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Management of Life-Threatening Asthma Severe Asthma Series Orlando Garner, MD; James Scott Ramey, MD; and Nicola A. Hanania, MD, FCCP
Asthma exacerbations can be life-threatening, with 25,000 to 50,000 such patients per year requiring admission to an ICU in the United States. Appropriate triage of life-threatening asthma is dependent on both static assessment of airway function and dynamic assessment of response to therapy. Treatment strategies focus on achieving effective bronchodilation with inhaled b2-agonists, muscarinic antagonists, and magnesium sulphate while reducing inflammation with systemic corticosteroids. Correction of hypoxemia and hypercapnia, a key in managing life-threatening asthma, occasionally requires the incorporation of noninvasive mechanical ventilation to decrease the work of breathing. Endotracheal intubation and mechanical ventilation should not be delayed if clinical improvement is not achieved with conservative therapies. However, mechanical ventilation in these patients often requires controlled hypoventilation, adequate sedation, and occasional use of muscle relaxation to avoid dynamic hyperinflation, which can result in barotrauma or volutrauma. Sedation with ketamine or propofol is preferred because of their potential bronchodilation properties. In this review, we outline strategies for the assessment and management of patients with acute life-threatening asthma focusing on those requiring admission to the ICU.
CHEST 2022; 162(4):747-756
KEY WORDS: critical care medicine; life-threatening asthma; mechanical ventilation; respiratory failure; sedation
Introduction Patients with asthma often experience severe exacerbation of the disease that, on occasion, may be life-threatening.1 Although the prevalence of asthma generally has increased in most countries, the incidence of lifethreatening exacerbations has decreased because of the improvement in management strategies, therapies, and health-care access.2 It is estimated that of 2 million patients with asthma exacerbations seeking treatment at the ED in the United States every year, approximately 25,000 to 50,000 patients will require ICU admission, with some requiring
ABBREVIATIONS: DHI = dynamic hyperinflation; ECMO = extracorporeal membrane oxygenation; HFNC = high-flow nasal cannula; IMV = invasive mechanical ventilation; LTAE = life-threatening asthma exacerbation; NIV = noninvasive ventilation; NMB = neuromuscular blockade; PEEP = positive end-expiratory pressure; PEF = peak expiratory flow; Ppaw = peak airway pressure; SA = static assessment; SABA = short-acting b2-agonist; SpO2 = oxygen saturation
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mechanical ventilation. In one study, of 33,000 patients with acute asthma exacerbation requiring hospital care, 10.1% required admission to the ICU and 2.1% required intubation and invasive mechanical ventilation (IMV).3 Therefore, it is imperative for clinicians working in an ICU to be familiar with the proper assessment and management strategies of life-threatening asthma exacerbation (LTAE).
Case Presentation A 41-year-old man with history of asthma was seen in the ED reporting shortness of
AFFILIATIONS: From the Section of Pulmonary, Critical Care and Sleep Medicine (O. Garner and N. A. Hanania), and the Department of Medicine (J. S. Ramey), Baylor College of Medicine, Houston, TX. CORRESPONDENCE TO: Orlando Garner, MD; email: oegc311986@ gmail.com Copyright Ó 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2022.02.029
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breath, productive cough, and wheezing that began 3 days previously. He did not report fever, sick contacts, chest pain, nausea, vomiting, or reflux, but had nasal congestion and postnasal drip of 1 year’s duration. He disclosed that he recently was discharged from the hospital after experiencing another asthma exacerbation, but had not filled the prescription given to him on discharge for controller medication and had been using only his rescue medication multiple times during the day and night. He has five dogs at home and has a 10-packyear history of smoking. On examination, temperature was 36 C, heart rate was 116 beats/min, respiratory rate was 28 breaths/min, and BP was 164/79 mm Hg, with an oxygen saturation (SpO2) of 90% on room air. He was sitting upright, using accessory muscles, and could not speak in complete sentences. Cardiac examination revealed tachycardia without any extra heart sounds. Diffuse wheezes were heard throughout both lung fields. In the ED, he was started on albuterol nebulization every 20 min along with oxygen 3 L by nasal cannula, improving SpO2 to 93%. However, the work of breathing did not improve, and abdominal paradox was observed at bedside. Chest radiography showed hyperinflation, but no infiltrates, and venous blood gas revealed a pH of 7.28 and PCO2 of 54 mm Hg. The patient received 125 mg of methylprednisolone intravenously and an infusion of 2 g of magnesium sulfate and was started on high-flow nasal cannula.
How We Do It Triaging
Appropriate disposition is vital in the management of acute asthma to avoid complications and to prevent death. Danker et al4 proposed a simplified severity score for asthma evaluation in the ED. This score (Table 1)4 is
TABLE 1
based on six parameters obtained by clinical evaluation and classifies patients according to mild, moderate, and severe exacerbations. Severe and moderate exacerbation groups have an OR for hospitalization of 12.2 (95% CI, 7.5-19.9) and 5.6 (95% CI, 3.5-8.9), respectively, when compared with the mild exacerbation group. A simplified severity score may aid in disposition of patients in the ED and in the decision for ICU admission. Static assessments (SAs) and dynamic assessments of acute asthma exacerbation in the ED also can help to triage patients. SA looks at severity at presentation, which in turn determines the aggressiveness of initial treatment. SA includes obtaining history of treatment adherence, severity of current exacerbation compared with previous episodes, and prior hospitalization or need for mechanical ventilation. Physical examination also can help to determine severity of illness. Tripoding and use of accessory muscles correlate with increased severity. Similarly, the absence of breath sounds (silent lungs) and presence of abdominal paradox breathing are red-flag features of an underlying life-threatening asthma episode. Objective SAs include the measurement of peak expiratory flow (PEF), FEV1, or both. A severe exacerbation usually is defined as a PEF or FEV1 of less than 50% to 60% of predicted normal values. Dynamic assessment is more helpful because it gauges response to treatment. A lack of improvement in expiratory flow rates after initial bronchodilator therapy with continuous or worsening symptoms suggests the need for hospitalization.5 Ventilation and perfusion mismatch is very common in acute asthma, and significant hypoxemia and hypercapnia may occur during an acute severe episode. However, depending on oxygen saturation alone sometimes may be misleading,
] Simplified Severity Score for Acute Asthma4 Severity Score
Sign or Symptom
Mild
Moderate
Severe
Pulse rate, beats/min
< 90
91-119
> 120
Wheezing
Absent
Present
Present
Rales
Absent
Present
Present
Prolonged expirium
Absent
Present
Present
Oxygen saturation, %
95-100
90-94
< 89
Use accessory muscles
Absent
Present
Present
Minimal no. of parameters required to qualify for categories
Any 3 of the above
Any 3 of the above or the use of accessory muscles only
Any 3 of the above or oxygen saturation of < 89% only
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and therefore blood gas examination or end-tidal capnography often are valuable tools for complete assessment. ICU admission should be considered in patients with hypoxemia (SpO2 < 92%) despite the use of supplemental oxygen, worsening hypercarbia, encephalopathy, presence of arrhythmia, or evidence of barotrauma (pneumothorax or pneumomediastinum) or for those who require oxygen by high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), or IMV.6 Pharmacologic Management of Acute Asthma
The main therapeutic goals for acute asthma are reversal of bronchospasm and correction of hypoxemia. In addition, implementing plans to prevent recurrence is crucial. The cornerstone, initial, conventional pharmacologic management of acute asthma includes the administration of repeated doses of inhaled shortacting b2-agonists (SABAs), inhaled short-acting anticholinergics (short-acting muscarinic antagonists), systemic corticosteroids, and on occasion, IV magnesium sulfate. Inhaled SABAs: SABAs are the first-line treatment for acute asthma. Continuous nebulization of albuterol is a safe approach, but intermittent dosing also is reasonable and is implemented more commonly (Table 2). Use of metered-dose inhalers with spacers allows for targeted albuterol dosing, but offers no significant advantage over nebulization.6-8 Also a high-dose strategy (7.5 mg) offers no benefit over a low-dose (2.5 mg) of albuterol.9 IV b2agonists should be reserved for when inhaled therapy is not feasible.10
b2-Agonists with higher intrinsic efficacy (full agonists), such as formoterol and isoproterenol, may offer a theoretical advantage over a partial agonist such as albuterol, especially when the latter does not yield a significant response. For example, the full agonist isoproterenol demonstrated superiority to albuterol in improvement of lung function and symptoms in asthma exacerbations. However, the potential for systemic adverse effects by activating receptors on nontarget sites such as the heart is higher.11 Inhaled Short-Acting Muscarinic Antagonists: Ipratropium bromide relaxes bronchial smooth muscle by antagonizing the muscarinic M3 receptor on smooth muscle of the airway, alleviating airway obstruction. Compared with SABAs, it has a slower onset of action (60-90 min) coupled with an average potency (15% increase in PEF) and unsustained benefits after ED admission. When used, ipratropium bromide should be
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administered in combination with SABAs, and it seems that its benefit is limited to patients with severe disease.12,13 Systemic Corticosteroids: Systemic corticosteroids improve outcomes in patients with acute asthma and reduce the likelihood of repeat exacerbation. They should be administered as soon as possible, because clinical effects may take 6 to 12 h to take effect.14 Although no significant difference in efficacy exists between oral and IV corticosteroids, the degree of respiratory distress may dictate the route of administration.12 We recommend starting with IV methylprednisolone in those with severe respiratory distress who are being admitted to the hospital or ICU. The potential role of inhaled corticosteroids in managing acute asthma has not been evaluated fully in large trials, although some studies in children and adults suggest a benefit.15 Magnesium Sulphate: Magnesium sulphate acts as a bronchodilator by inhibiting calcium channels and blocking parasympathetic tone.16 The role of IV magnesium in the treatment of acute asthma has been studied as an adjunct therapy to SABAs, ipratropium bromide, and corticosteroids. Evidence has shown that this intervention reduced hospital admissions in severe asthma and improved pulmonary function, but it has not been found to reduce mortality or need for NIV.17 The use of nebulized magnesium sulphate is much less clear, and studies have not shown consistent benefit.18 Controlled Oxygen Therapy: Acute asthma is associated with significant V_ /Q_ mismatch with perfusion of nonventilated areas causing hypercarbia and hypoxemia.19,20 If concomitant hypoxemia occurs (PaO2 < 55 mm Hg or SpO2 < 90%), oxygen therapy should be initiated with a goal SpO2 of > 92%. Hyperoxia may be harmful in some patients and should be avoided whenever possible.21,22 A randomized controlled trial found that patients who received 28% oxygen, compared with 100% oxygen, showed a fall in PaCO2, and those in the latter group showed an increase.23 Therefore, conservative SpO2 targets should be pursued in patients with acute severe asthma and those with impending respiratory failure. HFNC: Although HFNC is useful in patients with respiratory failure such as acute lung injury and ARDS, its role in acute severe asthma has not been well established. A study of 36 patients assigned to either HFNC or conventional oxygen therapy did not demonstrate any difference in clinical response,
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TABLE 2
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Medication
Dosage
Comments
Inhaled bronchodilators Albuterol nebulization
2.5-5 mg every 20 min for 3 doses, then 2.5-10 mg every 1-4 h as needed or 10-15 mg/h continuously
...
MDI (90 mg/puff)
4-8 puffs every 20 min up to 4 h, then every 1-4 h as needed
...
Isoproterenol nebulization
7.5 mg/h for 2 h
No longer available in the United States
Ipratropium bromide nebulization
0.5 mg every 20 min for 3 doses, then as needed
...
MDI
8 puffs every 20 min as needed up to 3 h
...
Systemic bronchodilators Epinephrine IM 1:1,000 (1 mg/mL)
0.3-0.5 mg IM every 20 min up to 3 doses
...
Subcutaneous 1:1,000 (1 mg/mL)
0.3-0.5 mg subcutaneously every 20 min up to 3 doses
...
0.1 mg/kg/min
...
...
Titrate by 0.1-0.2 mg/kg/min based on response or toxicity
Subcutaneous
0.25 mg subcutaneously every 20 min for 3 doses
...
Intravenous
Bolus 4-10 mg/kg followed by continuous infusion of 0.2-0.4 mg/kg/min
...
Intravenous Terbutaline
Albuterol
...
Not available in the United States
10-15 mg/kg (maximum, 250 mg) over 5-10 min, which can be repeated every 5 min
...
...
Not recommended by current guidelines
6 mg/kg over 30 min followed by an infusion of 0.5 mg/kg/h
Serum levels should be checked and kept between 8 and 12 mg/mL
Methylprednisolone
40-60 mg IV every 6 h for 24 h, taper to 40-60 every 12 h if improved
...
Prednisone
40 mg po daily for 5 d
...
1-2 g IV over 20 min
...
Intravenous Aminophylline Intravenous Corticosteroids
Other medications Magnesium sulfate Sedatives and muscle relaxants Ketamine
...
May cause laryngospasm
Subanesthetic dosing infusion
0.1-0.5 mg/h
...
Dissociative dosing infusion
1-4 mg/h
...
...
May cause myocardial depression
0.2-0.7 mg/kg/h
...
Dexmedetomidine Infusion Propofol Infusion Cisatracurium IV bolus followed by infusion
...
...
5-50 mg/kg/min
...
...
...
Loading 0.1-0.2 mg/kg followed by infusion of 1-3 mg/kg/min
...
MDI ¼ metered-dose inhaler.
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although a signal of improved heart and respiratory rate was found in the HFNC group.24 HFNC can be used in acute severe asthma, but it should not delay the use of NIV or endotracheal intubation. Case Presentation: Update
The patient was admitted to the ICU; however, respiratory distress worsened despite treatment. He became unable to speak and continued to assume a tripod posture, and subcostal retractions became notable. He became hemodynamically unstable, with minimal tachypneic and lung sounds. The patient progressed to LTAE, prompting a move to the ICU, and warranted consideration for other avenues of treatment and respiratory support. Pharmacologic Management of LTAE
Systemic b2-Agonists: When inhaled SABA treatment is not possible, IV albuterol is recommended by some national guidelines, although it is not available in the United States.25-27 Epinephrine has bronchodilating effects and can be used with various presentations (Table 2). Systemic terbutaline is another b2-agonist that can be used for asthma refractory to inhaled therapeutics. Although strong evidence of superiority of its use is lacking, it can be useful in patients who are not responding to conventional therapy. Caution is advised in patients with tachyarrhythmias and hypokalemia.28 Side effects include those commonly seen with inhaled albuterol, including hypokalemia, hyperlactatemia, hyperglycemia, tachycardia, and tremors.28 Methylxanthines: Aminophylline is a methylxanthine that traditionally has been used as an infusion in acute asthma. It is a nonselective phosphodiesterase inhibitor. However, aminophylline is an inferior bronchodilator to SABA monotherapy. Furthermore, aminophylline is associated with an increased risk of nausea, vomiting, and tachyarrhythmias. Because of the safety profile of aminophylline, its use is no longer recommended in the treatment of acute asthma.29 Heliox (Helium Plus Oxygen)
Normal airflow in the medium and small airways is laminar; during a life-threatening asthma episode, airflow in these airways often becomes turbulent, increasing the work of breathing. Helium has a lower density and higher viscosity than regular air, and thus can improve airflow through narrow airways. Heliox is a combination of helium and oxygen that reduces turbulent flow and promotes laminar flow. However, FIO2 requirements need to be < 30% for its proper use.
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Heliox has two preparations, 70:30 and 80:20, which can be delivered via face mask, nebulizer, or nonrebreather mask or through IMV.30 A meta-analysis found that heliox was associated with improvement in PEF, especially in severe (PEF > 50% predicted) and very severe (PEF < 50% predicted) exacerbations.31 Heliox can be used in patients with severe bronchospasm who do not respond to conventional therapies to facilitate medication delivery, and it has been reported to decrease dynamic hyperinflation (DHI), reducing the work of breathing and hypercarbia. Its effects in reducing intubation remain unknown. We favor using heliox over not using it. If intended effects are not seen within 15 min, the therapy should be abandoned.32 Biologics
Interest has been expressed in the use of biologics to reduce eosinophils in those with asthma. Benralizumab is an IL-5 receptor antibody that has been able to produce eosinopenia after a single dose. Nowak et al33 demonstrated that single-dose benralizumab coupled with steroids reduces the rate and severity of exacerbations in those seeking treatment at the ED and suggested possible efficacy in patients with asthma exacerbations with contraindications to steroids. However, the usefulness of other biologics in treating acute asthma has not been evaluated, and none of them is approved for treatment of acute exacerbations. Ventilation in LTAE
NIV: Few studies have examined the effect of NIV (either biphasic positive pressure ventilation or CPAP) in patients with LTAE. A Cochrane review concluded that the use of NIV with standard of care may be beneficial. Although no clear benefit in mortality or rate of intubation was found, statistically significant improvements occurred in respiratory rate, PEF, FEV1, number of hospital admissions, and length of ICU and hospital stays.34 CPAP at 10 cm H2O can be used as a rescue therapy from intubation, although we favor the use of biphasic positive pressure ventilation.35 Biphasic positive pressure ventilation allows use of expiratory positive airway pressure to match autopositive end-expiratory pressure (PEEP) and inspiratory positive airway pressure to create a driving pressure to support the work of breathing. We recommend starting at an expiratory positive airway pressure of 5 cm H2O and an inspiratory positive airway pressure of 10 cm H2O and titrating FIO2 for a goal SpO2 of approximately 92%. Inspiratory
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positive airway pressure should be titrated for improvement in the work of breathing. Intubation is recommended if no improvement in the work of breathing, PEF, FEV1, or PCO2 occurs within 30 to 60 min of initiation. IMV: Endotracheal intubation remains a rare event in patients with asthma, due in part to the improved therapeutics and reversible nature of the disease but some patients will require IMV. This is especially true in patients with refractory bronchospasm. Ideally most patients can be rescued from intubation, but those who present with frank respiratory distress, encephalopathy or are hemodynamically unstable should be intubated. Airway management of patients with LTAE is crucial because they usually have poor reserve, bag-mask ventilation can further worsen DHI, acidosis can precipitate cardiac arrest, and hemodynamic instability may arise from insensible losses. Patients with LTAE should always be considered as difficult airways due to potential complications that may arise peri-intubation.
pneumothoraces. Detection of pneumothorax on pointof-care ultrasound depends on the lack of movement of the parietal pleural on the visceral pleura, which is seen in patients with asthma exacerbation.40 Invasive mechanical ventilation goals in LTAE are to improve delivery of inhaled bronchodilators, to improve work of breathing, and to reduce DHI while preventing volutrauma and barotrauma. IMV can be detrimental in LTAE because it adds positive pressure to an already high airway pressure, exacerbating DHI further. Excessive DHI affects preload through high intrathoracic pressure, resulting in hemodynamic instability. Efforts must be made to relieve airway pressure and to decompress DHI with the ventilator settings.
A large endotracheal tube (> 8 mm) is favored to relieve the airway resistance generated through IMV.36 Delayed sequence intubation is an alternative to rapid sequence intubation that can be beneficial in LTAE. Delayed sequence intubation intends to separate the induction agent from the paralytic to resuscitate, preoxygenate and denitrogenate better. Peri-intubation resuscitation can prevent hemodynamic instability in patients who might have become hypovolemic from insensible losses.37 The shock index is a simple bedside calculation (heart rate/ systolic BP) that can help to identify occult shock and is predictive of peri-intubation cardiac arrest. If a patient has a shock index of > 1, pre-emptive resuscitation with fluids or vasopressors is needed.38 Ketamine should be used as an induction agent because it does not cause hemodynamic instability.39 As soon as the SpO2 goal is achieved, paralysis with rocuronium is favored. Rocuronium will allow patients to be passive while receiving IMV after intubation, facilitating ventilator management. Bag-mask ventilation should be avoided because it can worsen DHI or cause barotrauma.
Mechanical ventilation can be achieved with either assisted and controlled volume-cycled ventilation or with assisted and controlled pressure-cycled ventilation. The focus of initial ventilator settings should be to reduce DHI and to prevent lung injury. This is achievable by manipulating the minute ventilation, inspiratory to expiratory ratio, and peak airway pressure (Ppaw). Initially a low respiratory rate (8-10 breaths/ min) should be set to allow a prolonged expiration (Fig 1). Monitoring DHI response to low minute ventilation can be seen in flow-time scalar. The expiratory portion of this scalar should come back to baseline before a new breath is initiated, suggesting resolution of DHI. If breath stacking continues (ie, flowtime curve does not return to 0 before a new breath is started), decreasing the inspiratory time will allow for a faster breath to be delivered and for more time to be spent in expiration at the expense of increased Ppaw. Ideally, the inspiratory to expiratory ratio should be set at 1:2, but in LTAE, a ratio of 1:3 or 1:4 is acceptable. If breath stacking persists, disconnection from the ventilator circuit while gently compressing the chest for 30 to 60 s can be performed. Gentle chest compressions at end expiration during IMV has been reported as a maneuver to improve DHI. Deep sedation, or neuromuscular blockade (NMB), may be needed.41
Barotrauma occurs as a result of high pressures in distal airways. Pneumomediastinum or pneumothorax must be suspected in patients with tracheal deviation, crepitus, or sudden loss of breath sounds. Imaging studies are required to make the diagnosis. Portable chest radiographs may be used, but may not be readily available. Point-of-care ultrasound can be useful, but hyperinflated lungs may be confounded by
The tidal volume should be set approximately 6 to 8 mL/ kg of ideal body weight. Careful attention should be paid to plateau pressure, with a goal of < 30 cm H2O while adjusting tidal volume or respiratory rate to avoid lung injury. Ventilation may be limited because of high Ppaw and plateau pressure, but usually hypercarbia is well tolerated up to PaCO2 of 90 to 100 mm Hg. Permissive hypercarbia should be allowed to a pH of > 7.20 in those
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Shortness of Breath Tachypnea Wheezing
SABA, SAMA, SCS, oxygen Mild: Any 3 mild symptoms from Table 1 Moderate: Any 3 moderate symptoms from Table 1 or accessory muscle use
Calculate Simplified Severity Score
Severe: Any 3 severe symptoms from Table 1 or SpO2 < 89%
Mod-Severe
Mild Symptom Improvement
Consider MgSO4 Clinical Improvement?
Consider discharge home
No
ICU Evidence of Hypercapneic Respiratory Failure or Diaphragmatic Fatigue
Yes
Inpatient admission
Yes IPAP 10 cmH20 EPAP 5 cm H2O Tolerated?
Consider Systemic Bronchodilators Heliox
No Delayed Sequence Intubation
Mechanical Ventilation Initial Settings: AC, FIO2 100%, RR 8-10 breaths/min PEEP < 5 cmH20, TV 6-8 kg of IBW Keep Pplat < 30 cmH20
Consider Bronchoscopy + NAC if atelectasis* Gas Anesthesia / ECMO/ECCO2-R*
Encephalopathy RR > 30 breaths/min pH < 7.20, PCO2 > 90 Ketamine Propofol NMB Worsening dynamic hyperinflation Volutrauma or barotrauma
Decrease Ti Temporary Disconnect from MV Mechanical Chest Compression
*In extremis situations.
Figure 1 – Flowchart showing a management of life-threatening asthma exacerbation algorithm. AC ¼ assist control; ECCO-R ¼ extracorporeal carbon dioxide removal; ECMO ¼ extracorporeal membrane oxygenation; EPAP ¼ expiratory positive airway pressure; IBW ¼ ideal body weight; MV ¼ mechanical ventilation; MgSO4 ¼ magnesium sulphate; Mod ¼ moderate; NAC ¼ N-acetylcysteine; NMB ¼ neuromuscular blockade; PEEP ¼ positive end-expiratory pressure; RR ¼ respiratory rate; SABA ¼ short-acting b2-agonist; SAMA ¼ short-acting muscarinic antagonist; SCS ¼ systemic corticosteroid; SpO2 ¼ oxygen saturation; Ti ¼ inspiratory time; TV ¼ tidal volume.
patients without any contraindication (eg, myocardial depression or intracranial pathologic features).
pressure gradient needed to overcome the auto-PEEP. Measuring auto-PEEP should occur at least every 6 h.
Extrinsic PEEP should be set at a low level in intubated patients (< 5 cm H2O). Spontaneously breathing patients may benefit from matching the auto-PEEP with the extrinsic PEEP. This improves the work of breathing by decreasing the
FIO2 initially should be set at 100%, but then rapidly titrated down for a goal SpO2 of > 92%. If hypoxia persists, a workup for alternative causes, including pulmonary shunting, should ensue.42-44
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Nonventilatory Strategies for LTAE
Sedation: Patients with LTAE exhibit a degree of breathlessness and feeling of imminent death that are detrimental to NIV use or inhaled medication delivery. Light sedation can be used to help patients tolerate NIV and to deliver inhaled bronchodilators effectively. Deep sedation, with or without neuromuscular blockade, may be warranted in those requiring IMV. Use of sedatives should warrant an admission to the ICU because patients will require frequent monitoring. In a nonintubated patient, intermittent dosing of shortacting opioids can decrease breathlessness and can depress respiratory drive. Boluses of fentanyl can be used because it has a rapid onset of action and a short half-life. If a favorable response occurs, doses can be repeated every 30 min as needed. Morphine should be avoided because it can cause histamine release. Dexmedetomidine is an a2-agonist that can be used if more sedation is needed. It does not suppress the respiratory drive and causes appropriate anxiolysis. Effects will be seen within 5 to 15 min, which may be too long in some patients. Ketamine is an N-methyl-D-aspartate receptor antagonist that can be used at subanesthetic dosing or at dissociative dosing. Ketamine works within seconds, will not cause respiratory depression, and can have a bronchodilation effect. Infusions are started at subanesthetic dosing and titrated slowly up to effect. Side effects include bronchorrhea, sialorrhea, and laryngospasm. Benzodiazepines should be avoided because they are associated with worse outcomes. As soon as ketamine or dexmedetomidine infusions are started, equipment and induction medications for intubation should be available readily at bedside. Propofol is a good first choice for patients receiving IMV. It allows for deeper sedation and synchronization with the ventilator and has bronchodilatory properties. Using ketamine concomitantly also can potentiate the bronchodilation and can reduce propofol and opioid requirements, possibly decreasing the number of days of IMV. Some patients still may show high ventilator dyssynchrony despite high levels of sedation, depending on ventilator strategy. These patients may benefit from NMB to tolerate the low respiratory rates required to allow for complete exhalation. This can be facilitated by a bolus of cisatracurium after adequate sedation.
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Infusions should be avoided to prevent myopathy from the combination of steroids and NMB. Monitoring during NMB infusions includes train-of-four and serial creatinine kinase evaluations.45,46 Inhaled Anesthetics: Inhaled anesthetics can be used in patients with LTAE with high Ppaw, excessive hypercarbia, and refractory bronchospasm who are receiving IMV. Isoflurane or halothane can reduce bronchospasm, and evidence of improvement should be seen quickly, but only while the gases are being administered because their effect is short-lived. These anesthetics are delivered through an anesthesia ventilator, and their use may be limited by the experience of the ICU staff. Inhaled anesthetics can cause hemodynamic instability by reducing venous and vascular tone.47,48 Extracorporeal Membrane Oxygenation: LTAE is a reversible condition in which extracorporeal membrane oxygenation (ECMO) can serve as a bridge to recovery. Although ECMO is required seldomly, those with severe respiratory acidosis (pH < 7.2) with hemodynamically unstable DHI can benefit from it. Venovenous ECMO can be used with ultraprotective lung ventilation. As soon as bronchospasm and respiratory acidosis resolve, patients can undergo decannulation and extubation.49,50 The use of ECMO is very limited in acute asthma, although a recent retrospective study demonstrated benefit for those who required it.51 ECMO potentially can increase the risk of sepsis, multiorgan failure, acute kidney injury, stroke, bleeding, thrombosis, and cannula-related complications. Also, its complexity warrants its implementation in high-volume centers and may be cost prohibitive, and therefore may not be feasible in smaller hospitals.52 Extracorporeal CO2 removal is a form of extracorporeal gas exchange designed to remove CO2 from the blood across a gas exchange membrane at low blood flow rates (200-1,500 mL/min). This is performed without a clinically relevant effect on oxygenation, as opposed to ECMO, which is used mainly for oxygen delivery at high blood flow rates (2,000-7,000 mL/min). Extracorporeal CO2 removal has been referred to as low-flow ECMO and respiratory dialysis by some clinicians.53 Although its role in LTAE remains to be defined, the Protective Ventilation with Veno-venous Lung Assist in Respiratory Failure (REST) trial did not find a mortality benefit in patients with acute hypoxic respiratory failure compared with those receiving usual care.54
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Bronchoscopy and Mucolytics: Airflow limitation in asthma results from bronchospasm, airway inflammation, and mucus plugging, but pharmacotherapy addresses only the first two causes. Bronchoscopy, BAL with or without N-acetylcysteine instilled directly into the airway, has been described as a therapeutic option in patients in whom mucus plugging is considered the main driver of airflow limitation.55
Conclusions LTAE is a rare complication of asthma, but if not treated in a timely fashion, it can result in death. Patients should be started quickly on inhaled SABA, short-acting muscarinic antagonists, and IV corticosteroids. Systemic infusion of magnesium sulfate can be considered in some patients. In those with severe bronchospasm, heliox can be used to facilitate medication delivery, but therapy should be abandoned if no clinical improvement is seen after 15 min of use. Patients who have progressive respiratory distress should be admitted to the ICU for close monitoring and should be administered NIV if tolerated. However, intubation should not be delayed if the patient does not improve in 30 to 60 min. Extra care should be taken if a patient requires mechanical ventilation. Intubation should be performed in a delayed sequence, and lung protective strategies should be adopted with IMV. Salvage therapies such as the use of inhaled anesthetics, bronchoscopy, and BAL with or without N-acetylcysteine or ECMO can be considered in individual patients with refractory disease.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following: N. A. H. has received honoraria for serving as a consultant or advisor for GSK, Boehringer Ingelheim, Sanofi, Teva, Amgen, Astra Zeneca, and Novartis. His institution received research grant support from AstraZeneca, GSK, Sanofi, Genentech, Novartis, Gossamer Bio, and Boehringer Ingelheim. None declared (O. G., J. S. R.).
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