She has been seen by an allergist who confirmed multiple allergic
triggers for her asthma, including cat, dog, dust mites, and the mold
Alternaria. The mother states that she is disappointed in your treatment
plan for her daughter, and tells you that she is considering switching to
another doctor. When you ask the patient how she's been doing with her
asthma, she says "fine," and states that she is not experiencing any
shortness of breath. Upon exam, her lungs are clear to auscultation.
 
To be complete, you check spirometry, which reveals a forced expiratory volume in
1 second (FEV1) of 60% predicted. After giving her 2 puffs of albuterol, you
are relieved to see that her FEV1 has improved to 94% predicted, but caution
her that she needs to pay closer attention to properly caring for her asthma.
 
She says that there have been several times when she has had sudden,
severe asthma attacks when she was so short of breath that it was difficult
for her to talk. At those times, her symptoms seem to eventually improve
with albuterol. You ask her to call you if she has any further problems with
her asthma, but it seems that she is not listening and can hardly wait to
get out of your office.
 
Are you worried about this patient? You should be. She just mentioned 8 risk
factors that are known to be associated with an increased risk for a fatal
asthma attack:
 
Medication noncompliance;
 
 
Psychiatric diagnoses/depression;
 
 
Allergy to the mold Alternaria;
 
 
Conflict between the family and the healthcare provider regarding an asthma
management plan;
 
 
Poor perception of dyspnea despite documented airway obstruction;
 
 
Marked bronchial hyperreactivity as evidenced by significant changes in FEV1
with albuterol;
 
 
History of sudden, severe asthma attacks; and
 
 
Disregard for asthma symptoms and/or severity.
This review attempts to summarize the current state of knowledge on sudden
death from asthma, and explores the incidence, risk factors,
pathophysiology, and management approach. Over the last several decades, a
troubling increase in the asthma mortality rate led to a rich body of
literature on this subject, albeit much of it based on small groups of
patients or case reports. The bulk of this research was done during the
1980s and 1990s, and to omit it would leave a large gap in our discussion of
this topic. In an attempt to unravel the reasons behind this perplexing
trend, a number of possible explanations have been proposed. In an effort to
provide a complete review that incorporates the original and often unique
observations of these thoughtful investigators, their research is also
included in this review, even if it is not recent. It is my hope that this
review will stimulate new ideas and research to further understand the cause
and treatment of this condition.
 
It is troubling that despite increasing efforts to provide comprehensive
asthma care, the hospitalization and mortality rates from asthma continue to
rise in many parts of the world.[1] Although studies show some conflicting
results, asthma prevalence has significantly increased over the last 25
years in all regions of the United States, with current data showing a
higher prevalence in African-Americans compared with whites and
Hispanics.[2,3] Fortunately, with our current effective therapy, asthma
fatalities as an inpatient are exceedingly rare. However, it is indeed
frightening that in a number of studies, deaths from asthma may occur
suddenly, often in young people outside the hospital.[4] This fact, combined
with the unanticipated nature of these sudden attacks, helps explain the
lack of substantial data describing fatal or near-fatal asthma attacks. If
asthma hospitalization and mortality rates are not falling, then the
healthcare community is failing. In order to lower the asthma mortality
rate, we need to understand both the triggers and varying presentations of a
potentially life-threatening attack of asthma. This is particularly vital
when caring for a culturally diverse population of patients with a disease
that, by its nature, is variable over time.
 
Death from asthma generally occurs in the setting of a prolonged asthma
attack worsening over days or weeks,[5] and may be preceded by "status
asthmaticus," defined by Montserrat and colleagues[6] as prolonged bronchial
asthma that responds poorly to medical treatment. Death from asthma in this
instance may follow a slow, steady downward trend in pulmonary function,
often just after a viral respiratory infection.[7] However, a sudden,
fulminant form of asthma, which can progress from what appears to be
controlled asthma to death from respiratory arrest within minutes of the
onset of symptoms, has been described.[5-14] This unexpected, rapid
decompensation of asthma has been termed sudden asphyxic asthma (SAA) by
Wasserfallen and colleagues.[5] This should be differentiated from other
causes of sudden death, including pulmonary or cardiac disorders that
escaped detection prior to death; toxic effects of medications; or
prolonged, slow deterioration in which patients die regardless of intensive
medical therapy in the hospital.[11]
 
Recognizing important clues in a disease already characterized by large
variations in functional impairment may help identify patients at risk for
sudden death from asthma.[11] These high-risk patients are quite disparate
in some ways, but remarkably similar in others. Patients experiencing
sudden, life-threatening episodes of asthma tend to be less than 25 years
old; are frequently atopic; and may experience sudden, unexpected, profound
bronchospasm, which may proceed to respiratory arrest in a matter of
minutes.[14] If treated promptly and aggressively, these patients may
recover quickly, and remarkably in some patients, with no physical sequelae
from their life-threatening event. However, such episodes can be
psychologically very traumatic.
 
Although none of the following factors can fully explain what happens during
an episode of SAA, they seem to at least play an important role[6,14]:
 
Extreme bronchial reactivity;
Upper airway obstruction;
Changes in arterial oxygen concentration; and
Inability to detect added resistive respiratory loads.
If an asthmatic patient has experienced one such attack, he or she is at a
higher risk of experiencing it again.[14,15] In fact, some patients go on to
experience multiple respiratory arrest episodes.
 
 
Background and Incidence
 
Recent estimates of asthma prevalence suggest that approximately 10% of
Americans have asthma or have had asthma in their lifetime.[15,16] The
direct and indirect costs of illness due to asthma are enormous, with 43% of
that money spent on emergency department use, hospitalization, and
death.[17,18] Also, it is not possible to quantify the emotional toll on
family and friends when a disease widely considered to be "reversible and
treatable" takes the life of a loved one.
 
Physicians and other healthcare providers scratch their heads as they
witness increasing asthma hospitalizations and deaths despite our improved
modern treatment.[1] One percent of all deaths and 10% of nonviolent deaths
in children are due to asthma.[19] Furthermore, in a New Zealand study,
Dawson and colleagues[20] noted that 1% of patients admitted for treatment
for an acute episode of asthma required endotracheal intubation and
mechanical ventilation. Similarly, in South Australia, Ruffin and
associates[21] noted that near-fatal asthma (defined as respiratory arrest
secondary to asthma, PaCO2 > 50 mm Hg, or altered consciousness) represented
3% of all asthma hospital admissions.
 
Also in New Zealand, a 2-year survey of deaths from asthma determined that
rapid clinical deterioration (death occurring within 3 hours of apparent
onset of symptoms) was definitely precipitous in 29% of cases, and probably
precipitous in another 11%.[22] From this trial, it was estimated that 25%
of asthma deaths occurred within 30 minutes of the onset of the asthma
exacerbation, and 2 of 3 deaths occurred within 8 hours. In patients dying
outside of the hospital, 3 of 4 died before seeing a healthcare provider. In
half of the outpatient deaths, the patients were not even able to summon any
medical assistance. Macdonald and colleagues[22] noted that asthmatics dying
as inpatients were more likely to have an associated respiratory infection
and cyanosis at the time of presentation. Those dying suddenly from asthma
as outpatients, in contrast, were often not cyanotic, and were frequently
sent home from the emergency department or the hospital where they went on
to expire. Twenty-one percent of individuals who died as outpatients had
been hospitalized in the preceding month, compared with only 8% of those who
died as inpatients.
 
Adolescents, particularly those in the 10- to 14-year-old age group, seem
particularly susceptible to sudden death from asthma. Although the reasons
for this are not completely clear, they may include reduced compliance with
medications, inappropriate use of metered-dose inhalers, poor
self-management skills (including denial), and increased atopic
sensitivity.[14,19,23]
 
 
 
Patient Characteristics and Clinical Presentation
 
History and Physical Examination
When gathering the history from asthmatic patients, the following factors
are particularly noteworthy for assessing the risk of SAA:
 
Previous respiratory arrests;
History of seizure in the setting of an acute asthma attack;
Psychosocial factors and personality traits;
Perception of dyspnea (or lack thereof); and
Medication use -- types and amounts.
Respiratory arrest and related factors. In patients who experience SAA, one
of the most striking findings in their clinical history is that many of them
have had similar episodes.[5,14,15,24] These sudden episodes of severe
bronchospasm frequently occur in the early-morning hours, and are
characterized by unexpected, rapidly progressive dyspnea, which may proceed
to full respiratory arrest in a very short time.[13] In many instances,
patients seem to progress from fairly asymptomatic to unconsciousness over a
matter of minutes. It is clear that some attacks evolve so rapidly that the
person is unable to summon medical assistance or help from family or
friends.
 
If a patient has had a previous respiratory arrest or episode of respiratory
failure at any time (ie, no matter how long ago), he or she is at an
increased risk for a future episode.[24] Also, SAA episodes are not confined
to those with severe disease; such episodes may occur in asthmatics
classified as mild, moderate, or severe.[25] Some patients (or family
members) have reported recent, excessive allergen exposure immediately prior
to SAA,[5,26] whereas others are unaware of such exposures despite the fact
that the allergen seemed to play an important role in the life-threatening
attack.[14] It is important to note that any history of a seizure in the
setting of an asthma attack is a grave prognostic sign, and predicts an
increased chance of a future, life-threatening asthma episode.[14]
 
Psychosocial factors and personality traits. Although not all studies agree,
especially when considering those with major psychiatric diagnoses,[27]
there seems to be a strong correlation between asthma fatalities and certain
psychosocial factors and personality traits, including the following:[4,5,
28-30]
 
Stressful life events;
Denial of disease;
Family dysfunction;
Depression;
Poor self-care; and
Conflicts between parents of the child and medical staff regarding
management.
Although stressful life events may be associated specifically with SAA,[5]
most trials evaluating other psychological factors listed have not been
characterized in terms of speed of onset of the fatal attack.[30] Other
potential social influences include:
 
Adolescents experiencing a rebellious phase, which may affect compliance
because they reject doctors (and their advice) as authority figures[19]; and
 
 
Parental smoking, which is associated with increased bronchial reactivity in
asthmatic children, but has not been studied specifically for a relationship
to SAA.[31]
Perceived breathlessness and spirometric measurements. Patients at risk for
SAA may present with a seemingly benign medical history, because they may
not appreciate the degree of airway lability or obstruction that they are
experiencing; therefore, they may not complain about significant
dyspnea.[11,32] Although spirometric measurements (eg, FEV1) are thought to
correlate with perceived breathlessness, Burdon and colleagues[32] studied
the relationship of perceived dyspnea with degree of bronchial
responsiveness to inhaled histamine and found an inverse correlation between
perception of breathlessness and bronchial hyperresponsiveness (BHR). In
other words, those with the highest lability in airflow had the least
perception of their airway narrowing. This surprising finding has been
duplicated by others.[33] More recently, the study by Yoos and
colleagues[34] supports this assertion. The study was conducted on children
5-12 years old with asthma and their parents (N = 228). The participants
were asked to describe the symptoms that they associated with an asthma
exacerbation and their proposed action. Perceived asthma control was
compared with a structured assessment of severity advocated by the National
Asthma Education & Prevention Program (NAEPP). The study authors found that
136 unique symptoms were reported. Although 78% of parents reported at least
1 standard asthma symptom, 48% also reported nonstandard asthma symptoms. Of
interest, 65% of parents whose children's symptoms were consistent with
severe asthma reported "good control." It appears that patients who
experience wide swings in airway caliber may develop a perception tolerance,
and may be minimally aware (or more dangerously, unaware) of such swings in
pulmonary status. Of note, the degree of breathlessness that is experienced
by a patient seems to be consistent with the degree of fall from the
particular patient's baseline, rather than the actual numeric value on
spirometry.[32] Yoos and colleagues[34] concluded from their study that
improved communication about symptoms would improve asthma care, proposing
that strategies for improvement include standardized screening
questionnaires to assess symptoms, more frequent routine visits for children
with persistent asthma, and wide dissemination of realistic goals for
symptom control.
 
To investigate asthma attacks as they related to percentage of predicted
FEV1, over 13,000 children (mean age, 13 years) were investigated in a
retrospective cohort study.[35] A progressive decrease in the proportion of
individuals reporting an attack was associated with each increasing decile
of percentage of predicted FEV1.
 
Medications. Although one study showed no statistically significant
difference in the number or type of medications used for those with SAA
compared with those who had a respiratory arrest with a slower onset,[5]
others have noted an association between regular use of inhaled
beta-agonists and the risk of hospitalization or death from asthma.[36]
 
Inhaled corticosteroids (ICS) are widely accepted as one of the cornerstones
of effective treatment for persistent asthma. However, evidence on whether
use of ICS may help prevent death from asthma has been harder to obtain. A
group of Canadian investigators used the Saskatchewan Health database to
investigate the relationship between ICS use and death from asthma in 5- to
44-year-old patients.[37] In their analysis, the death rate from asthma
decreased by 21% for each canister of ICS used in the previous year. In
addition, the death rate from asthma in the first 3 months following
discontinuation of ICS was almost 5 times higher than those who continued
the drug.
 
Physical exam. Patients experiencing sudden asphyxic asthma have a higher
incidence of silent chest on auscultation.[5] However, respiratory rate,
pulse rate, blood pressure, use of accessory muscles of respiration, lung
hyperinflation on chest x-ray, and findings on electrocardiogram do not seem
to correlate with the speed of onset of the asthmatic symptoms.[5,10,38]
However, those who died in the hospital had persistent tachycardia and
tachypnea despite apparent initial clinical improvement with treatment.[19]
Another notable finding is that most patients requiring mechanical
ventilation due to SAA had an absence of secretions suctioned from the
airway.[5]
 
From a neurologic standpoint, those with SAA seem to have a higher rate of
altered consciousness on presentation to the emergency department, compared
with those who have a slower onset of symptoms; reports claim that as many
as half of patients with SAA present to the hospital in a coma.[5]
 
Laboratory and Arterial Blood Gas Findings
Some patients with acute severe asthma are hypokalemic, often despite the
presence of acidosis, which should raise measured levels of serum
potassium.[10, 38-40] This has been at least partially attributed to the use
of injected beta-agonists (such as epinephrine), which may acutely lower
serum potassium levels.[39,41]
 
Concentrations obtained measuring arterial blood gas levels in patients
suffering from an acute asphyxic asthma attack are often remarkable for:
 
Profound acidosis -- pH ranging from 6.90 to 7.0[5,10,14]; and
Severe hypercarbia -- PaCO2 average of 112.8 mm Hg.[5]
An anion gap metabolic acidosis due to lactate accumulation may accompany
the hypercarbic respiratory acidosis, although nongap metabolic acidosis has
also been described in this setting.[4440] There is no single screening
laboratory parameter that predicts who is at risk for SAA.
 
Spirometry and Peak Expiratory Flow-Rate Findings
Patients at risk for SAA may not be accurately identified by any single
pulmonary function parameter.[38] However, wide diurnal variation in peak
expiratory flow rates (PEFR) has been consistently associated with increased
risk of a life-threatening episode of SAA.[11,38, 42-44] As previously
discussed, these patients may have an altered perception of breathlessness
despite significant reductions in their pulmonary function. Patients with
increased bronchial hyperreactivity, as evidenced by wide swings in PEFR,
may occur across all levels of asthma severity.[38,45] Patients who
experience falls of greater than 50% in PEFR, especially in the morning,
have a higher risk of subsequent respiratory arrest from asthma.[43] This
may be further complicated in children, who have smaller airways to start
with and may experience a larger drop in airflow than an adult with a
comparable episode of bronchospasm.[46]
 
Asthmatic patients who experience wide variability, or gradual
deterioration, of pulmonary function have an increased risk for death from
asthma.[19,47] Zach and Karner[11] noted consistent failure of improvement
of FEF25-75 after bronchodilator treatment in 2 young asthmatics who
subsequently died from asthma; they believe that it is important to monitor
this parameter in asthmatics as well.
 
 
 
Pathophysiology -- How Are Patients With SAA Different?
 
As a group, asthmatics usually have a normal physiologic response to hypoxia
and hypercarbia -- namely, an increase in their respiratory rate and minute
ventilation.[48] However, abnormal hypoxic responses (that is, low
ventilatory responses in that setting) have been noted in those with chronic
obstructive pulmonary disease as well as several other groups of
nonasthmatic individuals[8,48,49]:
 
Long-distance runners and their family members;
Residents at high altitudes;
Patients with cyanotic congenital heart disease;
Certain racial groups; and
Parents of children who have suffered recurrent respiratory arrests.
One study found that 6 of 13 patients admitted to the hospital for acute
asthma accompanied by hypercarbia had an abnormal hypoxic response when
tested between acute episodes.[8] Similarly, Olson and Saunders[50] noted
impaired response to experimentally induced hypoxia in 2 asthmatics who had
experienced SAA, and Hudgel and Weil[51] noted that 2 of 3 asthmatics who
suffered a respiratory arrest had abnormally low ventilatory responses to
hypoxia. There are several potential explanations for low ventilatory
response:
 
Depressed hypoxic drive due to long-term hypoxia; this likely takes several
years to develop, however[51];
 
 
Autonomic dysfunction[51]; increased ventilatory drive depends on an intact
autonomic nervous system, and some asthmatics have a degree of autonomic
dysfunction; and
 
 
Abnormal chemoreceptor function.[13]
In a report by Olson and Saunders[50] of 2 patients who suffered sudden and
unexpected respiratory arrest, naloxone reversed the disordered ventilatory
control and restored response to both hypoxia and hypercarbia in one
patient.[13] Of note, enkephalins are present in the carotid body of cats,
and naloxone is known to increase the carotid body chemosensitivity of these
experimental animals.[13] Humans who have had a carotid body resection and
then subsequently breathe a hypoxic air mixture not only fail to increase
ventilation, but also hypoventilate and may become profoundly hypoxic.[13]
One theory, therefore, is that certain patients have abnormal carotid body
responsiveness and, thus, may not react appropriately to the moderate
hypoxia that is precipitated by bronchospasm. Although this is likely to
occur in only a minority of patients, this could hypothetically progress to
asphyxia and death.
 
There have also been multiple reports of patients who have experienced
respiratory arrests from asthma, and have borderline or abnormally low
ventilatory responses to hypercarbia.[7,8,13,51] It is important to note,
however, that the respiratory responses to hypoxia and hypercarbia are not
dependent on one another. Carbon dioxide retention in severe airflow
obstruction may also be caused by inappropriate sedation and respiratory
muscle fatigue.[7] On the other hand, neither reduced perception of dyspnea
nor altered responsiveness to hypercarbia differentiated asthmatics with
near-fatal episodes from control asthmatics.[21] (As an aside, the same
research group also noted a continued high degree of noncompliance with
treatment recommendations in this high-risk group of asthmatics, even after
they experienced a near-death episode.[21])
 
Because most asthmatics have normal responses to hypoxia and hypercarbia and
some nonasthmatics do not, asthma is not the determining factor for normal
vs abnormal respiratory response. The combination of asthma and abnormal
chemoreception to these circumstances, however, significantly increases the
risk of dying from asthma. Although any causal link still remains
speculative and not all individuals with this condition are affected, an
association between SAA and defective responses with hypoxia and hypercapnia
seems to exist.
 
Diurnal Variations
In one series, 8 of 10 respiratory arrests from asthma occurred between
midnight and 6:00 am.[44] Patients who suffered respiratory arrests also had
falls in their PEFR of > 50% in the morning compared with values during the
daytime and evening hours. This fall in PEFR was associated with, but not
absolutely predictive of, respiratory arrest, because 30% of all asthma
admissions were also noted to have this pattern. Another study of 30 asthma
deaths also showed that most patients died in the evening or nighttime
hours, and that drops in PEFR during the early-morning hours correlated with
serum and urine catecholamine levels.[52] On the other hand, some have found
no correlation between diurnal serum cortisol levels and diurnal variation
in airway obstruction; similarly, cortisol infusions do not seem to
eliminate morning dipping.[53-56]
 
Possibly related to diurnal variation is that patients with asthma have
shown increased responsiveness to inhaled allergens and histamine at night
compared with other times during the day.[57] Asthmatics may also have
increased exposure to allergens present in their bedroom during the
nighttime hours, including dust mites and pets. A patient with recurrent,
nocturnal, near-fatal asthma attacks was noted by Sears and Duckley[58] to
also have a reduced perception of breathlessness accompanying wide swings in
PEFR. The patient improved and no longer experienced these episodes after
treatment with bronchodilators combined with ICS and cromolyn.
 
Mechanisms of SAA as Inferred by Response to Therapy
Treatment of patients with an episode of SAA may be accompanied by an
initial period of apparent ineffectiveness of therapy, followed by a sudden,
dramatic fall in pulmonary resistance occurring minutes or hours into
therapy.[5] This may manifest as a sudden drop in insufflation pressures on
the ventilator or a sudden ability to increase volume in manually ventilated
patients, both of which suggest that severe bronchospasm may be the main
mechanism of airway obstruction.[5] Kravis[4] proposed sudden bronchospasm,
rather than severe airway edema and mucous production, as the etiology for
sudden, severe increases in required inspiratory ventilator pressures in 2
intubated asthmatics. These patients were suddenly unable to be ventilated
due to high inspiratory pressures, and suffered subsequent respiratory and
cardiac arrests. When disconnected and ventilated by hand, they were able to
be promptly resuscitated.[59] Hetzel and colleagues[44] also described 6
similar patients with respiratory arrests in the hospital who quickly
responded to manual ventilation and medical therapy.
 
Three patterns of response to therapy for an acute episode of asthma were
described by Smith.[60] These findings are supported by studies by Benfield
and Smith[61] and Jenkins and colleagues[62]:
 
Rapid responders who tend to be younger than 40 years old and less likely to
have had an infective episode;
 
 
"Usual" pattern of recovery that occurs over several days; and
 
 
Prolonged, slow responders who tend to be older than age 40, smoke or have a
history of smoking, and have had a respiratory infection that triggered the
attack.
Smith[60] noted that one cannot predict the speed of response to therapy
based on the severity of the attack. Several reports of SAA have noted
relatively rapid recovery, with extubation often accomplished within 12
hours of the onset of the attack.[14,63] Therefore, some have also suggested
laryngospasm or other vagally mediated reflexes from the upper aerodigestive
tract as contributing factors in sudden episodes of asthma.[64]
 
Bronchodilators, Airway Hyperresponsiveness, and SAA
Airway hyperresponsiveness correlates with a number of parameters, including
severity of asthma, the amount of medication required for control, the
presence of morning dipping, and diurnal variation in PEFR.[65] Prior to the
death of a 16-year-old boy from SAA, he was noted to have persistent,
increased BHR as measured by methacholine sensitivity.[65] Drazen and
colleagues[66] also investigated patients who experienced a near-fatal
asthma episode by measuring their BHR with methacholine challenge. Those
patients whose BHR decreased on intensive medical therapy with ICS fared
much better than those whose BHR did not change significantly despite
therapy. In fact, the latter group went on to die from their asthma. Central
to an analysis of the pathogenesis of sudden asphyxic asthma, therefore, is
an analysis of those factors that influence the degree of
hyperresponsiveness of the bronchial airway.
 
Questions have also been raised about the possible contribution of certain
forms of therapy (notably, inhaled bronchodilators) to increasing rates of
asthma hospitalization and mortality.[36,67] Regular inhalation of a
beta-sympathomimetic drug for 6 months was associated with poorer overall
control in the majority of patients with chronic asthma in a study done by
Sears and coworkers.[67] Patients treated with fenoterol, a potent inhaled
beta-agonist, on a regular basis compared with use on an "as-needed" basis
had more asthma symptoms and a higher rate of hospitalization. Similarly, an
increased risk of death or near death from asthma in patients taking regular
inhaled beta-agonists, especially fenoterol, has been noted.[36] The
question is whether the trend toward regular use of higher doses of longer
acting inhaled beta-agonists is an important causal factor in the worldwide
increase in morbidity and mortality from asthma.[67] It is not known,
however, whether the association between increased use of inhaled
beta-agonists and both hospitalization and death are simply markers for
severity of disease, or whether these agents themselves pose an independent
risk.[36] It is clear that regular use of inhaled beta-agonists without
accompanying use of ICS is not recommended, and is not in keeping with
current recommendations by expert panels and national asthma treatment
guidelines.[68]
 
Van Schayck and colleagues[69] also noted that regular use of inhaled
salbutamol led to an increase in bronchial hyperreactivity. On the other
hand, asthmatics, previously found to have an immediate asthmatic response
on antigen inhalation challenge, were able to tolerate many times more
antigen if pretreated with the inhaled beta-agonist rimiterol, and would
then show a late asthmatic response after inhaling the increased amount of
antigen.[70] Of note, in that group of 14 patients, this new, late-asthmatic
response was not associated with an increase in nonspecific bronchial
hyperreactivity. This study does, however, lend credence to the hypothesis
that regular use of short-acting inhaled beta-agonists without accompanying
ICS may allow asthmatics with allergen triggers to unknowingly tolerate
increased doses of allergen without symptoms until significant amounts of
allergen have been inhaled. Theoretically, this may lead to increased
bronchial wall edema and inflammation -- a pathologic finding seen both on
postmortem examination and through cellular analysis of fluid obtained by
bronchoalveolar lavage.[71]
 
Mast cells line the skin, lungs, and gastrointestinal tract and contain
histamine and other molecules. Activation of mast cells is followed by the
release of mast cell granules. This activation may follow bridging of
adjacent immunoglobulin (Ig)E molecules on the mast cell surface by an
allergen, or by other stimuli. Mast cells contain some preformed substances,
such as histamine and heparin, as well as others that take some time to
synthesize. Beta-agonists effectively prohibit immediate mast cell mediator
release after allergen exposure.[72] Page[72] postulated some years ago that
because inhaled beta-agonists inhibit histamine (and thus heparin) release,
one may prevent the natural neutralization of eosinophilic cationic proteins
by the more basic mast cell anion, heparin. He noted that heparin has been
shown to have a number of functions, including inhibition of lymphocyte
activation and trafficking; inhibition of increased vascular permeability;
and neutralization of eosinophilic proteins, including major basic protein,
eosinophilic cationic protein, and eosinophilic peroxidase. He also noted
that eosinophil proteins are rapidly incorporated into mast cells after
intradermal injection and that mast cells may play a role in neutralizing
these proteins. In addition, mast cell proteases also have a regulatory role
in degrading sensory neuropeptides, such as platelet-activating factor. He
argues that by preventing mast cell release of granule-bound heparin, we may
be preventing the body's natural "damage-control" mechanism designed to
minimize airway inflammation begun by antigen-stimulated mast cell mediator
release. Others have postulated that alterations in the genetically
determined amino acid composition of the beta-agonist receptor may play a
role in response to medications and contribute to adverse outcomes.[73]
 
Others have noted a possible increased mortality rate in those taking
salmeterol, and subgroup analysis suggests that the risk may be greater in
African-Americans compared with whites.[74] A case-control study of
salmeterol and near-fatal attacks of asthma, however, suggested that the use
of salmeterol by patients with chronic severe asthma was not associated with
an increased risk of a near-fatal attack.[75] However, this analysis was
limited by the size of the patient groups that were available for subgroup
analysis. Additional research on this topic, conducted by Nelson and
colleagues, is expected to be published later this year. Others have also
noted the absence of an association between the use of salmeterol and a risk
of fatal asthma attacks, but have noted an increased association between
fenoterol and nebulized beta-agonists and fatal asthma attacks.[76] Some
have noted significant advantages of regular use of long-acting
beta-agonists compared with regular use of short-acting beta-agonists.[75]
It is the accepted clinical practice, and the recommendation of the National
Institutes of Health (NIH) Expert treatment panel, that the preferred form
of treatment for moderate--to-severe persistent asthma is a long-acting
beta-agonist combined with an inhaled steroid. As per national treatment
guidelines, long-acting beta-agonists should not be used without ICS in the
treatment of asthma. The combination of long-acting beta-agonists and ICS is
a powerful treatment option for moderate-to-severe persistent asthma, and
forms the basis for the current treatment guidelines from the NIH.[68]
 
Although little experimental data exist to substantiate various theories, a
number of other possible adverse effects of inhaled beta-agonists have been
proposed to explain the negative outcomes that are associated with use of
this class of drug in asthmatics[19]:
 
Induction of ventricular arrhythmias;
 
 
Accumulation of metabolites that may have beta-adrenergic blocking activity;
 
 
Toxicity of propellants (eg, fluoroalkanes) present in aerosolized
formulations;
 
 
Significant tachyphylaxis leading to overuse; Prevention of mast cell
release of granule-bound heparin; and
 
 
Alteration in genetically determined amino acid composition of beta-agonist
receptors.
Some have also proposed that steroids enhance the adverse beta-adrenergic
side effects, leading to cardiotoxicity; however, most studies have found
that the majority of patients who die from asthma die from asphyxiation
related to undertreatment with steroids, rather than from any cardiotoxicity
from beta-agonists.[19]
 
Postmortem Examination of Patients Who Die From SAA
Postmortem examination findings of the lungs and other organs from patients
who have died from sudden asphyxic asthma may teach us more about the
pathogenesis of this disorder, and hopefully improve our ability to prevent
such episodes in the future. Pathologic examination of patients who have
died from asthma has revealed 3 patterns: endobronchial mucous suffocation,
mild mucous plugging, and empty airways.[12]
 
Endobronchial mucous suffocation is the pathologic finding typically found
in patients who die in status asthmaticus, often after failing to respond to
inpatient management over several days. Both large and small airways may be
full of thick, tenacious mucus, as well as vast amounts of eosinophils and
desquamated columnar epithelial cellular debris.[77,78] There may also be
extensive peribronchial edema and a thickened basement membrane on
microscopic examination.[78] Microscopic sections may also show intraluminal
mucus, which is continuous with intracellular secretory mucus.[12] Reid[12]
noted that the mucus secreted by patients with asthma may be fundamentally
different from the mucus produced by nonasthmatic individuals -- an area
that is receiving further investigation.
 
Mild mucous plugging has also been reported at postmortem examination. Of
interest, these patients were often thought to be only slightly suboptimal
in the hours just before death, but were noted to have precipitous
deterioration in pulmonary status and death within several minutes of onset
of severe respiratory symptoms.[12] The etiology of this sudden
deterioration is unclear, but sudden mucous plugging or overwhelming
allergen exposure has been proposed.
 
"Empty airways" is the other extreme after a fatal attack of asthma, in
which no mechanical obstruction is found, even if eosinophils and a
thickened basement membrane are present on pathologic
examination.[8,9,11,12,79] Clinically, most of these patients had airway
obstruction before death; therefore, it may be that sudden overwhelming
bronchoconstriction was the cause of death.[12] Although it is also possible
that cardiac arrhythmias may be responsible for a portion of these deaths,
it appears to be a minority.
 
Both peripheral airways and adjacent arteries in 6 patients who died from
sudden fatal asthma were studied by Saetta and colleagues[80]; these
patients were compared with nonasthmatic controls. The mean age of these
patients was 25 years, and all 6 patients had evidence of atopy. The lungs
were hyperinflated with typical findings of mucous plugging and bronchiolar
wall thickening. Pulmonary arteries near the peripheral airways in the study
population had similar diameters to the arteries in nonasthmatic control
patients, but they did not have changes typically seen in patients with
chronic hypoxia. Inflammatory infiltrates, consisting largely of eosinophils
and mononuclear cells, were found within both the bronchial tissue and the
adjacent vessel walls of pulmonary arteries, especially in those vessels
nearest an airway.[80]
 
One would think that those who die suddenly of apparent acute bronchospasm
should have empty airways on postmortem examination. In fact, pathologic
findings do not vary with the presentation of the fatal asthma attack.[19]
Patients who die of SAA may have findings of full, mucous-laden airways;
mild mucous plugging; or empty airways.[12,19] Whether sudden filling of the
peripheral airways or a primary bronchi with mucus can occur is not
known.[19] It may well be that in many patients, acute bronchospasm
superimposed on a process of gradual intraluminal mucous accumulation and
increasing edema may precipitate the final fatal event.[79]
 
Occasionally, additional medical problems, clinically unsuspected prior to
death, may be discovered on postmortem examination. Kravis and Kolski[81]
reviewed 13 childhood asthma deaths that occurred between 1969 and January
1984. Among the causes of these unexpected deaths in ambulatory chronic
asthmatics were undetected pneumothorax, bronchopneumonia, pulmonary edema,
cor pulmonale, and Klebsiella pneumoniae bacteremia.[81] Adrenal atrophy may
be seen in some of these patients as well, but it is not a universal finding
in those who have died suddenly from asthma.[20,81]
 
 
 
Summary and Treatment Recommendations
 
SAA may have a number of diverse mechanisms involved in its pathogenesis.
Timely identification of this subgroup prior to a near-fatal or fatal
episode may be difficult in some patients; however, a number of observations
have been made to help in this process.
 
SAA is characterized by rapidly progressive breathlessness, typically
leading to acute respiratory failure that requires endotracheal intubation
and artificial ventilation within 3 hours of the apparent onset of symptoms.
Patients who have had an SAA attack are at risk to have it happen again,
regardless of the occurrence of the original episode. There does not appear
to be any clear male or female sex predominance. Patients who experience SAA
tend to be younger and frequently have an atopic predisposition. Although
sometimes no such explanation can be found, both allergen exposure and
acutely stressful events have been implicated as precipitating factors for
SAA.
 
Several factors that may be extracted from the patient's history may suggest
a higher asthma risk profile; however, no single physical finding, pulmonary
function measurement, or other parameter can accurately identify these
patients in advance.[38] However, patients who demonstrate a number of risk
factors should be watched extremely closely. For example, young asthmatics
who do not seem to perceive their degree of airway obstruction, especially
when combined with denial of their disease and/or other psychosocial or
family problems, are at an extremely high risk of experiencing a potentially
fatal attack of asthma. Any past history of a seizure in the setting of an
asthma attack also is an ominous prognostic sign, and places a patient in a
very high-risk category.[14] Extreme variation in daily PEFR has also been
closely associated with this population of patients. If variability in PEFR
does not abolish with aggressive therapy, including high-dose inhaled
steroids, then systemic steroids should be considered in concert with
extremely close follow-up by all physicians who are involved.
 
Some investigators recommend steroid therapy during a steadily declining
airflow pattern on spirometry, even if the patient is not noting increasing
symptoms, because this pattern is associated with a definite increased risk
of death from asthma.[42] Spirometry (or at a minimum PEFR measurement)
needs to be done at every outpatient visit for patients with asthma. Also,
it is desirable to follow objective parameters of pulmonary function to
guide decisions regarding discharge from the hospital. Because many of these
patients are seen in the emergency department, and subsequently scheduled
for follow-up with a primary care provider or specialist, firm mechanisms to
ensure compliance with follow-up appointments need to be put in place. One
study noted that nearly half of patients seen in the emergency department
for a near-fatal asthma episode failed to appear for their outpatient
appointments following their life-threatening asthma attack.[21]
 
Patients known to have risk factors for SAA, or with documented SAA in the
past, should be educated on appropriate emergency measures should they
experience a sudden, severe bronchospastic episode. They should be given an
epinephrine kit for treatment of an acute episode, and should wear a medical
alert bracelet. In addition, such individuals should have several identified
"helpers" who are aware of their predisposition for SAA, and who can
promptly summon emergency assistance by calling 911 or similar means. If
parents are not complying with treatment plans for children with SAA,
doctors may need to contact appropriate agencies to ensure that adequate
treatment and emergency support are available if needed.
 
Whether regular use of inhaled beta-agonists (especially excessive use of
short-acting bronchodilators without ICS) may contribute to the risk of SAA
remains unclear. It stands to reason, however, that regular use of the
extremely effective available bronchodilators without additional
anti-inflammatory medications may temporarily allow ill-advised exposure to
chronic allergens and may temporarily block the development of dyspnea,
which could serve to warn the patient of impending trouble.[82] Patients
with increasing symptoms of asthma should rarely rely on increasing doses of
short-acting inhaled bronchodilators for prolonged periods of time unless
specifically instructed to do so after an assessment of the status of their
disease. A pattern of increasing bronchodilator use usually indicates the
need for increased doses of anti-inflammatory therapy, not just higher doses
of bronchodilators. For a comprehensive guide to the management of asthma
patients, the reader is referred to the National Institutes of Health
publication "Practical Guide for Diagnosis and Management of Asthma.[83]"
Patients who have had symptoms provoked by allergens or other substances
should avoid those triggers if at all possible, and not simply take
increasing amounts of bronchodilators to control the symptoms. This goal is
often difficult to accomplish because patients are understandably reluctant
to avoid pet exposure, change a job, or give up a hobby.
 
It is clear that an abnormal response to hypoxia and/or hypercarbia is found
in some patients with SAA. If an asthmatic patient is unfortunate enough to
also have that familial tendency toward abnormal ventilatory response in
these settings, then the risk for death from an acute episode of asthma
increases, due to the failure of the patient to detect and adequately adjust
to the increasing respiratory compromise.[40] Screening patients for their
physiologic responses to hypoxia or hypercarbia is neither practical nor
feasible in most clinical settings. If a patient at risk for SAA is unable
to adequately detect increasing airway obstruction, and is atopic and using
regular, short-acting inhaled beta-agonists (especially without ICS), he or
she could allow increasing airway inflammation and possibly increasing
exposure to allergens without the alert of symptoms. This could lead to
decreasing airway caliber and eventually result in a fatal episode.
 
Inhaled bronchodilators are clearly a crucial and important part of the
treatment of asthma. However, when dealing with a population of young (often
atopic) asthmatics, who may tend to both deny their disease and inadequately
perceive their degree of airway obstruction, extreme care needs to be
employed in the regular use of a medication that provides prompt, temporary
relief of symptoms without treating the underlying inflammatory process.
Because of the very high incidence of atopy in those at risk for SAA, this
population of asthmatics should be evaluated by a competent
allergist/immunologist to identify and minimize potential allergen triggers.
Referral of patients with history of SAA for skin testing and identification
of allergen triggers remains erratic.[84] Emergency department staff,
therefore, need to be much more aware of the relationship between atopy and
sudden death from asthma. The role of allergen immunotherapy in this
population of patients has not been investigated, but it may prove useful in
light of data suggesting that allergen immunotherapy may help ablate the
inflammatory late-phase response upon allergen inhalation. Given the
potential risk involved, however, immunotherapy in this population should be
approached with caution and close supervision, including a careful analysis
of the risk/benefit ratio prior to treatment. Use of monoclonal antibodies,
such as omalizumab, a humanized monoclonal IgG antibody directed against
IgE, has not been studied in patients with a history of SAA.
 
It is not possible at the time of presentation to distinguish a potentially
fatal attack from a nonfatal attack of severe asthma.[19] Patients with SAA
have a higher incidence of silent chest on presentation, and coma is more
frequent than those with a slower onset of symptoms.[5] They may experience
extreme acidosis due to hypercarbia, and a portion of these patients will
also have a superimposed metabolic acidosis, probably due to lactate
accumulation.
 
Initial management of SAA includes intramuscular epinephrine, oxygenation
with an airway and mechanical ventilation, and use of adequate doses of
intravenous corticosteroids (such as intravenous methylprednisolone 125 mg
STAT, and 1 mg/kg to 60-125 mg intravenously every 6 hours until stable and
spirometry has improved significantly).[15] Inhaled beta-agonists with or
without additional anticholinergic medications (often via nebulization in
this setting) are also a mainstay of therapy.[85] Intravenous magnesium
sulfate has also been used by several investigators for treatment of sudden
severe bronchospasm in doses of 1 g to 2 g infused intravenously over 30
minutes.[15,86,87] General anesthesia with halothane has been used in
severe, refractory cases, but may be associated with cardiovascular
complications, including myocardial depression and hypotension.[85]
 
Once artificial ventilation is initiated, these patients may have a fairly
quick recovery, and are often able to be extubated within 12 hours.
Treatment of SAA may be accompanied by a period of apparent ineffectiveness
of treatment, followed by a sudden improvement in both clinical status and
ventilatory pulmonary resistance.
 
Despite aggressive therapy, there will be some patients with asthma who
remain persistently prone to experience severe, near-fatal episodes. It is
clear that these patients need to be carefully evaluated by an asthma
specialist, and must be watched closely. They should be seen frequently (eg,
monthly or even more often until stable) for follow-up visits.
Unfortunately, it is seems that, even today, many patients still do not
receive effective asthma treatment, especially those with limited access to
medical care[89]; further efforts are especially needed in this population.
 
There are some similarities between patients with SAA and those who have
sudden anaphylaxis. In both situations, it is critical to have clear
instructions on how to proceed should a patient experience such an episode.
As previously mentioned, these patients should always carry a portable
epinephrine kit on their person. Because of the need to expand our knowledge
base in this disorder, the treating physician should always request a
postmortem examination for all patients who have a fatal asthma attack.
 
As our understanding of the pathogenesis and response to treatment of
patients with asthma increases, we will succeed in reversing the current
worldwide trend of unacceptable rates of asthma mortality. Perhaps the
ever-expanding area of pharmacogenetics will also allow us to more
effectively tailor medical therapy for each patient with asthma.
 
 
 
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Abstract
 
 
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Author
Mark T. O'Hollaren, MD
 Director, Allergy Clinic, LLC, Clinical Professor of Medicine, Oregon
Health & Science University, Portland, Oregon
 
Disclosure: Mark T. O'Hollaren, MD, has disclosed that he has served as an
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Labs.
 
 
Editor
Helen Fosam, PhD
Editor and Program Director, Medscape Allergy and Clinical Immunology
 
Disclosure: Helen Fosam, PhD, has disclosed no relevant financial
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