Journal Pre-proof

Management of Life-Threatening Asthma: Severe Asthma Series

Orlando Garner, MD, James Scott Ramey, MD, Nicola A. Hanania, MD, MS

PII: S0012-3692(22)00395-6
DOI: https://doi.org/10.1016/j.chest.2022.02.029
Reference: CHEST 4934

To appear in: CHEST

Received Date: 16 July 2021

Revised Date: 7 February 2022
Accepted Date: 16 February 2022

Please cite this article as: Garner O, Ramey JS, Hanania NA, Management of Life-Threatening Asthma:
Severe Asthma Series, CHEST (2022), doi: https://doi.org/10.1016/j.chest.2022.02.029.

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Copyright © 2022 Published by Elsevier Inc under license from the American College of Chest
Physicians.
 1 Word Count Abstract:178
2 Word Count Manuscript: 3840
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7 Management of Life-Threatening Asthma: Severe Asthma Series
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11 Orlando Garner MD1, James Scott Ramey MD2, Nicola A. Hanania MD, MS1
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13 1Sectionof Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine,
14 Houston, TX. 2Department of Medicine, Baylor College of Medicine, Houston, TX.

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15
16

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17 Conflict of Interest:
18 OG and JSR: None to declare.
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20 -p
NAH: Received honoraria for serving as a consultant or advisor for GSK, Boehringer
Ingelheim, Sanofi, Teva, Amgen, Astra Zeneca, Novartis. His institution received
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21 research grant support from Astra Zeneca, GSK, Sanofi, Genentech, Novartis,
22 Gossamer Bio and Boehringer Ingelheim
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24 Funding: None
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26 Prior presentation: None
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28 Tables: 2
29 Figures:1
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32 Running Title: Mangement Acute Severe Acute
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34 Corresponding Author:
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36 Orlando Garner MD,
37 oegc311986@gmail.com
38 400 Rosalind Redfern Grover Pkwy, Suite 3340
39 Midland, TX 79701
40 432-221-4691

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 1 Abstract
2

3 Asthma exacerbations can be life-threatening, with 25,000 to 50,000 cases a year

4 requiring admission to intensive care in the United States. Appropriate triage of life-

5 threatening asthma is dependent on both static assessment of airway function and

6 dynamic assessment of response to therapy. Treatment strategies focus on achieving

7 effective bronchodilation with inhaled beta2 agonists, muscarinic antagonists, and

8 magnesium sulphate while reducing inflammation with systemic corticosteroids.

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9 Correction of hypoxemia and hypercapnia, a key in managing life threatening asthma,

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10 occasionally requires the incorporation of non-invasive mechanical ventilation to

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decrease work of breathing. Endotracheal intubation and mechanical ventilation should
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12 not be delayed if clinical improvement is not achieved with the conservative therapies.
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13 However, mechanical ventilation in these patients often requires controlled

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14 hypoventilation, adequate sedation, and occasional use of muscle relaxation to avoid

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15 dynamic hyperinflation which can result in baro- or volu-trauma. Sedation with ketamine
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16 or propofol is preferred because of their potential bronchodilation properties. In this

17 review, we outline strategies for the assessment and management of patients

18 presenting with acute life-threatening asthma focusing on those requiring admission to

19 the intensive care unit.

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21
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23 Keywords
24 Life-threatening asthma, mechanical ventilation, sedation, critical care medicine,
25 respiratory failure
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27
28

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3
4
5 Abbreviations
6 DA: Dynamic Assessment
7 DSI: Delayed sequence intubation
8 DHI: Dynamic hyperinflation
9 ECCO2-R: Extracorporeal carbon dioxide removal
10 ECMO: Extracorporeal membrane oxygenation
11 ED: Emergency Department
12 EPAP: Expiratory positive airway pressure
13 FEV1: Forced expiratory volume in the first second
14 HFNC: High flow nasal cannula

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15 IB: Ipratropium bromide
16 IPAP: Inspiratory positive airway pressure

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17 ICU: Intensive care unit
18 IMV: Invasive mechanical ventilation
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IV: Intravenous
LTAE: Life-threatening asthma -p
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21 MgSO4: Magnesium sulfate
22 NIV: Non-invasive ventilation
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23 NMB: neuromuscular blockade

24 PEEP: positive end expiratory pressure
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25 PEF: Peak expiratory flow

26 POCUS: Point-of-Care Ultrasound
27 Ppaw: Peak airway pressure
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28 Pplat: Plateau pressure

29 SA: Static Assessment
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30 SABA: Short-acting β2-agonist

31 SAMA: Short-acting muscarinic antagonists
32 SpO2: Oxygen saturation
33 SSS: Simplified Severity Score
34 V/Q: Ventilation-perfusion
35
36
37

3
 1 Introduction

2 Patients with asthma often experience severe exacerbation of their disease which, on

3 occasions, may be life-threatening.1 While the prevalence of asthma has generally

4 increased in most countries, the incidence of life-threatening exacerbations has

5 decreased due to the improvement in management strategies, therapies and health

6 care access.2 It is estimated that out of 2 million asthma exacerbations presenting to

7 the emergency department (ED) in the U.S. every year, around 25,000-50,000 cases

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8 will require intensive care unit (ICU) admission with some requiring mechanical

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9 ventilation. In one study, of 33,000 patients with acute asthma exacerbation requiring

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hospital care, 10.1% required admission to the ICU and 2.1% required intubation and
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11 invasive mechanical ventilation.3 Therefore, it is imperative for clinicians working in an
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12 ICU to be familiar with the proper assessment and management strategies of life-
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13 threatening asthma exacerbation (LTAE).

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 1 Case

2 A 41-year-old male with history of asthma is seen in the ED complaining of shortness of

3 breath, productive cough and wheezing that began three days prior to presentation. He

4 denies fever, sick contacts, chest pain, nausea, vomiting or reflux but has year-long

5 nasal congestion and postnasal drip. He discloses that he was recently discharged from

6 the hospital after experiencing another asthma exacerbation but has not filled the

7 prescription given to him upon discharge for his controller medication and has only been

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8 using his rescue medication multiple times during the day and night. He has five dogs at

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9 home and is a 10 pack-year smoker. On examination, his temperature is 97.3°F, heart

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rate of 116 beats/min, respiratory rate of 28 breaths/min, blood pressure of 164/79
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11 mmHg with an oxygen saturation (SpO2) 90% on room air. He is sitting upright, utilizing
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12 accessory muscles and cannot speak in complete sentences. Cardiac examination

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13 reveals tachycardia without any extra heart sounds. Diffuse wheezes are heard

14 throughout both lung fields. In the ED, he is started on albuterol nebulization every 20
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15 minutes along with oxygen 3L by nasal cannula improving his SpO2 to 93%. However,
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16 his work of breathing does not improve, and abdominal paradox is observed at bedside.

17 Chest x-ray shows hyperinflation but no infiltrates and venous blood gas reveals pH of

18 7.28 and pCO2 of 54. The patient receives 125 mg of methylprednisolone

19 intravenously, an infusion of 2 g of magnesium sulfate and is started on high flow nasal

20 cannula.

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 1 How I Do It

2 Triaging

3 Appropriate disposition is vital in the management of acute asthma to avoid

4 complications and prevent death. Danker et al. proposed a simplified severity score

5 (SSS) for asthma evaluation in the ED. This score (Table 1) is based on six parameters

6 obtained by clinical evaluation and classifies patients into mild, moderate, and severe

7 exacerbations. Severe and moderate exacerbation groups had an odds ratio for

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8 hospitalization of 12.2 (95% CI 7.5-19.9) and 5.6 (95% CI: 3.5-8.9) respectively, when

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9 compared to the mild exacerbation group. SSS may aid in disposition of patients in the

10 ED and in the decision for ICU admission.4

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11 Static assessments (SA) and dynamic assessments (DA) of acute asthma exacerbation
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12 in the ED can also help triage patients. SA looks at severity at presentation which in turn
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13 determines the aggressiveness of initial treatment. SA includes obtaining history of

14 treatment adherence, severity of current exacerbation compared to previous episodes,

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15 prior hospitalization or need for mechanical ventilation. Physical examination can also
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16 help determine severity of illness. Tripoding and use of accessory muscles correlate

17 with increased severity. Similarly, the absence of breath sounds (silent lungs) and

18 presence of abdominal paradox breathing are red-flag features of an underlying life-

19 threatening asthma episode. Objective SA include the measurement of peak expiratory

20 flow (PEF) and/or forced expiratory volume in the first second (FEV1). A severe

21 exacerbation is usually defined as a PEF or FEV1 is less than 50-60% of predicted

22 normal values.

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 1 DA is more helpful as it gauges response to treatment. A lack of improvement in

2 expiratory flow rates after initial bronchodilator therapy with continuous or worsening

3 symptoms suggests need for hospitalization.5 Ventilation and perfusion mismatch is

4 very common in acute asthma and significant hypoxemia and hypercapnia may occur

5 during an acute severe episode. However, depending on oxygen saturation alone may

6 sometimes be misleading and therefore blood gas examination or end tidal

7 capnography are often valuable tools for complete assessment. ICU admission should

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8 be considered in patients with hypoxemia (SpO2<92%) despite use of supplemental

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9 oxygen, worsening hypercarbia, encephalopathy, presence of arrhythmia, evidence of

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barotrauma (pneumothorax or pneumomediastinum), or for those who require oxygen
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11 by high flow nasal cannula (HFNC), non-invasive (NIV) or invasive ventilation (IMV). 6
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12
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13 Pharmacologic Management of Acute Asthma

14 The main therapeutic goals for acute asthma are reversal of bronchospasm and
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15 correction of hypoxemia. In addition, implementing plans to prevent recurrence is very

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16 crucial. The cornerstone, initial, conventional pharmacologic management of acute

17 asthma includes the administration of repeated doses of inhaled short-acting β2-agonist

18 (SABA), inhaled short-acting anticholinergic (SAMA), systemic corticosteroids, and on

19 occasion intravenous magnesium sulfate.

20

21 Inhaled Short-acting Β2-agonists (SABA)

22 SABAs are the first-line treatment for acute asthma. Continuous nebulization of

23 albuterol is a safe approach but intermittent dosing is also reasonable and more

7
 1 commonly implemented (Table 2). Utilization of metered-dose inhalers with spacers

2 allow for targeted albuterol dosing but offers no significant advantage over

3 nebulization.6,7,8 There is also no benefit of a high dose strategy (7.5 mg) over a low

4 dose (2.5 mg) of albuterol.9 Intravenous β2-agonists should be reserved for when

5 inhaled therapy is not feasible.10

6 B2-agonists with higher intrinsic efficacy (full agonists) such as formoterol and

7 isoproterenol may offer a theoretical advantage over a partial agonist such as albuterol,

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8 especially when the latter does not yield a significant response. For example, the full

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9 agonist isoproterenol demonstrated superiority to albuterol in improvement of lung

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function and symptoms in asthma exacerbations. However, the potential for systemic
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11 adverse effects by activating receptors on non-target sites such as the heart is higher.11
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12
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13 Inhaled Short-Acting Muscarinic Antagonists (SAMA)

14 Ipratropium bromide (IB) relaxes bronchial smooth muscle by antagonizing the

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15 muscarinic receptor (M3) on smooth muscle of the airway alleviating airway obstruction.
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16 Compared to SABA, it has a slower onset of action (60-90 minutes) coupled with an

17 average potency (15% increase in PEF) and unsustained benefits after ED admission.

18 When used, IB should be used in combination with SABAs and it appears that its benefit

19 is limited to severe patients.12,13

20

21 Systemic Corticosteroids

22 Systemic corticosteroids improve outcomes in patients with acute asthma and reduce

23 the likelihood of repeat exacerbation. They should be administered as soon as possible,

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 1 as clinical effects may take 6-12 hours.14 While there is no significant difference in

2 efficacy between oral versus intravenous (IV) corticosteroids, the degree of respiratory

3 distress may dictate the route of administration.15 We recommend starting with IV

4 methylprednisolone in those with severe respiratory distress who are being admitted to

5 the hospital or ICU. The potential role of inhaled corticosteroids in managing acute

6 asthma has not been fully evaluated in large trials although some studies in children

7 and adults suggest a benefit.16

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9 Magnesium Sulphate

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Magnesium sulphate acts as a bronchodilator by inhibiting calcium channels and
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11 blocking parasympathetic tone.17 The role of intravenous magnesium in the treatment of
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12 acute asthma has been studied as an adjunct therapy to SABA, IB and corticosteroids.
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13 Evidence has shown that this intervention reduced hospital admissions in severe

14 asthma and, improved pulmonary function but has not been found to reduce mortality or
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15 need for NIV.18 The use of nebulized magnesium sulphate is much less clear, and
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16 studies have not shown consistent benefit.19

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18 Controlled Oxygen Therapy

19 Acute asthma is associated with significant ventilation-perfusion (V/Q) mismatch with

20 perfusion of non-ventilated areas causing hypercarbia and hypoxemia.20-22 If there is

21 concomitant hypoxemia (PaO2<55 mmHg or SpO2<90) oxygen therapy should be

22 initiated to a goal SpO2 of >92%. Hyperoxia may be harmful in some patients and

23 should be avoided whenever possible.23,24 A randomized controlled trial found that

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 1 patients who received 28% oxygen, compared to 100% oxygen, had a fall in PaCO2

2 and those in the latter group had an increase.25 Therefore, conservative SpO2 targets

3 should be pursued in patients with acute severe asthma and those with impending

4 respiratory failure.

6 High Flow Nasal Cannula (HFNC)

7 Although HFNC is useful in patients with respiratory failure such as acute lung injury

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8 and ARDS, its role in acute severe asthma has not been well established. A study of 36

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9 patients assigned to either HFNC or conventional oxygen therapy did not demonstrate

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any difference in clinical response, although there was a signal of improved heart and
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11 respiratory rate in the HFNC group.26 HFNC can be used in acute severe asthma, but it
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12 should not delay the utilization of NIV or endotracheal intubation.

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14 Case - Update
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15 The patient is admitted to the ICU, however respiratory distress worsens despite
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16 treatment. He is now unable to speak, continues to tripod and subcostal retractions are

17 noticeable. He becomes hemodynamically unstable, tachypneic and lung sounds are

18 minimal. The patient has now progressed to LTAE, prompting a move to the ICU and

19 warrants consideration for other avenues of treatment and respiratory support.

20

21

22 Pharmacologic Management of Life-Threatening Asthma Exacerbation (LTAE)

23 Systemic Beta2-Agonists

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 1 When inhaled SABA treatment is not possible, intravenous (IV) albuterol is

2 recommended by some national guidelines although it is not available in the US.27,28 29

3 Epinephrine has bronchodilating effects and can be used in various presentations (table

4 2). Systemic terbutaline is another β2-agonist that can be utilized for asthma refractory

5 to inhaled therapeutics. Although strong evidence of superiority of its use is lacking , it

6 can be useful in patients who are not responding to conventional therapy. Caution is

7 advised in patients with tachyarrhythmias and hypokalemia.30

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8 Side effects include those commonly seen in inhaled albuterol including hypokalemia,

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9 hyperlactatemia, hyperglycemia, tachycardia, and tremors.30

10 Methylxanthines
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11 Aminophylline is a methylxanthine that has traditionally been used as an infusion in
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12 acute asthma. It is a nonselective phosphodiesterase inhibitor. However, aminophylline

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13 is an inferior bronchodilator to SABA monotherapy. Furthermore, aminophylline is

14 associated with increased risk of nausea, vomiting and tachyarrhythmias. Because of

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15 the safety profile of aminophylline, its use is no longer recommended in treatment of

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16 acute asthma.31

17

18 Heliox (Helium/Oxygen)

19 Normal airflow in the medium and small airways is laminar; during a life-threatening

20 asthma episode, airflow in these airways often becomes turbulent increasing the work of

21 breathing. Helium has a lower density and higher viscosity than regular air and thus can

22 improve airflow through narrow airways. Heliox is a combination of helium and oxygen

23 that reduces turbulent flow and promotes laminar flow. However, FiO2 requirements

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 1 need to be <30% for its proper use. Heliox has two preparations, 70:30 and 80:20,

2 which can be delivered via face mask, nebulizer, non-rebreather mask or through IMV.32

3 A meta-analysis found that heliox was associated with improvement in PEF, especially

4 in severe (PEF >50% of predicted) and very-severe exacerbations(PEF <50% of

5 predicted).33 Heliox can be used in patients with severe bronchospasm who do not

6 respond to the conventional therapies, to facilitate medication delivery and it has been

7 reported to decrease dynamic hyperinflation (DHI) reduce work of breathing and

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8 hypercarbia. Its effects in reducing intubation are still unknown. We would favor utilizing

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9 heliox over not using it. If intended effects are not seen within 15 minutes, therapy

10 should be abandoned.34
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11 Biologics
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12 There has been interest in the use of biologics to reduce eosinophils in those afflicted
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13 with asthma. Benralizumab is an interleukin (IL) -5 receptor antibody, that has been able

14 to produce eosinopenia after a single dose. Nowak et al demonstrated that single dose
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15 benralizumab coupled with steroids reduced the rate and severity of exacerbations of
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16 those who presented to the ED and suggested possible efficacy in patients with asthma

17 exacerbations with contraindications to steroids.35 However, the utility of other biologics

18 in treating acute asthma has not been evaluated and none of them is approved for

19 treatment of acute exacerbtions

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21 Ventilation in Life-Threatening Asthma Exacerbation (LTAE)

22 Non-Invasive Ventilation (NIV)

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 1 Few studies have looked at the effect of NIV (either biphasic positive pressure

2 ventilation (BPAP) or continuous positive airway pressure (CPAP)) in patients with life-

3 threatening asthma exacerbation. A Cochrane review concluded that the use of NIV

4 with standard of care may be beneficial. Although there was no clear benefit in mortality

5 or rate of intubation, there were statistically significant improvements in respiratory rate,

6 PEF, FEV1, number of hospital admissions, length of ICU and hospital stay.36

7 CPAP at 10 cmH20 can be utilized as a rescue therapy from intubation, although we

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8 favor the use of BPAP.37 BPAP allows use of expiratory positive airway pressure

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9 (EPAP) to match auto-positive end expiratory pressure (PEEP) and inspiratory positive

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airway pressure (IPAP) to create a driving pressure to support work of breathing. We
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11 recommend starting at an EPAP of 5 cmH2O, an IPAP of 10 cmH2O and titrate FiO2 for
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12 a goal SpO2 ~92. IPAP should be titrated for improvement in work of breathing.
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13 Intubation is recommended if there is no improvement in work of breathing, PEF, FEV1,

14 or pCO2, within 30-60 minutes of initiation.

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16 Invasive Mechanical Ventilation

17 Endotracheal Intubation remains a rare event in patients with asthma, due in part to the

18 improved therapeutics and reversible nature of the disease but some patients will

19 require IMV. This is especially true in patients with refractory bronchospasm. Ideally

20 most patients can be rescued from intubation, but those who present with frank

21 respiratory distress, encephalopathy or are hemodynamically unstable should be

22 intubated. Airway management of patients with LTAE is crucial since they usually have

23 poor reserve, bag-mask ventilation can further worsen DHI, acidosis can precipitate

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 1 cardiac arrest and hemodynamic instability may arise from insensible losses. Patients

2 with LTAE should always be considered as difficult airways due to potential

3 complications that may arise peri-intubation.

4 A large endotracheal tube (>8 mm) is favored to relieve the airway resistance generated

5 through IMV.38 Delayed sequence intubation (DSI) is an alternative to rapid sequence

6 intubation that can be beneficial in LTAE. DSI intends to separate the induction agent

7 from the paralytic to better resuscitate, preoxygenate and denitrogenate. Peri-intubation

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8 resuscitation can prevent hemodynamic instability in patients who might have become

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9 hypovolemic from insensible losses.39 The shock index (SI) is a simple bedside

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calculation (heart rate/systolic blood pressure) that can help identify occult shock and is
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11 predictive of peri-intubation cardiac arrest. If a patient has an SI >1, preemptive
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12 resuscitation with fluids or vasopressors is needed.40 Ketamine should be used as an

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13 induction agent because it does not cause hemodynamic instability.41 Once SpO2 goal

14 is achieved, paralysis with rocuronium is favored. Rocuronium will allow for patients to
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15 be passive on IMV after intubation, facilitating ventilator management. Bag-mask

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16 ventilation should be avoided because it can worsen DHI or cause barotrauma.

17 Barotrauma occurs due to high pressures in distal airways. Pneumomediastinum or

18 pneumothorax must be suspected in patients with tracheal deviation, crepitus or sudden

19 loss of breath sounds. Imaging studies are required to make the diagnosis. Portable

20 chest x-rays may be used but might not be readily available. Point-of-care ultrasound

21 (POCUS) can be useful but hyperinflated lungs might be confounded by

22 pneumothoraces. Detection of pneumothorax on POCUS depends on the lack of

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 1 movement of the parietal pleural on the visceral pleura, which is seen in patients with

2 asthma exacerbation.42

3 Invasive mechanical ventilation goals in LTAE are to improve delivery of inhaled

4 bronchodilators, improve work of breathing, reduce DHI while preventing volutrauma

5 and barotrauma. IMV can be detrimental in LTAE as it adds positive pressure on an

6 already high airway pressure, exacerbating DHI further. Excessive DHI affects preload

7 through high intrathoracic pressure resulting in hemodynamic instability. Efforts must be

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8 made to relieve airway pressure and decompress DHI with the ventilator settings.

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9 Mechanical ventilation can be achieved with either assisted/controlled volume cycled

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ventilation or assisted/controlled pressure cycled ventilation. The focus of initial
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11 ventilator settings should be to reduce DHI and prevent lung injury. This is achievable
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12 by manipulating the minute ventilation (Ve), inspiratory to expiratory ratio (I:E) and peak
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13 airway pressure (Ppaw). Initially a low respiratory rate (8-10 breaths per minute) should

14 be set to allow a prolonged expiration (figure 1). Monitoring DHI response to low Ve can
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15 be seen in in flow-time scalar. The expiratory portion of this scalar should come back to
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16 baseline before a new breath is initiated, suggesting resolution of DHI. If breath stacking

17 continues (i.e., flow-time curve does not come back to zero before a new breath is

18 started), decreasing the inspiratory time will allow for a faster breath to be delivered and

19 for more time to be spent in expiration at the expense of increased Ppaw. Ideally the I:E

20 ratio should be set at 1:2, but in LTAE a ratio of 1:3 or 1:4 is acceptable. If breath

21 stacking persists, disconnection from the ventilator circuit while gently compressing the

22 chest for 30-60 seconds can be performed. Gentle chest compressions at end

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 1 expiration during IMV has been reported as a maneuver to improve DHI. Deep sedation,

2 or neuromuscular blockade (NMB), may be needed.43

3 The tidal volume should be set around 6-8 ml/kg of ideal body weight. Careful attention

4 should be paid to plateau pressure (Pplat) with a goal of <30 cmH20 while adjusting

5 tidal volume or respiratory rate to avoid lung injury. Ventilation may be limited due to

6 high Ppaw and Pplat but usually hypercarbia is well tolerated up to PaCO2 of 90-100

7 mmHg. Permissive hypercarbia should be allowed to a pH of >7.20 in those patients

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8 without any contraindication (e.g., myocardial depression or intracranial pathology).

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9 Extrinsic PEEP (ePEEP) should be set at a low level in intubated patients (<5 cm H2O).

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Spontaneously breathing patients may benefit from matching their auto-PEEP with the
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11 ePEEP. This improves work of breathing by decreasing the pressure gradient needed to
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12 overcome the auto-PEEP. Measuring auto-PEEP should occur at least every 6 hours.
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13 FiO2 should be initially set at 100% but rapidly titrated down for a goal SpO2 >92%. If

14 there is persistent hypoxia, work up for alternative causes, including pulmonary

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15 shunting, should ensue.44,45, 46

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16

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18 Non-Ventilatory Strategies of Life-Threatening Asthma Exacerbation (LTAE)

19 Sedation

20 LTAE patients exhibit a degree of breathlessness and feeling of imminent death that are

21 detrimental to NIV use or inhaled medication delivery. Light sedation can be utilized to

22 help patients tolerate NIV and deliver inhaled bronchodilators effectively. Deep

23 sedation, with or without neuromuscular blockade, may be warranted in those requiring

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 1 IMV. Use of sedatives should warrant an admission to the ICU since patients will require

2 frequent monitoring.

3 In a non-intubated patient, intermittent dosing of short-acting opioids can decrease

4 breathlessness and depress respiratory drive. Boluses of fentanyl can be utilized since

5 it has a rapid onset of action and a short half-life. If there is a favorable response, doses

6 can be repeated every 30 minutes as needed. Morphine should be avoided since it can

7 cause histamine release.

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8 Dexmedetomidine is an α2-agonist that can be utilized if more sedation is needed. It

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9 does not suppress the respiratory drive and causes appropriate anxiolysis. Effects will

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be seen within 5-15 minutes, which may be too long in some patients.
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11 Ketamine is an N-Methyl-D-aspartate receptor antagonist which can be utilized at
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12 subanesthetic dosing or at dissociative dosing. Ketamine works within seconds, won’t

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13 cause respiratory depression, and can have a bronchodilation effect. Infusions are

14 started at subanesthetic dosing and slowly titrated up to effect. Side effects include
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15 bronchorrhea, sialorrhea and laryngospasm. Benzodiazepines should be avoided as

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16 they are associated with worse outcomes. Once ketamine or dexmedetomidine

17 infusions are started, equipment and induction medications for intubation should be

18 readily available at bedside.

19 Propofol is a good first choice for patients on IMV. It allows for deeper sedation,

20 synchronization with the ventilator and has bronchodilatory properties. Utilizing

21 ketamine concomitantly can also potentiate the bronchodilation, reduce propofol and

22 opioid requirements, possibly decreasing IMV days.

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 1 Some patients may still have high ventilator dyssynchrony despite high levels of

2 sedation depending on ventilator strategy. These patients may benefit from NMB to

3 tolerate the low respiratory rates required to allow for complete exhalation. This can be

4 facilitated by a bolus of cisatracurium after adequate sedation. Infusions should be

5 avoided to prevent myopathy from the combination of steroids and NMB. Monitoring

6 during NMB infusions includes train-of-four and serial creatinine kinase evaluations.47,48

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8 Inhaled Anesthetics

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9 Inhaled anesthetics can be used in LTAE with high Ppaw, excessive hypercarbia and

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refractory bronchospasm in patients on IMV. Isoflurane or halothane can reduce
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11 bronchospasm and evidence of improvement should be seen quickly but only while the
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12 gas is being administered as their effect is short-lived. These anesthetics are delivered
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13 through an anesthesia ventilator and their use might be limited by the experience of the

14 ICU staff. Inhaled anesthetics can cause hemodynamic instability by reducing venous
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15 and vascular tone.49,50

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17 Extra Corporeal Membrane Oxygenation

18 LTAE is a reversible condition where extra corporeal membrane oxygenation (ECMO)

19 can serve as a bridge to recovery. Although ECMO is seldomly required, those with

20 severe respiratory acidosis (pH <7.2) with hemodynamically unstable DHI can benefit

21 from it. Veno-venous ECMO can be utilized with ultra-protective lung ventilation. Once

22 bronchospasm and respiratory acidosis resolve, patients can be decannulated and

23 extubated.51,52 The use of ECMO is very limited in acute asthma although a recent

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 1 retrospective study demonstrated benefit for those who required it.53 ECMO can

2 potentially increase risk for sepsis, multiorgan failure, acute kidney injury, stroke,

3 bleeding, thrombosis, and cannula related complications. Also, its complexity warrants

4 its implementation in high-volume centers and may be cost prohibitive, and therefore

5 not feasible in smaller hospitals.54

6 Extracorporeal carbon dioxide removal (ECCO2-R) is a form of extracorporeal gas

7 exchange designed to remove carbon dioxide from the blood across a gas exchange

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8 membrane at low blood flow rates (200-1500 ml/minute). This is done without a clinically

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9 relevant effect on oxygenation, as opposed to ECMO, which is employed mainly for

10
-p
oxygen delivery at high blood flow rates (2,000-7,000 ml/minute). ECCO2-R has been
re
11 referred to as low-flow ECMO and respiratory dialysis by some clinicians.55Although its
lP

12 role in LTAE is still yet to be defined, the REST trial did not find a mortality benefit in
na

13 patients with acute hypoxic respiratory failure compared to usual care.56

ur

14
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15 Bronchoscopy and Mucolytics

16 Airflow limitation in asthma results from bronchospasm, airway inflammation and mucus

17 plugging, but pharmacotherapy only addresses the first two causes. Bronchoscopy,

18 bronchoalveolar lavage with or without N-acetylcysteine (NAC) instilled directly into the

19 airway has been described as therapeutic option in patients where mucus plugging is

20 considered the main driver of airflow limitation.57

21

22 Conclusions

19
 1 LTAE is a rare complication of asthma but if not treated in a timely fashion can result in

2 death. Patients should be quickly started on inhaled SABA, SAMA, IV corticosteroids.

3 Systemic infusion of MgSO4 can be considered in some patients. In those with severe

4 bronchospasm, heliox can be used to facilitate medication delivery but therapy should

5 be abandoned if there is no clinical improved after 15 minutes of use. Patients who have

6 progressive respiratory distress, should be admitted to the ICU for close monitoring and

7 and placed on NIV if tolerated. However, t intubation should not be delayed if the patient

of
8 does not improve in 30-60 minutes. Extra care should be taken if a patient requires

ro
9 mechanical ventilation. Intubation should be performed in a delayed sequence and lung

10
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protective strategies should be adopted on IMV. Salvage therapies such as the use of
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11 inhaled anesthetics, bronchoscopy and BAL with or without NAC or ECMO can be
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12 considered in individual refractory cases.

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16

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3 41. Merelman AH, Perlmutter MC, Strayer RJ. Alternatives to Rapid Sequence
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32 50. Shutes B, Frazier WJ, Tobias JD. An Unusual Complication With the
33 Administration of a Volatile Anesthetic Agent for Status Asthmaticus in the
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36 51. Maqsood U, Patel N. Extracorporeal membrane oxygenation (ECMO) for near-
37 fatal asthma refractory to conventional ventilation. BMJ Case Rep.
38 2018;2018:bcr2017223276. Published 2018 Mar 20. doi:10.1136/bcr-2017-
39 223276
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41 extracorporeal life support for adult respiratory failure due to status
42 asthmaticus. ASAIO J. 2009;55(1):47-52. doi:10.1097/MAT.0b013e3181901ea5
43 53. Patel S, Shah NM, Malhotra AM, et al. Inflammatory and microbiological
44 associations with near-fatal asthma requiring extracorporeal membrane

24
 1 oxygenation. ERJ Open Res. 2020;6(1):00267-2019. Published 2020 Jan 27.
2 doi:10.1183/23120541.00267-2019
3 54. Kim JH, Pieri M, Landoni G, et al. Venovenous ECMO treatment, outcomes, and
4 complications in adults according to large case series: A systematic review. Int J
5 Artif Organs. 2021;44(7):481-488. doi:10.1177/0391398820975408
6 55. Hermann A, Staudinger T, Bojic A, et al. First experience with a new miniaturized
7 pump-driven venovenous extracorporeal CO2 removal system (iLA Activve): a
8 retrospective data analysis. ASAIO J. 2014;60(3):342-347.
9 doi:10.1097/MAT.0000000000000073
10 56. McNamee JJ, Gillies MA, Barrett NA, et al. Effect of Lower Tidal Volume
11 Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard
12 Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic
Respiratory Failure: The REST Randomized Clinical Trial [published online ahead

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13
14 of print, 2021 Aug 31]. JAMA. 2021;10.1001/jama.2021.13374.

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15 doi:10.1001/jama.2021.13374
16 57. Henke CA, Hertz M, Gustafson P. Combined bronchoscopy and mucolytic
17
18
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therapy for patients with severe refractory status asthmaticus on mechanical
ventilation: a case report and review of the literature. Crit Care Med.
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19 1994;22(11):1880-1883.
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 1
2
3
4
5
6
7
8
9 Tables
10
11 Table 1. Simplified Severity Score for Acute Asthma4
12
Severity Score
Sign/Symptom Mild Moderate Severe

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Pulse rate <90 91-119 >120

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Wheezing Absent Present Present
Rales Absent Present Present

-p
Prolonged expirium Absent re Present Present

O2 Saturation 95-100% 90-94% <89%

Use accessory Absent Present Present
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muscles
Minimal number of Any 3 of the above Any 3 of the above or Any 3 of the above or
parameters required the use of accessory O2 Saturation <89%
na

to qualify for muscles only only

categories
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21
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23
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26
27
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31

26
1
2
3
4
5
6
7
8 Table 2. Pharmacotherapy in Asthma Exacerbation
9
Medication Dosage Comments
Inhaled Bronchodilators
Albuterol
Nebulization 2.5-5 mg every 20 minutes
for 3 doses, then 2.5-10

of
mg every 1-4 hours as
needed or 10-15 mg/h

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continuously.

MDI (90mcg/puff)
-p
4-8 puffs every 20 minutes
up to 4 hours, then every
re
1-4 hours as needed
lP

Isoproterenol Nebulization 7.5 mg/h for 2 hours No longer available in the

U.S.
Ipratropium Bromide
na

Nebulization 0.5 mg every 20 minutes

for 3 doses then as
needed.
ur

MDI 8 puffs every 20 minutes

Jo

as needed up to 3 hours.
Systemic Bronchodilators
Epinephrine
Intramuscular 1:1000 0.3-0.5 mg IM every 20
(1mg/mL) minutes up to 3 doses

Subcutaneous 0.3-0.5 mg sq every 20

1:1000 (1mg/mL) minutes up to 3 doses

Intravenous 0.1 mcg/kg/min

Terbutaline
Subcutaneous 0.25 mg sq every 20
minutes for 3 doses

27
 Intravenous Bolus 4-10 mcg/kg
followed by an continuous
infusion of 0.2-0.4
mcg/kg/minutes.
Albuterol 10-15 mcg/kg (max 250
Intravenous mcg) over 5-10 minutes
which can be repeated
every 5 minutes
Aminophylline 6 mg/kg over 30 minutes
Intravenous followed by an infusion of
0.5 mg/kg/h.
Titrate by 0.1-0.2
mcg/kg/minute based on
response or toxicity.
Not available in the U.S.
Not recommended by
current guideline
Serum levels should be
checked and kept between
8 to 12 mcg/ml.

of
Corticosteroids

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Methylprednisolone 40-60 mg IV every 6 hours
for 24 hours, taper to 40-

-p
60 every 12 hours if
improved.
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Prednisone 40 mg PO daily for 5 days
Other Medications
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Magnesium Sulfate 1-2 g IV over 20 minutes.

na

Sedatives and Muscle Relaxants

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Ketamine May cause laryngospasm

Subanesthetic dosing 0.1-0.5 mg/h
Jo

Infusion
1-4 mg/h
Dissociative dosing
Infusion
Dexmedetomidine 0.2-0.7 mcg/kg/hour May cause myocardial
Infusion depression
Propofol 5-50 mcg/kg/minute
Infusion
Cisatracurium Loading 0.1-0.2 mg/kg
IV bolus followed by followed by infusion of 1-3
infusion mcg/kg/min
1 MDI: metered-dose inhaler
2
3
4
5
6
7

28
1
2
3
4 Figure 1. Management of LTAE Algorithm

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