommend the use of helium in patients who do not re- have mixed results. A study that compared the effects of spond to standard therapies or in those patients with very- nebulized magnesium sulfate as an add-on therapy to neb- severe disease.1 ulized albuterol in 74 subjects with asthma and with mild- to-moderate exacerbations showed no improvements in Epinephrine pulmonary function.25 In contrast, a placebo-controlled double-blind clinical trial that included 60 subjects under- Epinephrine should be used only if asthma is associated going a severe asthma exacerbation found improvements with or angioedema. It is recommended that after treatment with inhaled magnesium sulfate in post– this therapy should not be used routinely during an asthma 1 bronchodilator FEV1 and compared with exacerbation. Although epinephrine can be administered placebo.26 Another study, in subjects with severe asthma directly into an endotracheal tube, there is insufficient ev- Ͻ exacerbations, defined as FEV1 50% predicted on pre- idence to support the routine use of this mode of delivery sentation, also showed improvements in lung function af- in patients with due to acute asthma.31 If ter adjuvant therapy with nebulized magnesium sulfate to there is a history of anaphylaxis, the patient and close salbutamol.27 family should be proficient in the self-administration of Although it seems that, in the pediatric population, the epinephrine by using a pre-packaged self-injection kit. If use of nebulized magnesium may have a role in mild-to- an asthma exacerbation is associated with anaphylaxis, moderate exacerbations, there is evidence that favors the epinephrine should be administered as soon as the symp- use of this therapy in severe exacerbations.28 Most re- toms develop. cently, Goodacre et al29 studied the effects of nebulized or intravenous magnesium sulfate in acute asthma in a large Patient-Initiated Therapy double-blind placebo-controlled multicenter trial. A total of 1,109 subjects with severe acute asthma evaluated in the All patients with asthma, particularly those with a his- emergency department from 34 centers in the United King- tory of exacerbations, should be provided with an asthma dom were included in the study.29 The rate of hospitaliza- action plan. The asthma action plan is a set of written tion did not differ between the controls and either form of instructions created by the provider specifically for each magnesium sulfate, and the rate of hospitalization also was patient. It provides a guide for patient-initiated therapy not different between the nebulized or intravenous forms.29 according to self-monitored symptoms and/or PEF, and

786 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 THERAPY FOR ACUTE ASTHMA

History and physical exam

Confirm the diagnosis of asthma

MILD to MODERATE SEVERE VERY SEVERE

- Can speak in - Speaks in incomplete - complete sentences sentences - Drowsiness - Pulse 100-120 beats/min - Frequency > 30 breaths/min - Silent chest

- SpO2 > 90% - Use of accessory - PEF > 50% respiratory muscles - Pulse > 120 beats/min

- SpO2 < 90% - PEF < 50% - Albuterol 4–10 inhalations via pMDl/20 min for x 3 or - Albuterol 2.5 mg nebulization Transfer to the - O if SpO < 93% 2 2 emergency - Oral prednisone department 50 mg

- PEF > 60-80% - SpO > 94% Re-evaluate in 1 hour 2 NO - Adequate support system

YES Discharge

Fig. 1. Treatment of asthma in the out-patient setting. The diagnosis of asthma is based on a history, physical examination, family history, and . Disorders that mimic asthma include congestive heart failure, COPD, pulmonary embolism, , tracheal tumors, , and . PEF ϭ , pMDI ϭ pressurized metered-dose inhaler. From Reference 1, with permission. provides a framework on when to seek medical care.1 The contact their provider to alert them about a self-managed use of an asthma action plan has been associated with exacerbation so that adjustments in the therapy can be reductions in unscheduled office and emergency depart- made. ment visits and hospitalizations.32 An asthma action plan typically has recommendations regarding when to use ex- Treatment in the Out-Patient Setting tra doses of albuterol. The need for extra doses of albuterol after 1–2 d typically signals the need for additional ther- Unscheduled out-patient visits due to asthma are frequent. apy. Doubling the dose of inhaled may ben- Patients evaluated in this setting for acute asthma should be efit some patients, but it has not been consistently shown interviewed and physical examined promptly to determine if to improve outcomes.18 In the majority of patients, the there are any life-threatening conditions. A focused history asthma action plan should include instructions regarding and examination should be carried out in all patients. Even in oral corticosteroids. It has been recommended for patients those patients in whom asthma is a well-known diagnosis, an to receive 40–50 mg of every day for 5–7 d if effort should be made to reasonably rule out asthma-mim- symptoms do not improve after 2–3 d of increasing the icking conditions. The history should be focused on the tim- frequency of reliever inhaled medications (ie, albuterol), ing of the symptoms, any identifiable cause (eg, exposures, there is a rapid deterioration of their symptoms, the FEV1 , non-adherence), severity of symptoms, previous or PEF to Ͻ60% predicted, or if there is a history of severe severe exacerbations, and any changes in medication and/or sudden exacerbations.1 At this point, patients should regimens.1 The physical examination is critical to de-

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 787 THERAPY FOR ACUTE ASTHMA cide the level of care that the patient will require (Fig. so continuous monitoring of these patients is warranted. In 1). Patients with mild-to-moderate disease can speak in the advanced stages of an asthma exacerbation, the pul- complete sentences, have an increased fre- monary physical examination may reveal a silent chest, quency, a resting pulse of 100–120 beats/min, oxygen which may herald impending respiratory failure. Patients saturation of 90–95%, and PEF Ͼ 50% predicted. with severe asthma should also be monitored for potential Patients with a severe asthma exacerbation speak in complications of asthma, such as pneumothorax, pneumo- incomplete sentences, typically sit in a forward position , and anaphylaxis. (also known as a tripod position), have a breathing fre- If possible, and without delaying therapy, all patients quency Ͼ30 breaths/min, use accessory respiratory should have an objective measure of their lung function muscles, have a resting pulse Ͼ120 beats/min, oxygen because health-care professionals may underestimate or saturation Ͻ90%, and PEF Ͻ50% predicted. Patients with overestimate the severity of the clinical presentation. PEF life-threatening asthma present with confusion, drowsi- or FEV1 measurements should be performed every hour to ness, and a silent chest on physical examination (the bron- assess the progression of the disease and determine the chospasm is so severe that there is minimal movement of therapy and the need for hospitalization. An oxygen satu- air through the airways). Patients with a mild-to-moderate ration of Ͻ90% indicates the need for intense therapy.1 asthma exacerbation can be safely treated as an out-patient Arterial blood gas determinations are not indicated in all

(Fig. 1). patients but should be considered in patients with FEV1 These patients should be treated with albuterol 4–10 Ͻ 50% predicted.33 Patients with a P Ͻ 60 mm Hg or aO2 via pressurized metered-dose inhaler every an oxygen saturation Ͻ 90% should be treated with sup- 20minfor1horasingle treatment (2.5 mg plemental oxygen. Although a chest radiograph is not rou- albuterol). Oral steroids should be administered at this tinely recommended in asthma, it should be obtained in all time. Oxygen should be administered if oxygen saturation patients with atypical features and in those who do not is Ͻ93%. After 1 h, the patient should be reevaluated. If respond to initial therapy. there is improvement in the symptoms or PEF, the patient Inhaled albuterol should be administered promptly. Al- may be discharged. The asthma action plan should be though most patients will respond adequately to intermit- carefully reviewed with the patient, and oral corticoste- tent dosing, continuous nebulization has been effective in roids should be continued for 5–7 d. A follow-up appoint- severe asthma exacerbations (10–15 mg/h or 0.5 mg/kg/h ment should be scheduled 2–7 d later to verify the im- in children).7 Systemic corticosteroids should be adminis- provement of symptoms.1 Patients who do not improve tered within the first hour of presentation, unless the PEF Ͼ after 1 h of therapy, or those with a severe or life-threat- or FEV1 is 70% their personal best or of predicted after ening exacerbation should be emergently transferred to the 30 min of therapy. All patients with moderate-to-severe emergency department or acute care facility. While wait- exacerbations should receive systemic corticosteroids. Pa- Ͻ ing for transport patients should be treated with albuterol tients should be hospitalized if the PEF or FEV1 is 25% and ipratropium bromide, oxygen, and systemic cortico- of their personal best or of predicted before therapy, or if, steroids. after1hoftherapy is Ͻ 40% of their personal best or predicted.34 Discharge may be considered, depending on Therapy in the Emergency Department the patient risk factors if the lung function is 40–60% predicted after therapy. Patients with a lung function Ͼ 60% Patients with mild-to-moderate asthma exacerbations should be discharged after consideration of the risk factors may present to the emergency department to seek medical and with establishing appropriate follow-up. High-risk pa- care. These patients should be treated as an out-patient tients are those with a history of a near-death event or when following the recommendation detailed above. Pa- intubation, noncompliance, or psychiatric illness, or with tients with severe or life-threatening asthma should always difficulty accessing a medical care. be managed in the emergency department. A focused, ex- pedited history and physical examination should be carried Management of Patients Admitted to the Hospital: out in all patients. It is critical to rule out other conditions Wards and ICU Care that may mimic a severe asthma exacerbation, such as pneumonia, congestive heart failure, pneumothorax, and Careful consideration must be given to the level of care . In patients with a severe exacerba- required when a patient with an exacerbation of asthma is tion, careful attention should be placed on the level of admitted to the hospital. In general, guidelines suggest that consciousness, oxygen saturation, breathing frequency, patients should be admitted for observation and further Ͻ resting pulse, and , and on the use of ac- treatment if the pretreatment FEV1 or PEF is 25% of cessory respiratory muscles. Patients with severe asthma predicted or of personal best or if the post-treatment values may have a fast deterioration of their clinical presentation, are Ͻ 40% after emergency department treatment. Typi-

788 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 THERAPY FOR ACUTE ASTHMA cally, patients who demonstrate a poor response to therapy the patient has been adherent to treatment with inhaled Ͻ ( 10% increase in PEF/FEV1), persistent or unresponsive corticosteroids. , altered mental status, , or have significant comorbid conditions (myocardial ischemia, Management of Status Asthmaticus in the ICU tachyarrhythmias, or pneumonia) should be admitted to the ICU. Patients admitted to the ICU include individuals who re- Therapy on an in-patient unit is similar to treatment quire ventilator support or those with severe asthma for whom given in the emergency department and inhaled ␤ agonist therapy failed. Most often they have refractory hypercapnia, (2.5 mg) is usually given every 1–4 h by nebulization. persisting or worsening , deteriorating PEF/FEV1, Dosing intervals are usually based on the patient’s clinical drowsiness, confusion, or impending signs of respiratory ar- status by evaluating the level of dyspnea, breathing fre- rest. Elective intubation by an experienced clinician is always recommended as soon as signs of deterioration are present. quency, and PEF/FEV1 before and after treatments. One study in hospitalized patients found that intermittent on- Intubation and may lead to hypoten- demand therapy resulted in fewer nebulizations, fewer pal- sion and secondary to high positive intrathoracic pitations, and a shorter hospital stay compared with 4-hourly pressures. Care must be taken to assure that intravascular intermittent therapy.35 Transitioning from nebulization to volume is adequate before intubation, and a bolus of intra- a pressurized metered-dose inhaler with a holding cham- venous normal saline solution is often recommended before ber can be initiated once the patient is stable, and, typi- initiation of mechanical ventilation. 42 cally, 4–6 puffs of a short-acting ␤ agonist are given An observational study by Darioli and Perret demon- every 4–6 h. If the spacer and/or holding chamber is not strated a strategy of permissive hypercapnia, achieved by made with anti-static plastic, then guidelines suggest that limiting peak airway pressures to 50 cm H2O, resulted in they be pre-washed with detergent and air-dried or primed decreased mortality when compared with historic controls. Despite a lack of high-quality evidence that supports this with at least 20 puffs of albuterol before use.1 practice, this approach has become the standard of care. Although many patients maintain good oxygen satu- Hypercapnic may cause cerebral vasodilata- rations despite severe , some patients tion, cerebral edema, and pulmonary vasoconstriction, develop small airway mucus plugging even after the and should be avoided in patients with increased intra- PEF/FEV normalize. Guidelines suggest that oxygen 1 cranial pressure (as might occur with anoxic brain in- should be administered via nasal cannula or oronasal jury after cardiopulmonary arrest). However, hypercap- mask to maintain an arterial oxygen saturation of 93– nia is usually well tolerated by most patients as long as 95% in adults and 94–98% in children. In severe exac- 42 the PaCO does not exceed 90 mm Hg. Low values of erbations, low-flow oxygen therapy by titrating the 2 arterial pH are tolerated by most patients, but sodium saturation to 93–95% was associated with better phys- bicarbonate may be considered in the setting of an ar- iological outcomes than with high-flow 100% oxygen terial pH Ͻ 7.20.43 36-38 therapy. Although there are no studies that determined the optimal The role of continuing short-acting mode of mechanical ventilation, it seems prudent to use the therapy is controversial, and most guidelines do not mode with which one is most familiar. Most researchers have recommend that ipratropium be continued once the pa- recommended an initial minute ventilation of 90–130 mL/kg tient is admitted to the hospital. One study in adults ideal body weight (approximately 6–9 L/min for a 70-kg indicated that these patients benefitted from the addition patient), with further adjustments based on pH and the pla- of ipratropium for up to 3 days after admission.39 How- teau airway pressure. Based on studies by Tuxen and Lane44 ever, a study in hospitalized children found no benefit and Peters et al,45 we usually use a tidal volume of 8–9 mL/kg when nebulized ipratropium bromide was added to neb- with a breathing frequency of 10–14 breaths/min, a flow of ulized albuterol.13 100 L/s, and 0 PEEP. However, many institutions prefer to The guidelines suggest that oral corticosteroids should use tidal volumes of 6–8 mL/kg ideal body weight.44,45 We be continued at a daily dose equivalent to 50 mg of pred- adjust the setting to maintain a plateau pressure of 30 cm H2O nisolone or prednisone as a single morning dose or 200 mg and judiciously adjust ventilator-applied PEEP based on its of in divided doses for adults or 1–2 ability to lower intrinsic PEEP. mg/kg/d up to a maximum dose of 40 mg in children.1 Special consideration for the treatment of severe asthma in This dose is continued for the duration of the hospitaliza- the ICU needs to be addressed because larger and more- tion, and patients are frequently sent home after complet- frequent doses are needed in because the ing a 5–7–d course of prednisone for adults and 3–4–d dose-response curve and the duration of activity are adversely course for children. Results of studies40,41 indicated that affected by the degree of .46 Our approach tapering the course of prednisone is not needed as long as for adults in the ICU is to use continuous nebulization of

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 789 THERAPY FOR ACUTE ASTHMA albuterol until the patient stabilizes, with a breathing fre- dard care with inhaled bronchodilators and corticoste- quency of Ͻ 30 breaths/min, a heart rate Ͻ 120 beats/min, roids, some patients with near-fatal asthma may gain and stable or improving hypercapnia. There are data to sup- benefit with intravenous aminophylline.8 The usual load- ␤ port the concept that higher doses of 2 agonists are required ing dose of 5 mg/kg is given intravenously over 20 min in the setting of mechanical ventilation. MacIntyre et al47 and then infused at a rate of 0.5–0.7 mg/kg/h. Such demonstrated that only 2.9% of a radioactive aerosol deliv- patients are rare, and the potential adverse effects are ered by a small-volume nebulizer was delivered to the lower not uncommon (arrhythmias and vomiting). Blood lev- airway. One approach is to measure the change in peak-to- els should be checked daily for all patients receiving plateau pressure after nebulizing 2.5 mg of albuterol and by aminophylline infusions. observing the effect. If the peak-to-plateau pressure does not Oral inhibitors have been shown to increase decrease by Ն15%, then we increase the dose by 2.5 mg in FEV1 within 1–2 h, but their usefulness in the setting of an incremental manner until the gradient decreases or the exacerbation of asthma is unclear. In a randomized place- patient experiences toxicity (tachycardia or muscle tremors). bo-controlled trial of Ͼ 500 adults with severe asthma With the newer high efficiency , we have not had Յ (FEV1 50% after1hoftreatment), intravenous mon- to go above a dose of 5.0 mg for any patient. telukast significantly improved the FEV1 at 60 min but did Although guidelines suggest that patients with exacerba- not reduce the need for hospitalization.54 Because oral tions of asthma should be treated with no more than 40– is rapidly absorbed and has a strong safety 80 mg of prednisolone or 200 mg of hydrocortisone per day, profile, we have used 10 mg of montelukast via the oral- our practice has been to use higher doses of intravenous gastric tube in intubated patients with asthma for whom 48 in this population. Haskell et al showed initial therapy failed. that subjects with status asthmaticus who received 125 mg of ␤ The routine use of systemic 2 agonists are not recom- intravenous methylprednisolone every 6 h improved more mended in the routine therapy of exacerbations of asthma. rapidly than subjects who received 40 mg of drug over the Some guidelines suggest the potential benefit of subcutane- first2doftreatment. Both 125-mg and 40-mg doses were ous epinephrine in patients who do not respond to standard superior to the 15 mg every 6-h dose.48 Although the ultimate therapy or if there is a suspicion of anaphylaxis.1 In one improvement was not different in this study, we tend to use study, 60% of the subjects who did not respond to2hof the higher doses of corticosteroids for the first 24–48 h un- inhaled ␤ agonists, expiratory flow increased after subcuta- less the patient has poorly controlled diabetes. This study was 2 neous administration of epinephrine.55 It should not be used not powered to show a difference in length of intubation or in patients with coronary artery disease, and care must be ICU stay but supports the concept of considering higher doses taken to avoid hypokalemia, , or tachyarrhyth- of corticosteroids in patients with severe asthma who are mias. intubated.48 Adverse effects, such as hyperglycemia, sleep disturbance, or mental status changes, may be more likely at Historically, general anesthesia was occasionally used in these higher doses. patients with refractory status asthmaticus. More recently, and have been used because of their abil- Unproved Alternate Therapy in Status Asthmaticus ity to reduce bronchoconstriction. Propofol can be titrated to anesthetic depth sedation and often reduces the need of neu- Although the application of noninvasive ventilation (NIV) romuscular blockade in patients with a rapid breathing fre- has proved to be safe and effective in COPD, the use of NIV quency, but caution should be exercised because there have in severe asthma is not clearly defined. A systematic review been reports of propofol-induced .56 Ketamine, found 5 studies with Ͼ200 subjects with severe asthma an intravenous general anesthetic, has sedative, analgesic, randomized to NIV or placebo.49 Two of the studies and bronchodilating properties.57 Ketamine has sympathomi- found no difference in the number of subjects who re- metic properties and may increase intracranial and systemic quired intubation and mechanical ventilation;50,51 blood pressure, and may induce tachycardia. whereas one study demonstrated fewer admissions in There are case reports of the use of extracorporeal life the NIV group.50 NIV should not be attempted in pa- support in patients with refractory status asthmaticus who tients who are agitated or uncooperative, and patients have progressive hypercapnia and respiratory acidosis despite should be monitored closely if NIV is attempted. Al- mechanical ventilation and aggressive inhaled and systemic though retrospective studies are encouraging about the therapy.58 Fulminant asthma would seem like an ideal setting potential benefits of NIV, in our experience, many pa- for extracorporeal life support because the disorder is revers- tients with acute, severe asthma are unable to tolerate ible and seldom associated with multi-organ failure. Fortu- NIV.52,53 nately, extracorporeal life support is rarely indicated because Although intravenous aminophylline is not likely to result the outcome with more conservative therapy is almost always in any additional bronchodilation when compared with stan- successful. However, results of studies indicate that it may be

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Hasegawa T, Ishihara K, Takakura S, Fujii H, Nishimura T, Okazaki M, nosis of an asthma exacerbation is confirmed. Systemic cor- et al. Duration of systemic corticosteroids in the treatment of asthma ticosteroids should be administered without delay, and, unless exacerbation; a randomized study. Intern Med 2000;39(10):794-797. there is a contraindication, the oral route is preferred. Nebu- 16. Jones AM, Munavvar M, Vail A, Aldridge RE, Hopkinson L, Rayner lized magnesium is not routinely recommended based on the C, O’Driscoll BR. Prospective, placebo-controlled trial of 5 vs 10 findings of recent trials. Although controversy exists, intra- days of oral prednisolone in acute adult asthma. Respir Med 2002; 96(11):950-954. venous magnesium sulfate can be beneficial in severe exac- 17. Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. erbations. 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Discussion call it cough variant asthma but cough Rubin: People in the ICU who die dominant is preferred because nearly of asthma don’t die of albuterol defi- Peters: I’ll start off by asking a ques- all have additional asthma symptoms ciency, and they’ve almost all received tion of myself and of the others here. when queried. These are the patients steroids; if they haven’t, it’s surpris- In the asthma literature, when some- who, when we do a bronchial chal- ing. Studies that looked at fatal asthma, one comes in with acute severe asthma lenge test, have a slow recovery in particularly the large Prairie Provinces you start by checking a peak flow or their lung function. These are also fatal asthma study some 20 years ago, FEV1. The patient is often breathing some of the patients who we’re look- showed that, on autopsy, these airways 30 breaths/min and very tachycardic. ing at, but there seems to be a sub- are just plugged up with mucus,3,4 and You start the treatment, and, after group of these secretory hyper- the mucus in asthma is actually far 30 min to an hour of treatment, the responders. We’ve postulated that they more viscous and tenacious than that patient’s breathing frequency and heart may be a subgroup of patients who of either or COPD se- rate are better, yet the patient’s peak respond better to anticholinergics. cretions. flow and FEV1 have not significantly improved. How do you explain this? Peters: That’s very interesting. As Peters: Again, this wasn’t a talk My answer to this is, obviously, when a junior faculty, we would see these about mechanical ventilation or I you have significant , you people admitted to the hospital, and might have to take my gloves out and challenge Neil [MacIntyre] to a box- dilate your airways, and, as you get their FEV would completely normal- 1 ing match because we approach me- rid of the trapped air, your FEV1 and ize, and they would say, “I feel fine” chanical ventilation in status asthmati- peak flow may not change but your but they were still hypoxic and requir- residual volume decreases and your cus quite differently.5 However, I think ing O . We would say: “OK, let’s work work of breathing improves. So, the 2 the smartest thing Neil ever said to me them up for pulmonary embolism and physiology of acute asthma has some was “Use the mode of ventilation get a CT angiogram. They would of- features similar to COPD studies that you’re most comfortable with” be- ten get this huge workup and then, show that one cannot rely solely on cause these patients have complicated over 4-5 days, they would finally nor- the change in FEV to determine if a and dynamic airway physiology and 1 malize the oxygen saturation on room bronchodilator therapy is beneficial.1 you really need to know how to make air. Sometimes we would start them I say that, without doing adjustments in your ventilator settings. or some assessment of air-trapping, on CPAP or BPAP. Frequently, these So we don’t use pressure control in you really don’t know what the opti- asthmatics would come in over and our medical ICU because that is not mal treatment is. over again with the same problem, and, the mode we use the most. But I feel after the second or third admission, Bruce [Rubin] is right, mucus plug- Rubin: Jay, your last comment I we would finally say, “OK this is ei- ging is a big problem and may require think nailed it. When we hear world ther small airway mucus plugging with changes in ventilator settings and close experts talk about acute asthma, they or its micro-. So observation in suctioning these pa- talk about inflammation and broncho- let’s quit working them up for shunts tients when secretions cause problems. spasm and mucus hypersecretion, and and other causes of hypoxemia be- then they’ll speak for 45 min about cause they clearly follow the same pat- MacIntyre: I don’t think we dis- biomarkers, bronchospasm, and med- tern over and over.” I think as we see agree much at all. I think the way you ications, and I never hear mucus again. these patients, we get more comfort- harm someone on a ventilator with And, indeed, there are some patients able saying exactly what you said is asthma (or COPD, for that matter) is who have what we call secretory hy- their pathophysiology. Some asthmat- you don’t recognize the air-trapping per-responsiveness,2 which seems to ics clearly develop mucus plugging and how much it’s driving up overin- be driven, in part, by elas- and atelectasis that requires a longer flation of the thorax and how much tase. Some of these patients have period of time to resolve than their it’s impairing venous return. I think cough dominant asthma; we used to bronchospasm. the air-trapping, like Bruce said, is

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 793 THERAPY FOR ACUTE ASTHMA driven to a large extent by small air- see that the inappropriate use of PEEP monary arrest. In spite of this, most ways and mucus plugging. may do more harm than good. We try patients are successfully resuscitated to only use PEEP in low doses when and are able to be treated for the acute Peters: We went through and looked using ventilation in patients in status asthma episode. They get through the at all the early literature.6-8 Almost asthmaticus and only when we can status asthmaticus but die of the brain every death in people with status asth- document that the static compliance injury. maticus (Ͼ80%) was related to an- gets better and the air-trapping actu- oxic brain injury from acute cardio- ally gets less when we add PEEP. I Peters: That’s a very good point pulmonary arrest on the wards before feel PEEP is a double-edged sword in because most people who die of they got to the ICU. There are patients this setting. asthma die before they ever get to who are morning dippers who develop the hospital. I was talking about the worsening obstruction late at night.9 I †Hess: But is not that a minute ven- percentage who die in the hospital, feel that our failure to follow peak tilation effect primarily? and usually they die of either com- flows or FEV1 for the first couple of plicating factors (eg, pneumonia or days is very big mistake because some MacIntyre: Oh yes. The 3 factors sepsis) or their severe disease. They patients do pretty well where their peak that drive air-trapping are minute ven- also die because physicians under- flows are up at 60-70% and the next tilation, the inspiratory-expiratory ra- estimate their severity and they’re morning they’re down to 30-40%. tio, and lung mechanics. admitted to the ward rather than in Those people really need to be in a an area where they’re closely ob- monitored area and are at high risk for Lugogo: I agree with what was said served. But that’s a very good point. ending up in the ICU. regarding the most common cause Every year we have a case in our of death in fatal asthma events. In city of a young person who died at *Newhouse: The corollary of what my experience, the patients who died home, many of them with mild has just been said by Bruce and Neil is of status asthmaticus died of com- asthma who unexpectedly had an that the FEV1 and peak flow are lousy plications related to acute brain in- acute severe attack. It also brings up tests of peripheral airway obstruction. jury. In the few cases I have seen, the point that patients with severe the patients had cardiopulmonary ar- asphyxic asthma have severe exac- Peters: Well said. rest at home, which seems to me is erbations associated with the use of an indication that people don’t know or nonsteroidal anti-inflam- †Hess: Your hypothesis of why NIV when they’re in trouble or under- matory drugs. Again, the EPR-3 may be beneficial in asthma due to perceive the fact that they are in trou- guidelines11 recommend that patients reversing atelectasis is appealing. But ble. Quite often it seems like these with asthma severe enough to be hos- could it also be the result of the pos- patients are those with milder asthma pitalized avoid aspirin and nonsteroi- itive pressure providing mechanical at baseline and, therefore, are not on dal anti-inflammatory drugs. bronchodilation, as a non-medication any therapy before the fatal event. In bronchodilator? fact, our patients with severe asthma *Newhouse: There’s the very fa- seem to be the ones who know what mous silent chest story, where the pa- Peters: It’s interesting because, in the to do. They tend to double their ste- tient is sent to the floor because the physiology literature, the strongest bron- roids and use their bronchodilators, wheezing has gone away and was chodilator I know is a healthy patient and call the office for assistance with found dead the next morning. taking a large, deep breath. If you think their symptoms. It is the people who about it, that theory that positive pres- are not quite as severe who don’t have Wise: I would like to raise a ques- sure may be acting as a bronchodilator the perception of when things are go- tion. You mentioned treatment of gas- rather than just getting rid of the atel- ing south. I know that there is a small troesophageal reflux disease in asthma ectasis is also quite interesting. proportion of patients who have acute and we’ve done studies in both adults asphyxic asthma who go from being and children without symptomatic gas- MacIntyre: Just be careful; it’s a well to not well very quickly, and that’s troesophageal reflux disease or heart- two-edged sword. The positive pres- a tricky situation. But the vast major- burn, and the use of proton pump inhib- sure may offer some advantages as ity of people have days of slowly pro- itors in those kids was not at all effective you guys have described, but it can gressive deterioration in symptoms be- in preventing asthma exacerbations.12,13 also contribute to the air-trapping. fore they become acutely unstable. Unfortunately, by the time they call Peters: I think that’s very impor- Peters: That’s a very good point. In for help, depending on where they live, tant to . There are randomized the studies by Tuxen10 and others, you they might have suffered a cardiopul- controlled studies that randomized

794 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 THERAPY FOR ACUTE ASTHMA subjects with asthma to proton pump viously, with regard to regularly REFERENCES ␤ inhibitors or placebo, showing no scheduling short-acting 2 agonists. benefit in patients who did not have The reason I keep beating this drum 1. McFadden ER Jr, Kiser R, DeGroot WJ. symptomatic gastroesophageal re- is that we have precious little time Acute bronchial asthma. Relations be- flux disease. However, there is a with patients with chronic lung dis- tween clinical and physiologic manifes- study published by the National Jew- eases when they’re in acute care set- tations. N Engl J Med 1973;288(5):221- 225. ish group14 that evaluated subjects tings, and we need to leverage that with refractory asthma who did not 2. Rubin BK, Priftis KN, Schmidt HJ, Henke time to the maximum to prepare them MO. Secretory hyperresponsiveness and respond to maximum asthma ther- for success after discharge. This must pulmonary mucus hypersecretion. Chest apy. When they performed an en- include clawing back time we spend 2014;146(2):496-507. doscopy, they found pretty signifi- with these patients on unnecessary 3. Hessel PA, Mitchell I, Tough S, Green cant upper airway and esophageal FH, Cockcroft D, Kepron W, Butt JC; care. We could be sending respira- changes consistent with gastroesoph- Prairie Provinces Asthma Study Group. tory therapists or others into these Risk factors for death from asthma. Prai- ageal reflux disease. These subjects’ rooms to better prepare and educate rie Provinces Asthma Study Group. Ann asthma improved with aggressive our patients and families. When as- Allergy Asthma Immunol 1999;83(5): gastroesophageal reflux disease ther- 362-368. ␤ apy, and some even required surgi- suming that short-acting 2 agonists 4. Rubin BK, Tomkiewicz R, Fahy JV, Green cal fundoplication to control their are not used as a treatment enhancer FH. Histopathology of fatal asthma: drown- ing in mucus. Pediatr Pulmonol 2001;(Suppl asthma.14 However, we are talking vis a` vis what Bruce described but just a straight 4 times a day (or other 23):88-89. about a very small subgroup of asth- 5. Mansel JK, Stogner SW, Petrini MF, Nor- matics. I sure don’t want to give the frequency) after they’ve resolved man JR. Mechanical ventilation in patients impression that any information sug- their difficulties. So it’s about re- with acute severe asthma. Am J Med 1990; gests that everybody with significant viewing the order after the patient’s 89(1):42-48. asthma should be put on gastroesoph- initial order. Many initial orders do 6. Webb AK, Bilton AH, Hanson GC. Severe bronchial asthma requiring ventilation. A not get reviewed or modified based ageal reflux disease therapy. review of 20 cases and advice and manage- on patient improvement for the ment. Postgrad Med J 1979;55(641):161- George: The EPR-311 doesn’t do a length of their hospital stay. 170. good job of talking about managing 7. Picado C, Montserrat JM, Roca J, Rodrí- acute asthma in community settings. Ev- Peters: I’m glad you brought that guez-Roisin R, Estopa´ R, Xaubet A, et al. Mechanical ventilation in severe exacerba- idence of that is in New York City and up again because the guidelines ref- tion of asthma. Study of 26 cases with six Philadelphia; we usually have one kid erence a study that randomized sub- deaths. Eur J Respir Dis 1983;64(2):102- die in school every year. Now, the EPR-3 jects after the first2hoftreatment 107. did release a separate 2-page report15 to either 4 times a day albuterol ver- 8. Hetzel MR, Clark TJ, Branthwaite MA. for school nurses on how to manage Asthma: analysis of sudden deaths and ven- sus treatment when requested by the tilator arrests in hospital. Br Med J ;1(6064): asthma in the schools, it’s not integrated 17 subject. This study showed equiv- 808-811. into the regular guidelines, and I don’t alent or even better outcomes with a 9. Horn CR, Clark TJ, Cochrane GM. Is there see that in the Global Initiative for shorter length of stay in the as-needed a circadian variation in respiratory mor- 16 Asthma either. You’re talking about group. I couldn’t agree with you bidity. Br J Dis Chest 1987;81(3):248- an area where you have a lot of children 251. more, if the time saved could be used with asthma, nurses who may or may 10. Tuxen D. Detrimental effects of positive by the in pro- end-expiratory pressure during controlled not be in the schools for any routine viding asthma education, I think we mechanical ventilation of patients with se- period, and kids are being managed by would be far better off. Finally, vere airflow obstruction. Am Rev Respir a variety of different individuals, their Dis 1989;140:5-9. albuterol is being held away from them I’d like to stress that we teach school 11. National Asthma Education and Prevention (eg, in the school office) and when they nurses and physicians in an annual Program. Expert Panel Report 3 (EPR-3): understand that the kid is having an asthma education course. The Guidelines for the Diagnosis and Manage- hardest thing to teach them is how ment of Asthma-Summary Report 2007. J asthma flare they usually go to 2 puffs Allergy Clin Immunol 2007;120(5 Suppl): every 4 hours. I think this is a gap in the to write an asthma action plan. It’s S94-S138. guidelines that really needs to be ad- hard for me to believe that there 12. Writing Committee for the American Lung dressed if we’re going to have some are practicing physicians who have Association Asthma Clinical Research Cen- impact. never written an asthma action plan. ters, Holbrook JT, Wise RA, Gold BD, We have a long way to go in terms Blake K, Brown ED, et al. Lansoprazole for children with poorly controlled asthma: Giordano: I want to go back to the of getting well-written, logical action a randomized controlled trial. JAMA 2012; question I posed to Bob [Wise] pre- plans into the hands of patients. 307(4):373-381.

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13. American Lung Association Asthma Clini- 15. National Heart, Lung and Blood Institute. 17. Bradding P, Rushby I, Scullion J, Morgan cal Research Centers, Mastronarde JG, An- Is the asthma action plan working? A tool MD. As required versus regular nebulized thonisen NR, Castro M, Holbrook JT, Leone for school nurse assessment. https://www. salbutamol for the treatment of acute asthma. FT, Teague WG, et al. Efficacy of esome- nhlbi.nih.gov/files/docs/resources/lung/asth_ Eur Resp J 1999(2);13:290-294. prazole for treatment of poorly controlled act_plan_frm.pdf. Accessed March 5, asthma. N Engl J Med 2009;360(15):1487- 2018. * Michael T Newhouse MD, invited discussant. 1499. 16. Global Initiative for Asthma. Global strat- Dr Newhouse is the chief medical officer for 14. Good JT Jr, Kilakowski CA, Groshong SD, egy for asthma management and preven- InspiRx. Murphy JR, Martin RJ. Refractory asthma: tion. Updated 2017. http://ginasthma.org/ importance of to identify 2017-gina-report-global-strategy-for-asthma- † Dean R Hess PhD RRT FAARC, discussant. phenotypes and direct therapy. Chest 2012; management-and-prevention/. Accessed July Dr Hess is Managing Editor of RESPIRATORY 141(3):599-606. 26, 2017. CARE.

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