[ Asthma How I Do It ]

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 inflam-
mation with systemic corticosteroids. Correction of hypoxemia and hypercapnia, a key in
managing life-threatening asthma, occasionally requires the incorporation of noninvasive me-
chanical 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 hypo-
ventilation, adequate sedation, and occasional use of muscle relaxation to avoid dynamic hy-
perinflation, 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 mechanical ventilation. In one study, of

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 life-
threatening 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
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

ABBREVIATIONS: DHI = dynamic hyperinflation; ECMO = extracor-
poreal membrane oxygenation; HFNC = high-flow nasal cannula;
IMV = invasive mechanical ventilation; LTAE = life-threatening
asthma exacerbation; NIV = noninvasive ventilation; NMB = neuro-
muscular 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
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

chestjournal.org 747
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-pack-
year 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 ] Simplified Severity Score for Acute Asthma4
Sign or Symptom Mild
Pulse rate, beats/min < 90
Wheezing Absent
Rales Absent
Prolonged expirium Absent
Oxygen saturation, % 95-100
Use accessory muscles Absent
Minimal no. of parameters Any 3 of the above
required to qualify for
categories
748 How I Do It
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,
Severity Score
Moderate Severe
91-119 > 120
Present Present
Present Present
Present Present
90-94 < 89
Present Present
Any 3 of the above or the use Any 3 of the above or oxygen
of accessory muscles only saturation of < 89% only
[ 162#4 CHEST OCTOBER 2022 ]
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 short-
acting 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 b2-
agonists 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
chestjournal.org
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,
749
TABLE 2 ] Pharmacotherapy in Asthma Exacerbation
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 0.5 mg every 20 min for 3 doses, then as ...
nebulization 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 0.3-0.5 mg subcutaneously every 20 min up ...
(1 mg/mL) to 3 doses
Intravenous 0.1 mg/kg/min ...
Terbutaline ... 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
Albuterol ... Not available in the United States
Intravenous 10-15 mg/kg (maximum, 250 mg) over 5-10 ...
min, which can be repeated every 5 min
Aminophylline ... Not recommended by current
guidelines
Intravenous 6 mg/kg over 30 min followed by an infusion Serum levels should be checked and
of 0.5 mg/kg/h kept between 8 and 12 mg/mL
Corticosteroids
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 ...
Other medications
Magnesium sulfate 1-2 g IV over 20 min ...
Sedatives and muscle relaxants
Ketamine ... May cause laryngospasm
Subanesthetic dosing infusion 0.1-0.5 mg/h ...
Dissociative dosing infusion 1-4 mg/h ...
Dexmedetomidine ... May cause myocardial depression
Infusion 0.2-0.7 mg/kg/h ...
Propofol ... ...
Infusion 5-50 mg/kg/min ...
Cisatracurium ... ...
IV bolus followed by infusion Loading 0.1-0.2 mg/kg followed by infusion ...
of 1-3 mg/kg/min

MDI ¼ metered-dose inhaler.

750 How I Do It [ 162#4 CHEST OCTOBER 2022 ]

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.
chestjournal.org
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
751
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.
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.
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
752 How I Do It
pneumothoraces. Detection of pneumothorax on point-
of-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.
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, flow-
time 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
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
[ 162#4 CHEST OCTOBER 2022 ]
 Shortness of Breath
Tachypnea
Wheezing

SABA, SAMA, SCS, oxygen

Mild: Any 3 mild symptoms from Table 1

Moderate: Any 3 moderate symptoms

Calculate from Table 1 or accessory muscle use
Simplified Severity
Score
Severe: Any 3 severe symptoms from
Table 1 or SpO2 < 89%

Mild
Mod-Severe Symptom
Improvement

Consider MgSO4
Consider discharge home
Clinical Improvement?

No Yes

ICU
Evidence of Hypercapneic Inpatient admission
Respiratory Failure or
Diaphragmatic Fatigue

Yes

IPAP 10 cmH20 Consider

EPAP 5 cm H2O Systemic Bronchodilators
Tolerated? Heliox

No
Encephalopathy
Delayed Sequence
RR > 30 breaths/min
Intubation
pH < 7.20, PCO2 > 90

Mechanical Ventilation Ketamine

Initial Settings: Propofol
AC, FIO2 100%, RR 8-10 breaths/min NMB
PEEP < 5 cmH20, TV 6-8 kg of IBW
Keep Pplat < 30 cmH20 Decrease Ti
Worsening dynamic hyperinflation
Temporary Disconnect from MV
Volutrauma or barotrauma
Mechanical Chest Compression

Consider
Bronchoscopy + NAC if atelectasis*
*In extremis situations.
Gas Anesthesia / ECMO/ECCO2-R*

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 pressure gradient needed to overcome the auto-PEEP.
depression or intracranial pathologic features). Measuring auto-PEEP should occur at least every 6 h.

Extrinsic PEEP should be set at a low level in intubated FIO2 initially should be set at 100%, but then rapidly
patients (< 5 cm H2O). Spontaneously breathing patients titrated down for a goal SpO2 of > 92%. If hypoxia
may benefit from matching the auto-PEEP with the extrinsic persists, a workup for alternative causes, including
PEEP. This improves the work of breathing by decreasing the pulmonary shunting, should ensue.42-44

chestjournal.org 753
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 short-
acting 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.
754 How I Do It
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
[ 162#4 CHEST OCTOBER 2022 ]
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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