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.

4 Journal of Intensive Care Medicine 25(1)

4



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

Mannam and Siegel 5

5



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.


6



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.

Mannam and Siegel 7

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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.


8



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

Mannam and Siegel 9

9



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.


10



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%

Mannam and Siegel 11

11



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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