Management of Life-Threatening Asthma in The Author(s...
Transcript of Management of Life-Threatening Asthma in The Author(s...
Analytic Reviews
Management of Life-Threatening Asthma inAdults
Praveen Mannam, MD, MS,1 and Mark D. Siegel, MD1
AbstractAsthma remains a troubling health problem despite the availability of effective treatment. A small but significant number ofasthmatics experience life-threatening attacks culminating in intensive care unit admission. Standard treatment includes high dosesystemic corticosteroids and inhaled bronchodilators. Patients with especially severe attacks may develop respiratory failure andneed endotracheal intubation and mechanical ventilation. Severe airway obstruction may lead to dynamic hyperinflation and thepossibility of hemodynamic collapse and barotrauma. Fortunately, most intubated asthmatics survive if physicians adhere to keymanagement principles intended to avoid or minimize hyperinflation. The purpose of this review is to discuss the pathogenesis oflife-threatening asthma and to provide practical guidance to promote rationale, safe, and effective management.
Keywordsdynamic hyperinflation, fatal asthma, near fatal asthma, status asthmaticus, permissive hypercapnia, respiratory failure, mechanicalventilation, corticosteroids, bronchodilators
Received January 23, 2009, and in revised form April 2, 2009. Accepted for publication April 16, 2009.
The best treatment of status asthmaticus is to treat it three days
before it occurs.
Thomas L. Petty, MD, Master FCCP1
Introduction
Asthma is a disease characterized by airway inflammation
and airflow obstruction. Treatment with inhaled steroids and
bronchodilators has greatly improved asthma control and
decreased morbidity. Nevertheless, death from asthma remains
an important and preventable problem. In the last two decades,
improved treatment for those requiring mechanical ventilation
has radically improved short-term prognosis. This review will
describe the epidemiology of life-threatening asthma, charac-
terize its pathology and pathogenesis, and summarize current
management principles, emphasizing a safe and effective
approach to mechanical ventilation.
Epidemiology
More than 22 million Americans suffer from asthma.2 Most are
treated as outpatients, but a minority experience uncontrolled
disease requiring hospital visits. In the United States, acute
asthma results in 1-2 million emergency-department (ED) vis-
its annually, 450 000 hospital admissions, and approximately
5000 deaths.3 In a year-long study of 3372 patients with acute
asthma conducted in 37 centers in France, 26% presented with
life-threatening asthma and 7% were admitted to the intensive
care unit (ICU).4 In another study done over 10 years at a ter-
tiary hospital, 4% of hospitalized asthma patients were admit-
ted to the ICU.5
Patients with prior intubation or ICU admission are at great-
est risk for life-threatening asthma.6,7 Other risk factors include
use of more than 2 canisters of short-acting b agonist per
month, difficulty perceiving airway obstruction or worsening
asthma, low socioeconomic status, illicit drug use, major psy-
chosocial problems or psychiatric disease, and comorbidities,
such as cardiovascular or other chronic lung disease.2 Inhaled
long-acting b agonists prescribed as monotherapy may increase
mortality, particularly if used without inhaled corticosteroids.8
In the United States, Puerto Rican and African American males
have a 360% and 200% higher risk respectively of asthma-
related death compared to whites and asthma mortality is
45% higher in females than in males.9
1 Pulmonary and Critical Care Section, Yale University School of Medicine,
New Haven, Connecticut
Corresponding Author:
Mark D. Siegel, LCI 105; P.O. Box 208057, 333 Cedar St., Yale University
School of Medicine, New Haven, CT 06520.
Email: [email protected]
Journal of Intensive Care Medicine25(1) 3-15ª The Author(s) 2010Reprints and permission: http://www.sagepub.com/journalsPermissions.navDOI: 10.1177/0885066609350866http://jicm.sagepub.com
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Precipitants
Common triggers of asthma flares include viral upper respira-
tory tract infection, nonsteroidal anti-inflammatory drugs in
susceptible individuals, exercise, stress, sulfites, and inhalation
of crack cocaine or heroin.10,11 Respiratory tract infections are
among the most common precipitants. In 12% to 56% of ED
patients, respiratory tract infections are identified as a trig-
ger.4,12 Of hospitalized asthmatics, 37% have evidence of a
recent infection, most commonly influenza A or rhinovirus13
and as many as 59% of hospitalized patients with near fatal
asthma had evidence of viral infection, commonly picornavirus
and adenovirus.14
Two distinct presentations characterize life-threatening
asthma exacerbations.15 The first and most common type
(80%-85%) presents with several days of worsening symptoms
and distress. Pathologically, mucus plugs obstruct the airways
and eosinophilic inflammation predominates.16 Response to
therapy is often delayed. The less common subset (15%-20%)
present with ‘‘acute asphyxic asthma,’’ characterized by worsen-
ing dyspnea developing within hours of presentation, often in
response to an acute irritant. Disease may be relatively mild at
baseline. Pathology may reveal neutrophils16 and evidence of
bronchoconstriction with smooth muscle shortening.15 Response
to therapy is often rapid (Table 1). Because many asthmatics
underestimate the duration of their symptoms, it may be difficult
to distinguish between these subtypes by history alone.
Pathophysiology
Hyperinflation
Airway obstruction with hyperinflation is the sine qua non of
asthma flares.17 When severe, airway narrowing due to bronch-
oconstriction, wall edema, and mucus plugging (Figure 1)
causes expiratory flow limitation; in the setting of insufficient
expiratory time, this precludes return to functional residual
capacity (FRC) at end-exhalation, resulting in dynamic hyper-
inflation (DHI). Other contributing factors include postinspira-
tory respiratory muscle activity, glottic narrowing, and reduced
pulmonary elastic recoil.18-21
Dynamic hyperinflation has important consequences from
both a respiratory and hemodynamic perspective. Distended
alveoli can compress the pulmonary capillaries, increasing dead
space and making gas exchange less efficient, while airway
occlusion leads to severe ventilation/perfusion mismatch.22 In
addition, DHI increases the work of breathing because
ventilation occurs along a less compliant portion of the pressure
volume curve.23 At the same time, the diaphragm may flatten,
placing it at a mechanically disadvantageous position, reducing
force of contraction. The combination of increased work of
breathing and inefficient ventilation may precipitate respiratory
muscle fatigue and failure if these conditions persist.
Dynamic hyperinflation may cause profound hemodynamic
changes. Prominent among these include increased intrathor-
acic pressures caused by retained air, which leads to decreased
venous return, ventricular preload, and stroke volume. When
severe, hyperinflated lungs can compress the heart, further
impairing preload. In addition, large intrathoracic pressure
swings during the respiratory cycle can have dramatic hemody-
namic effects. Increased intrathoracic pressure during expira-
tion may impede systemic venous return, resulting in
decreased right ventricular (RV) preload and stroke volume.
As a consequence, this may lead to decreased left ventricular
(LV) preload and stroke volume several beats later, during
inhalation. Also during inhalation, large drops in intrathoracic
pressure may augment venous return and RV preload. This will
tend to shift the interventricular septum toward the LV, further
impairing LV diastolic filling and preload. If severe, these fac-
tors may contribute to wide systolic blood pressure drops dur-
ing inhalation, beyond the 10 mm Hg that is normally seen,
resulting in pulsus paradoxus.24
Table 1. Patterns of Fatal Asthma
Type1 (Slow Onset) Type 2 (Acute Asphyxic Asthma)
Time course Subacute (1 or more days) Acute deterioration (hours)Incidence 80%-85% 15%-20%Airways Extensive mucus plugging Bronchospasm. Empty airwaysInflammation Eosinophils NeutrophilsResponse to treatment Slow—minimal initial response to bronchodilators Faster—good response to bronchodilators
Figure 1. Airway pathology in fatal asthma. Photomicrograph of theairway of a young woman who succumbed to a fatal asthma attack. Keyfindings include a marked inflammatory infiltrate (arrowhead), adisordered airway epithelium overlying a thickened basement mem-brane (arrow), and a large endobronchial mucus plug (asterisk).Photomicrograph courtesy of Drs Geoffrey Chupp and Robert Homer,Yale School of Medicine. Reproduced with permission from ACCP.
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Clinical Presentation and Assessment ofSeverity
Initial Assessment
Patients typically present with classic symptoms such as dys-
pnea, cough, or wheezing of variable duration. For unclear rea-
sons, many patients, particularly those with a history of severe
and near fatal asthma, have impaired perception of dyspnea and
may underestimate the severity of their attacks.25 A brief his-
tory should be taken concurrent with initial management. It is
crucial to identify patients at risk for fatal asthma (Table 2).
Directed questions should focus on timing and onset of symp-
toms, exacerbating factors, medication use, allergies, and a his-
tory of prior severe attacks.26,27
Important signs may help identify patients at greatest risk
for life-threatening asthma (Table 3). Key signs include tachy-
cardia, tachypnea, anxiety, diaphoresis, and inability to speak
in complete sentences or phrases. Accessory muscle use may
be prominent. Wheezing may be severe, although the chest
may become silent as airflow decreases with the onset of
respiratory failure. Depressed mental status is ominous. A
search should focus on potential complications such as pneu-
mothorax, pneumomediastinum, and subcutaneous emphy-
sema. It must be stressed that life-threatening asthma may
present with highly variable signs and symptoms and may pres-
ent in the absence of many of these signs.28
Differential Diagnosis
In evaluating asthma, it is useful to remember the clinical
aphorism ‘‘All that wheezes is not asthma.’’ It is important to
consider alternative diagnoses, especially if the presentation
is atypical, the patient is older, or if a prior diagnosis of asthma
has not been established (Table 4). Potential life-threatening
mimics include congestive heart failure, anaphylaxis, upper
airway obstruction, and pulmonary embolism. Other considera-
tions include chronic obstructive pulmonary disease (COPD),
pneumonia, vocal cord dysfunction, and, as a diagnosis of
exclusion, hyperventilation disorder. Upper airway obstruction,
particularly vocal cord dysfunction, may become self-evident
when there is no evidence of lower airway obstruction after
intubation.
Patient Monitoring
To objectively quantify the degree of obstruction and monitor
the response to therapy, patients should be monitored by
measuring the peak expiratory flow rate (PEFR) or forced
expiratory volume in 1 second (FEV1). A PEFR or FEV1 less
than 40% of predicted or personal best characterizes severe
exacerbation; a value <30% of predicted or personal best is
life-threatening.2 In critically ill patients, these maneuvers
should be deferred because they may provoke bronchos-
pasm.29,30 Measurement of pulsus paradoxus may also help
identify patients with severe disease.24 However, pulsus
paradoxus may be absent in severe asthma31 if the patient
develops respiratory muscle fatigue and cannot generate suffi-
ciently large intrathoracic pressure swings. Regardless of the
severity of initial presentation, patients who do not respond
promptly to treatment tend to have a more severe course,
requiring admission to the hospital or ICU.32
Pulse oximetry should be used to monitor arterial oxygen
saturation. In addition, pulse oximetry can be used to measure
the severity of airflow obstruction as there is a correlation
with the respiratory variation in pulse oximetry baseline
Table 2. Risk Factors for Asthma-related Death
� Previous severe exacerbation (eg, intubation or intensive care unitadmission for asthma)
� Two or more hospitalizations or >3 emergency visits in the pastyear
� Heavy use of short acting beta agonist� Difficulty perceiving airway obstruction or the severity of worsen-
ing asthma� Low socioeconomic status� Illicit drug use� Major psychosocial problems or psychiatric disease� Comorbidities, such as cardiovascular disease or chronic lung
disease
Table 3. Levels of Severity of Acute Asthma Exacerbations
Life-threatening asthmaAny one of the following in a patient with severe asthma:FEV1 <30% best or predictedSpO2 <92% PaO2 <8 kPa (60 mm Hg)PaCO2 > 6 kPa (45 mm Hg)Silent chestCyanosisFeeble respiratory effort, exhaustionConfusion or comaHypotension or bradycardia
Near fatal asthmaRaised PaCO2 and/or requiring mechanical ventilation with raisedinflation pressures
Table 4. Differential Diagnosis of Severe Asthma
Congestive heart failureMyocardial infarctionPulmonary embolismUpper airway obstructionForeign body aspirationTracheobronchomalaciaEndobronchial lesionChronic obstructive pulmonary disease (COPD)BronchiolitisVocal cord dysfunctionHyperventilation syndromeAcute bronchitis/pneumonia
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tracing and presence of pulsus paradoxus in patients with
severe asthma.33 The value of arterial blood gases to monitor
ventilation is uncertain. Decades old evidence has shown that
initial blood gases do not reliably predict a patient’s subse-
quent course.28 In nonintubated asthmatics, a respiratory alka-
losis with mild hypoxemia is common.34 Hypercapnia and a
concomitant respiratory acidosis indicate more severe dis-
ease, associated with worse airway obstruction. A quiet chest
on auscultation, inability to talk, and cyanosis correlate with
hypercapnia.35 A respiratory acidosis that develops or wor-
sens during treatment and normalization of arterial partial
pressure of carbon dioxide (PaCO2) are potentially ominous
signs if the patient is deteriorating or failing to improve clini-
cally. Importantly, severe obstruction and impending respira-
tory failure may occur without hypercapnia.34 The absence of
hypercapnia should not preclude ventilatory support in a
patient who is clinically deteriorating. Conversely, hypercap-
nia in isolation is not an indication for intubation if a patient is
clinically improving or has not had sufficient opportunity to
respond to therapy.
Some patients may develop a nonanion gap hyperchlore-
mic acidosis as a result of compensatory renal bicarbonate
excretion.36 Lactic acidosis is commonly seen in sicker
patients, and may result from a combination of factors, includ-
ing hypoxemia, respiratory muscle exertion, and catechola-
mine therapy.37,38
The chest x-ray (CXR) is normal in most patients; some
show evidence of hyperinflation (Figure 2) and only 2% show
abnormalities such as atelectasis, pneumonia, pneumomediasti-
num, or pneumothorax.39 Although not routinely indicated in
mild, straightforward exacerbations, the CXR may be useful
in severe exacerbations or atypical presentations with fever
or leukocytosis. Chest x-rays are needed for all patients admit-
ted to the ICU and should be done promptly after intubation to
ensure proper positioning of the endotracheal tube.
Criteria for ICU admission
Patients with severe exacerbations (FEV1 or PEFR <40%), par-
ticularly those not responding despite 1 to 2 hours of therapy
should be considered for ICU admission.2 Those with risk fac-
tors for fatal asthma and/or signs of severe illness, such as
altered mental status, hypercarbia (PaCO2 > 45 mm Hg), or
hypoxemia (PaO2 < 60 mm Hg on room air) requiring supple-
mental oxygen, should be considered ICU candidates as well.40
In many hospitals, the need for frequent albuterol treatments or
continuous therapy may mandate ICU admission, given the
caregiver workload required, regardless of severity.
Pharmacotherapy
The primary aims of treatment are to relieve airflow obstruc-
tion quickly and to promptly institute therapy to decrease air-
way inflammation.40 Key therapies include repetitive
administration of rapid-acting inhaled bronchodilators, early
use of systemic glucocorticosteroids, and oxygen. Commonly
used drugs and dosing schedules are shown in Table 5.
Bronchodilators
Inhaled short-acting b agonists such as albuterol, levalbuterol,
and pirbuterol are the drugs of choice to relieve acute symp-
toms.26 b-agonists relax smooth muscle, decrease bronchocon-
striction and airway obstruction, and may begin to provide
symptomatic relief within 3 to 5 minutes.2 Other actions
include mast cell stabilization and inhibition of release of
inflammatory mediators.41 Delivery of b agonists with a
metered dose inhaler (MDI) combined with a spacer device
appears to be as effective as nebulization.42 However, nebuli-
zers may be more effective for acutely dyspneic patients who
may have trouble using the MDI. The standard doses for
asthma treatment are 2.5 to 5 mg by nebulization every 20 min-
utes for 3 doses, then 2.5 to 10 mg every 1 to 4 hours as needed.
If using an MDI with a spacer, an appropriate dose is 4 to
8 puffs every 20 minutes for up to 4 hours, then every 1 to 4
hours as needed, although modifications may be necessary for
individual patients. For critically ill patients not responding to
intermittent therapy, continuous nebulization with administra-
tion of 10 to 15 mg over 1 hour is used.2 Many patients with
acute severe asthma respond to this treatment but there are
some who do not respond to high doses of albuterol. In 1 study,
70% of patients responded to 2.4 to 3.6 mg albuterol by MDI in
1 hour while 30% of patients did not.43 The nonresponder
group was characterized by higher severity of airway obstruc-
tion and may have relative resistance to typical doses of b-
agonists.
Figure 2. Hyperinflation in acute asthma. Chest radiograph of ayoung woman who presented to intensive care unit (ICU) withsevere asthma showing hyperinflation. Courtesy of Dr Lloyd N.Friedman, Yale School of Medicine.
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Parenteral b2-agonists, such as terbutaline or epinephrine
administered subcutaneously or intravenous (IV) albuterol,
have been used in patients not responding to inhaled therapy
and in extremis, but there is very little evidence to support this
therapy.44 Known cardiac disease and age greater than 40 are
relative contraindications to parenteral therapy; however, a
study of 95 asthmatic patients without recent myocardial
infarction concluded that subcutaneous epinephrine is tolerated
well in adults >40 years.45
Anticholinergic Agents
Inhaled anticholinergics such as ipratropium may provide a
useful adjunct to b agonists, further promoting bronchodilation
and alleviating symptoms.46,47 The doses used are 0.5 mg
every 20 minutes for 3 doses then as needed by nebulization
or 8 puffs every 20 minutes as needed up to 3 hours by MDI.2
Anticholinergics appear to be most helpful in patients with
severe obstruction. The lack of significant side effects argue for
their use in patients with insufficient response to b-agonists
alone.46,48
Methylxanthines
Methylxanthines such as theophylline and aminophylline were
once widely used to treat acute asthma. Concerns about their
narrow therapeutic range and the development of effective
inhaled bronchodilator therapy have marginalized their use.
The benefit of methylxanthines when added to inhaled b ago-
nists is uncertain at best. A meta-analysis of 15 randomized
controlled trials found that IV aminophylline failed to provide
additional bronchodilation compared to standard care with bagonists and adverse effects were more common with amino-
phylline.49 Methylxanthines may be considered in patients
already taking them.26 In these patients, if serum levels are low,
aminophylline can be given as 5 mg/kg IV loading dose fol-
lowed by 0.4 mg/kg per hour IV. Side effects of theophylline
increase at plasma levels above 20 mg/mL and may include
headache, nausea and vomiting, abdominal discomfort, and
restlessness. At high concentrations, convulsions, cardiac
arrhythmias, and death may occur.50 Theophylline should be
initiated by a physician familiar with the side effects; close
monitoring of the serum levels is warranted.
Corticosteroids
Inflammation contributes significantly to airway obstruction in
severe asthma. To address inflammation, systemic corticoster-
oids must be administered immediately, although they gener-
ally require several hours to take effect.2 Steroids act through
multiple mechanisms, including inhibition of the inflammatory
effects of the NFkB transcriptional system, the mitogen-
activated protein kinase (MAPK) pathway, and phospholipase
A2a.51 The oral and IV routes are equally effective,52 so that
the oral route may be used if patients can swallow. Prednisone
at dose of 40-80 mg per day in divided doses or equivalent
doses of IV methylprednisolone are recommended by the latest
U.S guidelines.2 This is substantially lower than the prior
guidelines that recommend 120–180 mg of methylpredniso-
lone given IV, divided into 3 or 4 doses per day28 and reflects
analysis showing low dose corticosteroids (�80 mg/day of
methylprednisolone or � 400 mg/day of hydrocortisone)
appear to be adequate in the initial management of hospitalized
patients with severe asthma.53
Inhaled steroids may cause nonspecific vasoconstriction and
reduction of airway wall edema vascular congestion and plasma
exudation in addition to anti-inflammatory effects.54 Some stud-
ies have shown the benefit of inhaled steroids in acute asthma
when added to inhaled bronchodilators in patients not receiving
systemic steroids55,56 but in 1 study, inhaled corticosteroids con-
ferred no added benefit to patients already receiving systemic
steroids.57 Inhaled corticosteroid therapy can be considered in
patients not responding to conventional therapy.
Leukotriene Receptor Antagonists
Leukotriene receptor antagonists (LRAs) are frequently used in
chronic asthma and have both bronchodilator and anti-
inflammatory properties. In 1 study, 7 mg or 14 mg of monte-
lukast given IV in the emergency room resulted in rapid
improvement in the FEV1 within 12 minutes.58 However, IV
LRAs are not available in the United States. Another study
evaluated oral zafirlukast for acute exacerbations59 and a single
dose of 160 mg improved the FEV1 and reduced the need for
hospitalization. LRAs may be useful adjuncts in the treatment
of severe asthma but further studies are needed to evaluate their
role in patients with life-threatening disease.
Table 5. Common Drugs Used in the Initial Treatment of Acute Severe Asthma
Albuterol: 2.5 to 5 mg by nebulization every 20 minutes for 3 doses, then 2.5 to 10 mg every 1 to 4 hours as needed or 4 to 8 puffs every 20minutes for up to 4 hours, then every 1 to 4 hours as needed. For critically ill patients, use continuous nebulization with administration of 10 to15 mg over 1 hour.Ipratropium bromide: 0.5 mg every 20 minutes for 3 doses then as needed by nebulization or 8 puffs every 20 minutes as needed up to 3 hoursby metered dose inhaler (MDI).Corticosteroids: 40-80 mg per day in divided doses or equivalent dose of intravenous (IV) methylprednisolone.Magnesium sulfate: 2 g IV over 20 minutes, repeat in 20 minutes if clinically indicated (total 4 g unless hypomagnesemic).Theophylline: 5 mg/kg IV over 30 minutes loading dose followed by 0.4 mg/kg per hour IV maintenance dose. Watch for drug interactions andfollow serum levels.Leukotriene modifiers: Consider montelukast 10 mg per oral (PO) daily.
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Magnesium
A single dose of IV magnesium (2 gm infused over 20 minutes)
is safe and effective in some patients with acute severe asthma
and can improve spirometric values up to 10% to 16%.60,61
Intravenous magnesium is recommended for patients who are
unresponsive to initial treatment with FEV1 less than 40% of
predicted.2 Magnesium should be given with caution to patients
with renal insufficiency. Magnesium given by inhalation may
be useful as well, although the benefit appears to be less than
IV therapy.62 A meta-analysis concluded that there appears
to be improvement in FEV1 by a mean value of 0.30 L with this
therapy and a trend toward less hospitalization.63 However,
considerable heterogeneity in the included trials precluded
definitive conclusions.
Oxygen Therapy
Patients with acute severe asthma are frequently hypoxemic
and require supplemental oxygen to maintain a saturation
greater than 90%.2 The average PaO2 in asthmatic patients is
about 69 mm Hg on room air and oxygen tensions less than
50 mm Hg are infrequent and were seen in just 8% of
patients.28 In most acute asthma exacerbations, hypoxemia can
be easily corrected with minimal supplementation. Care must
be taken against excessive use of oxygen as this may result
in reduction of carbon dioxide elimination and precipitate
hypercapnic respiratory failure.64
Ventilation
Noninvasive Positive Pressure Ventilation
The literature on the use of noninvasive positive pressure ven-
tilation (NPPV) for asthma is sparse. In a small prospective
study comparing NPPV to usual care in 30 patients presenting
with an acute attack, NPPV decreased the need for hospitaliza-
tion and improved the FEV1, FVC, PEFR, and respiratory
rate.65 Larger studies demonstrating the value of NPPV are
needed before it can be recommended.66 At present, a trial of
NPPV may be warranted in selected patients who are alert,
hemodynamically stable, and able to protect their airway.
Contraindications to NPPV include cardiac or respiratory
arrest, nonrespiratory organ failure, severe encephalopathy,
hemodynamic instability, or unstable cardiac arrhythmia, facial
surgery, trauma, or deformity, upper airway obstruction, inabil-
ity to cooperate/protect the airway, inability to clear respiratory
secretions and high risk for aspiration.67
Invasive Mechanical Ventilation
A subset of asthmatics who deteriorate or fail to improve
despite maximal therapy will require intubation and mechani-
cal ventilation. The decision to intubate an asthmatic patient
requires careful clinical judgment. However, important signs
include persistent or progressive hypoxemia and hypercarbia,
hemodynamic instability, worsening of mental status, apnea,
or signs of muscle fatigue or failure. Once it becomes apparent
that intubation is warranted, the process must not be delayed as
patients can deteriorate rapidly.
Intubation
Asthmatics requiring intubation pose special challenges
(Table 6). Intubation should be performed by an experienced
operator using a large bore endotracheal tube to allow adequate
secretion management. Airway manipulation can produce lar-
yngospasm or exacerbate bronchospasm.68 Immediately after
intubation, there is an elevated incidence of arrhythmias sec-
ondary to electrolyte, acid base disturbances, or secondary to
b agonist or methylxanthine therapy. Arrhythmias are usually
transient and rarely life-threatening. Short-term sedation for
intubation can be achieved with either etomidate or thiopen-
tone, which are a short-acting imidazole and barbiturate,
respectively.69 Rapid sequence intubation using an IV seda-
tive/anesthetic with succinylcholine is preferred to secure the
airway rapidly while preventing aspiration of stomach
contents.68
Hypotension has been reported in 25% to 35% of patients
after intubation.70 Contributing factors include underlying
intravascular volume depletion, loss of endogenous catechola-
mine release, anesthetic and sedative-induced vasodilation, and
high intrathoracic pressures that can impede venous return.
Vigorous bagging peri-intubation can cause or exacerbate DHI
by reducing expiratory time, contributing to hypotension. Ade-
quate venous access is essential and should be implemented
preintubation if possible. Central venous access can also assist
in determining the volume status and empiric IV fluids given
preintubation may be prudent if volume depletion is suspected.
Hypotension after intubation can be managed by fluid bolus
and temporary disconnection of the patient from the ventilator
if DHI is present. It is important to distinguish decreased
venous return from barotrauma and tension pneumothorax as
a cause of hypotension. Tension pneumothorax must always
be considered and equipment for needle or tube thoracostomy
should be immediately available. Signs suggestive of tension
pneumothorax include reduced breath sounds on one side of the
chest, tracheal shift, and failure to respond hemodynamically to
disconnection from the ventilator. If time permits, a chest
radiograph may be obtained to confirm pneumothorax, but in
Table 6. Recommendations for Process of Intubation
� Performed by experienced anesthetist or intensivist.� Ensure adequate sedation and paralysis for intubation.� Intubate by direct laryngoscopy.� Correct electrolyte disturbances.� Ensure adequate fluid hydration.� Monitor with continuous pulse oximetry and telemetry.� Preoxygenate before intubation.� Prepare for rapid correction of hypotension, arrhythmias or
barotrauma.� Ensure adequate venous access before intubation. Arterial line
blood pressure monitoring is useful but not mandatory.
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emergent conditions, it may be necessary to intervene before a
chest x-ray can be obtained.
Drugs for Mechanical Ventilation
Sedation. Adequate sedation is important during mechanical
ventilation to ensure patient comfort, to reduce dysynchrony
with the ventilator, and to decrease the risk of barotrauma.
Respiratory distress exacerbated by hypercapnia and profound
airway obstruction can make mechanical ventilation exceed-
ingly challenging. Adequate sedation is therefore a critical
adjunct. Although light sedation is optimal (i.e., allowing the
patient to be easily arousable), heavier sedation may be needed
in many patients to achieve synchrony with the ventilator.
Sedation and paralysis may decrease endogenous CO2 produc-
tion thus ameliorating hypercarbia seen in life-threatening
asthma attacks.
Benzodiazepines, particularly midazolam and lorazepam,
are commonly used for sedation. Doses should be titrated to
achieve the intended depth of sedation. If repeated boluses are
necessary, continuous infusions of midazolam (0.04-0.2 mg/kg
per hour) or lorazepam (0.01-0.1 mg/kg per hour) may be
needed. Propofol may be particularly useful given its rapid
onset of action and ability to titrate. Propofol may also have
bronchodilator effects.71 Opioids may be useful as well. In
addition to their analgesic properties, opioids exert powerful
respiratory depressant effects that may aid patient-ventilator
synchrony. Morphine should be avoided as large boluses can
cause histamine release and worsen bronchoconstriction.
Fentanyl is a safe alternative.
Paralytic agents. Neuromuscular blocking agents (NMBAs),
particularly vecuronium, cis-atracurium, and pancuronium,
may be required if sedation alone proves ineffective. Potential
benefits include improved patient-ventilator synchrony,
reduced oxygen consumption and carbon dioxide production,
and decreased risk of barotraumas.23 Neuromuscular blocking
agents are associated with important potential complications,
particularly myopathy and muscle weakness, as well as
increased risk of ventilator-associated pneumonia, loss of the
ability to evaluate mental status and neurological function, and
prolonged length of ICU stay.72,73 Neuromuscular blocking
agents should be given by intermittent dosing if possible and
stopped immediately when no longer needed. Infusions, if
used, should be stopped every 4 to 6 hours to prevent accumu-
lation and to allow patient evaluation. Finally, if NMBAs are
used, heavy sedation to the point of anesthesia is mandatory.
Ventilator Management
Asthmatics requiring intubation are among the most challenging
to care for in the ICU. The goals of mechanical ventilation are to
ensure adequate gas exchange while avoiding the complications
associated with DHI, particularly barotrauma and hemodyna-
mic compromise, while awaiting response to pharmacologic
therapies. Timely recognition of DHI and the use of protective
ventilation strategies are key to avoiding complications.
Monitoring for DHI
Proper attention must be paid to ensure sufficient lung empty-
ing during expiration. The complications of DHI can be sudden
and cataclysmic and it is therefore essential to recognize it so
that ventilator settings can be adjusted accordingly. Although
some DHI may be unavoidable, the degree of hyperinflation
can be mitigated by carefully monitoring lung mechanics and
making necessary ventilator adjustments.
Several parameters of varying utility have been used to
monitor for DHI. Examples include (a) increased peak airway
pressures (Ppk) and plateau pressures (Ppl) during volume-
regulated ventilation; (b) reductions in tidal volume/minute
volume during pressure-regulated ventilation; (c) increased chest
wall girth; (d) increased patient effort; (e) persistent expiratory
flow at end-expiration or intrinsic positive end-expiratory pres-
sure (PEEPi); and (f) hemodynamic compromise.74 Airway pres-
sure measurements—Ppk, Ppl, and PEEPi—are readily available
and may help identify DHI. Unfortunately, none of these mea-
surements are perfect and each has drawbacks.
The use of airway pressures to measure DHI requires
patient-ventilator synchrony and absence of spontaneous
respiratory activity. Leaks around the endotracheal cuff or in
the ventilator circuit can result in faulty measurements. Sub-
stantial variation in measurements between breaths is an impor-
tant clue suggesting that airway pressures should not be relied
upon until synchrony and cessation of respiratory muscle
activity is achieved.
For many reasons, Ppk is an unreliable measure of DHI.75
Ppk represents the sum of pressures required to overcome
the elastic recoil pressure of the inflated respiratory system
(ie, the Ppl) and to overcome resistance in the airway (Pr):
Ppk ¼ Pplþ Pr
Pr is a function of the airway resistance (Raw) and inspira-
tory flow rates (Fi):
Pr ¼ Raw� Fi
Changes in Raw and modifications in the set Fi can alter Pr
and, consequently, Ppk without necessarily affecting DHI. In
particular, an increase in Fi, used to shorten inspiratory time
in an effort to promote sufficient expiratory time, as discussed
below, may increase Ppk even though DHI decreases.76 Con-
versely, a decrease in Fi may lower Ppk while exacerbating
DHI. In addition, the clinical consequences of elevated airway
pressures resulting from proximal airway obstruction are
unknown, recognizing that these pressures may dissipate dis-
tally and be less likely to contribute to barotraumas.75 Because
Ppk may be elevated, it may be necessary to adjust the ventila-
tor appropriately to ensure that set tidal volumes are delivered.
The presence of DHI can be deduced by observing persistent
end-expiratory air flow. However, simply observing flow does
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not allow DHI to be quantified. PEEPi can be measured using
an end-expiratory hold maneuver, which allows equilibration
of pressures in the distal airways and alveoli with the airway
opening (Figure 3). Unfortunately, measured PEEPi may
underestimate DHI in severe asthma, because measurement
assumes airway patency, a necessary condition to ensure that
pressures at the airway opening reflect those in the distal air-
ways and alveoli. In severe asthma, airway closure and plug-
ging may occlude many airways at end-expiration, leading to
underestimation of DHI (Figure 4).77 Thus, marked pulmonary
hyperinflation may be present despite relatively low measured
PEEPi. Similarly, PEEPi may remain constant or rise despite
improvement in DHI as plugging and airway closure resolve.
In general, end-inspiratory Ppl provides a better estimate of
DHI than Ppk or PEEPi.75 It is important to remember that Ppl
is affected by chest wall compliance (Ccw). When Ccw is low,
for example if patients are obese or if they have chest wall
deformities, an elevated Ppl may lead to an overestimate of
DHI if these influences are not accounted for. Nevertheless, the
American College of Chest Physicians (ACCP) consensus
statement on mechanical ventilation has concluded that Ppl
provides the best measure of lung hyperinflation.78 In general,
the Ppl should be kept <30 cm H2O to minimize the risk of
DHI-associated complications.70,79
Mode of Ventilation and Settings
Mechanically ventilated asthmatics are at great risk for devel-
oping DHI. Spontaneously breathing patients cannot inspire
beyond total lung capacity (TLC). In contrast, during mechan-
ical ventilation, machine-delivered breaths can push inhalation
beyond TLC, leading to dangerous levels of DHI, resulting in
hemodynamic collapse or barotauma, particularly tension
pneumothorax. In the early years of mechanical ventilation,
attempts to ventilate asthmatics aggressively to prevent
hypercapnia had the unintentional effect of increasing compli-
cations, particularly barotrauma, hemodynamic compromise,
and death.80 Subsequently, a classic study by Darioli et al
showed that a protective approach to mechanical ventilation,
which allowed hypercapnia to develop as necessary to avoid
hyperinflation, led to substantially improved outcomes as long
as oxygenation was maintained.81 Subsequent studies have
confirmed that careful ventilator management that avoids
hyperinflation dramatically decreases the complications
associated with mechanical ventilation.82
Figure 3. Idealized pressure and flow waveforms showing thedetermination of intrinsic positive end-expiratory pressure (PEEPi) inventilated patients. A representation of idealized pressure and flowwaveforms of ventilator set with zero extrinsic PEEP (PEEPe). Theexpiratory flow does not return to baseline before the initiation ofnext breath. This is a sign of incomplete exhalation and developmentof PEEPi). Closure of the expiratory valve at end of expiration willcause the flow to drop immediately to zero. The alveolar pressurewill equilibrate with the airway pressure and allow measurement ofPEEPi.
Figure 4. Underestimation of dynamic hyperinflation by measure-ment of intrinsic positive end-expiratory pressure (iPEEP). As a resultof mucus plugs and dynamic airway compression at the end ofexpiration some alveolar units are not in communication with theairway. In this representation, the measured PEEPi estimates only theupper alveolar unit. This results in underestimation of hyperinflation.We must interpret the low measured PEEPi in an asthmatic patientwith caution when other indicators of hyperinflation are present.Reproduced with permission from Leatherman JW, Ravenscraft SA.Critical Care Med. 1996.
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Determinants of DHI include (1) tidal volume (2) expiratory
time, and (3) the degree of airflow obstruction.83 Reversal of
airflow obstruction depends on pharmacologic therapy while
the other 2 parameters require manipulation of the ventilator.
Dynamic hyperinflation can be limited by ensuring sufficient
expiratory time to maximize lung deflation after each breath.
Expiratory time can be maximized by decreasing minute ven-
tilation (VE) by lowering respiratory rates, tidal volumes, or
both and by increasing inspiratory flow rates.68 Although arter-
ial CO2 almost always rises, decreasing VE is the most reliably
effective way to prevent or ameliorate DHI.83 Increases in Fi
may play an adjunctive role, but are generally not as effective
and may produce intolerable elevations in Ppk. In addition,
increases in Fi may stimulate the respiratory drive, producing
unwanted increases in VE.84
Ventilator settings must be crafted to meet the individual
patient’s needs, particularly as dictated by measures of DHI.
Frequent changes may be necessary as the patient’s condition
evolves. Examples of reasonable initial settings are shown in
Table 7. These settings have been shown to be appropriate for
80% of ventilated patients with severe asthma while resulting
in only mild DHI in the remaining 20%.76 In some patients with
severe airflow obstruction and dangerous levels of DHI, further
reductions in tidal volume and respiratory rate may be
necessary.
The deliberate use of hypoventilation will necessarily result
in hypercapnia and a concomitant respiratory acidosis. PaCO2
levels up to 80 mm Hg and pH as low as 7.15 are tolerated
without any apparent permanent sequelae.82,85 Higher levels
of PaCO2 may be necessary in some patients85 and appear to
be well tolerated as long as oxygenation is assured. Bicarbonate
therapy to combat acidosis is rarely indicated but may be con-
sidered in cases of severe acidosis causing cardiac arrhythmias
or cardiovascular collapse. Hypercapnia may increase intracra-
nial pressure and must be minimized in the presence of head
injury, intracranial bleeding, or space-occupying lesions. Other
relative contraindications to permissive hypercapnia include
severe hypertension, severe metabolic acidosis, hypovolemia,
severe refractory hypoxemia, severe pulmonary hypertension,
concomitant use of b-adrenergic blocking agents, and presence
of coronary artery disease.86 Given that hypercapnia is likely to
increase the patient’s respiratory drive and discomfort, aggres-
sive sedation and, sometimes, neuromuscular blockade may be
necessary to control ventilation.
The mode of ventilation used is less important than setting
specific goals that minimize DHI. Volume cycle is well estab-
lished as a primary support mode in asthma.68 Because VE can
be directly controlled in volume cycle ventilation, it is the
mode preferred by the authors. Pressure control ventilation can
also be used to achieve the same parameters described in Table
7, as long as vigilance is maintained to avoid DHI. Pressure
control ventilation has been advocated as the choice mode of
ventilation by some authors87 although there is no evidence that
pressure control ventilation offers any advantages over volume
cycle ventilation in the management of the severe asthmatic.
Pressure control ventilation can be disadvantageous in
severely obstructed patient for several reasons. Changes in air-
way mechanics can lead rapidly to dramatic changes in tidal
volumes; constant vigilance is required to prevent under and
overventilation. The use of pressure limitation does not guaran-
tee that DHI will not occur. In the presence of high Raw, high
levels of inspiratory pressure may be necessary to achieve ven-
tilation. It is important to note that as long as flow continues,
distal airway and alveolar pressures cannot be measured. Thus,
if an inspiratory pressure >30 cm H2O is used, there is some risk
that distal pressures will also exceed 30 cm H2O, placing the
patient at risk for barotrauma. If high levels of inspiratory pres-
sure are used, there is significant risk that hyperinflation will
occur during recovery as airway obstruction subsides. Constant
monitoring is required to prevent this from happening.79
Use of Extrinsic PEEP
Dynamic airway collapse toward the end of expiration in some
lung units can contribute to air trapping and DHI. As in patients
with COPD, extrinsic PEEP (PEEPe) could splint open these
airways and promote more effective emptying of the lung.88
Traditional teaching has recommended against using PEEPe
in severe asthma, however, because of concerns that it would
impede exhalation and exacerbate hyperinflation.79 In a study
of 6 ventilated patients with severe airflow obstruction, a step-
wise increase of PEEPe from 5 to 15 cm H2O increased hyper-
inflation and reduced cardiac output and blood pressure.89
However, this observation has not been universal. In a more
recent study, 5 of 8 patients with airway obstruction demon-
strated increased expiratory flow and decreased evidence of
hyperinflation when PEEPe was applied.90 Thus, at least some
asthmatics may benefit from the cautious addition of PEEPe.
Extrinsic PEEP should never be set above measured PEEPi; a
goal of 80% of the PEEPi is a reasonable target. Among spon-
taneously breathing patients, PEEPe may help overcome
PEEPi and make it easier for them to trigger a breath.91
Unconventional Therapies
General Anesthesia
Several case reports have described the use of general
anesthesia for the management of life-threatening asthma,
although there has been no systematic study of its efficacy.92
Table 7. General Principles of Mechanical Ventilation
Controlled hypoventilation with low tidal volume, respiratory rate,and longer expiratory time to reduce hyperinflationRecommended Initial Ventilator Settings� Tidal volume 8 cc/kg� Rate 10-12 breaths/min� Inspiratory flow rate 80-100 cc/h� Plateau pressure <30 cm H2O� Inspiration:Expiration ratio >1:3� FIO2 to maintain saturation >90%
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Inhalational anesthesia, using either halothane or isoflurane,
may exert useful bronchodilating effects in refractory patients.
Hypotension is an important potential side effect. The use of
inhalational anesthesia is limited by the need for special equip-
ment and an anesthesiologist.93 The bronchodilating effect of
IV ketamine has been used to treat asthma. However, ketamine
has sympathomimetic effects and great caution must be exer-
cised in patients with hypertension and elevated intracranial
pressure.94
Heliox
Heliox is a blend of helium and oxygen usually in a 80:20 or
70:30 ratio. It has been used to reduce the work of breathing,
improve ventilation by reducing turbulent airflow, and improve
delivery of bronchodilators to the distal airways. The utility of
heliox is controversial. A recent meta-analysis concluded that
available evidence failed to support routine use in nonintubated
asthmatics.95 However, several reports have described
improvement in pulsus paradoxus in nonintubated patients.96,97
In a report in intubated patients, heliox appeared to improve
airway pressures, CO2 retention, and acidosis.98 Unfortunately,
most ventilators are designed for a mixture of oxygen and air
and the low density of helium alters flow through the valves,
regulators, and tubing. As a result, pressure changes and
response to therapy may be hard to assess reliably in intubated
patients.99 Heliox is used in premixed concentrations, hence
the fraction of administered oxygen that may be used is lim-
ited.100 In select patients, heliox may be considered as a tem-
porizing measure until bronchospasm responds to traditional
therapy. However, the inconvenience, increased cost, and lack
of discernible benefit in most patients preclude widespread use.
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO) has been used
rarely to treat life-threatening asthma. The technique has been
described in several case reports.101-103 Bronchoscopy with
lavage has been proposed to remove mucus plugs in intubated
patients with life-threatening asthma104,105; however, its use
cannot be routinely recommended as there is a risk of worsen-
ing bronchospasm and gas exchange.106
Weaning and Extubation
Weaning from the ventilator should commence as soon as the
patient’s condition allows 70 Signs that weaning is appropriate
include improved air movement on examination and the ability
to tolerate ventilation sufficient to normalize the PaCO2. When
patients are ready, sedation should be minimized or stopped and
spontaneous breathing trials begun.107 Barring contraindica-
tions, patients should be extubated once they successfully com-
plete a spontaneous breathing trial. In a minority, a myopathy
caused by prior treatment with high-dose corticosteroids and
neuromuscular blockade may impose a barrier to extubation.
Follow-Up Care
Patients admitted to the ICU and particularly those requiring
intubation are at high risk for recurrence of life-threatening
asthma. In a study following intubated patients with near fatal
asthma after discharge from hospital, mortality was 10.1% after
1 year, 14.4% after 3 years, and 22.6% after 6 years, all occur-
ring from asthma attacks.108 Noncompliance and poor access to
medical care contribute to the development of subsequent
exacerbations. Patients require extensive education on the use
of peak flow meters for monitoring and must learn to recognize
signs of worsening control such as increasing need for b agonist
rescue therapy. They should also be counseled to avoid triggers
and to develop an emergency plan. Patients must be treated
with inhaled steroids and close follow up with an asthma spe-
cialist should be considered prudent.
Summary
Managing patients with life-threatening asthma is one of the most
difficult challenges facing critical care physicians. Although any
asthmatic is theoretically at risk for life-threatening attacks, it is
becoming clear that those with life-threatening asthma are a
unique group characterized by poor baseline asthma control and
severely inflamed airways. Fortunately, advances in manage-
ment, emphasizing high doses of corticosteroids and safe
mechanical ventilation techniques, ensure survival in the vast
majority who come to the ICU. Still, the severe morbidity asso-
ciated with life-threatening asthma makes it critical that outpati-
ent management be enhanced to prevent this disorder.
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