1. health and fitness
2. disease
3. asthma

State of the Art
The Assessment and Management of Adults with
Status Asthmaticus
THOMAS C. CORBRIDGE and JESSE B. HAll
Pulmonary Division, Department of Medicine, Northwestern University Medical School and the Rehabilitation Institute of Chicago, and
Section of Pulmonary and Critical Care Medicine, University of Chicago Hospitals and Clinics, Chicago, Illinois
Contents
Clinical Assessment
Medical History
Physical Examination
Measurement of Airflow Obstruction
Response to Therapy
Arterial Blood Gases
Radiographic Studies
Admission Criteria
Pharmacologic Management
Standard Therapies
Beta-agonists
Corticosteroids
Oxygen
Anticholinergics
Theophylline
Unproved Alternative Therapies
Magnesium Sulfate
Heliox
Antibiotics
Mechanical Ventilation
Noninvasive Ventilation
Intubation
Sedation
Paralysis
Lung Hyperinflation and Barotrauma
Inhalational Anesthetics
Bronchoalveolar Lavage
Extubation
Preventing Future Episodes of Status Asthmaticus
Summary
this disease (2, 3), which, in conjunction with smooth musclemediated bronchoconstriction and intraluminal mucus, results in
airflow obstruction. Fortunately, most patients with asthma do not
have debilitating disease, and symptoms are easily controlled with
a limited number of medications and education. But in others, the
disease paints a much more malignant picture of daily breathlessness and persistent, severe functional impairment-a picture
not dissimilar from patients with emphysema and fixed airflow limitation.
All patients with asthma are at risk of developing a severe
asthma attack that places them at risk of developing respiratory
failure-a disorder referred to as status asthmaticus (SA). Asthma
attacks can occur at any time and at any pace. Some patients
develop sudden and unexpected increases in airflow obstruction
resulting primarily from bronchial smooth muscle-mediated bronchospasm. This syndrome, aptly termed sudden asphyxic asthma,
may be quite different from more slowly progressive forms of airflow obstruction (4). Recent studies have demonstrated that patients dying of sudden exacerbations of asthma have diminished
eosinophils and increased neutrophils in the airway submucosa
(5), and less intraluminal mucus (6), compared with patients with
slower onset disease. The more common story is the patient who
develops progressive symptoms over days before finally presenting to the emergency department in respiratory distress. In these
patients, airway wall inflammation and edema playa significant
role. Yet many patients miss the opportunity to treat effectively
worsening airway inflammation, opting instead to increase their
use of beta-agonists as the sole treatment strategy (7). No matter
the tempo, patients with SA have a life-threatening illness (8, 9)
that can result in ventilatory failure and death.
The purpose of this article is to review the clinical assessment
and management of these critically ill patients. We emphasize four
key areas of management: (1)assessment of disease severity, (2)
use of pharmacologic agents to treat airflow obstruction, (3) intubation and mechanical ventilation, and (4) strategies to prevent
recurrent episodes of status asthmaticus.
CLINICAL ASSESSMENT
Asthma is a disease characterized by wheezing, dyspnea, and
cough resulting from airway hyperreactivity and variable degrees
of reversible airflow obstruction (1). Current paradigms emphasize the role of airway wall inflammation in the pathogenesis of
(Received in original form July 11, 1994 and in revised form December 6, 1994)
Correspondence and requests for reprints should be addressed to Thomas
Corbridge, M.D., Rehabilitation Institute of Chicago, 345 East Superior Street,
Chicago, Il60611.
Am J Respir Crit Care Med
Vol 151. pp 1296-1316, 1995
Patients in SA are typically anxious, breathless, fatigued, sitting
upright in bed, and preoccupied with the task of breathing. Their
distress is heightened by the loud, bright, and noisy critical care
setting, which further interferes with the gathering of useful clinical information. In the face of these distractions, a swift and
directed assessment of disease severity and risk of clinical deterioration is crucial. This generally requires an analysis of several factors, including the medical history, physical examination,
bedside measurements of airflow obstruction, response to initial
therapy, arterial blood gas measurements, and radiographic
State of the Art
studies. This multifactorial analysis is necessary because no single clinical measurement has been found to predict outcome reliably (10)~
Medical History
Several features of past severe attacks place patients at increased
risk for near fatal or fatal asthma. These include a history of intubation, hypercapnia, pneumomediastinum or pneumothorax, hospitalization despite chronic oral steroid use, underlying psychiatric
illness, and medical noncompliance (11, 12). A history of near fatal asthma requiring mechanical ventilation is the greatest single
predictor of subsequent asthma death (13). Kikuchi and colleagues
(14) recently reported that patients with a prior history of near fatal asthma, but in remission, have a blunted hypoxic ventilatory
response and diminished dyspnea during inspiratory resistive loading as compared with asthmatics without prior severe exacerbations. Accordingly, diminished patient perception of dyspnea or
gas exchange abnormalities likely increase the risk of future Iifethreatening or fatal attacks.
Features of the current attack that are worrisome include symptoms of long duration, late arrival for care, extreme fatigue, an
altered mental state, and sleep deprivation. Deterioration despite
optimal treatment, including the concurrent use of oral steroids,
identifies high-risk patients who are unlikely to improve quickly,
Accelerated use of inhaled beta-agonists also identifies patients
at higher risk for fatal asthma (see below). Comorbid conditions
such as coronary artery disease place patients at greater risk
during SA, and they may predispose to complications of drug
treatment.
Physical Examination
Particular attention should be paid to the general appearance of
the patient; this provides the quickest and most useful guide to
disease severity, response to therapy, and need for mechanical
ventilation. Brenner and colleagues (15) observed that adults with
SA who assumed the upright position had a significantly higher
pulse rate, respiratory rate, and pulsus paradoxus and a significantly lower Pa02 and peak expiratory flow rate (PEFR) than did
patients who were able to lie supine. If upright patients were also
diaphoretic, PEFR was even lower.All upright patients in the study
of Brenner and colleagues demonstrated sternocleidomastoid
retraction, a finding that usually indicates severe airflow obstruction. However, Kelsen and colleagues (16) showed 520/0 of patients
with a FE~ less than 1.0 L did not demonstrate use of accessory
muscles.
Inability to lie supine, diaphoresis, an impaired sensorium, an
inability to speak, and use of accessory muscles all indicate severe disease. Still, care must be taken in interpreting patient positioning. In our experience exhausted patients deteriorating to the
point of respiratory arrest may assume the supine position and
be mistaken for a patient who is sleeping after successful treatment of airflow obstruction.
Vital signs of severe asthma are respiratory rate greater than
30 breaths/min, tachycardia greater than 120 beats/min, and pulsus
paradoxus greater than 12 mm Hg (17). Pulsus paradoxus (PP)
is the difference between maximal and minimal systolic arterial
blood pressure during the respiratory cycle. In severe airflow obstruction, PP is greater than the normal value of 4 to 10 mm Hg
and typically greater than 15 mm Hg. This circulatory consequence
of SA is a result of large swings in pleural pressure. During forced
expiration, large positive pressure in the thorax diminishes blood
return to the right heart. During vigorous inspiratory efforts against
obstructed airways blood flow to the chest is augmented. Right
ventricular (RV) filling increases early in inspiration and may shift
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the intraventricular septum toward the left ventricle (LV). This confirmational change in the LV may cause diastolic dysfunction and
incomplete filling of this chamber. Additionally, large negative
pleural pressure may directly impair LV emptying by increasing
LV afterload (18, 19). Finally, lung hyperinflation may represent
a further afterload on the RV by increasing pulmonary artery pressure (20). The net effect of these cyclical respiratory events is to
accentuate the normal inspiratory reduction in stroke volume.
Pulsus paradoxus can be a valuable sign indicating asthma
severity (21), but it must be emphasized that the PP also falls in
the fatiguing asthmatic unable to generate significant changes
in pleural pressure, and that the absence of a widened PP does
not always ensure a mild attack (16, 17, 22, 23).
Consideration should be given during the physical examination to possible complications of acute asthma (see Table 1). Examination of the head and neck should focus on identifying
barotrauma and upper airway obstruction. Tracheal deviation,
asymmetric breath sounds. a "mediastinal crunch;' and subcutaneous emphysema all suggest pneumomediastinum or pneumothorax and a potentially worse clinical course. Stridor suggests
upper airway obstruction (which may mimic acute asthma), although in our experience wheezes from lower airway obstruction
are occasionally heard best during auscultation of the anterior
neck. The mouth and neck should be inspected for mass lesions
or signs of previous surgery such as tracheostomy or thyroidectomy. The lip and tongue should be inspected for signs of angioedema.
The classic sign of wheezing correlates poorly with the degree
of airflow limitation (24). Severely obstructed patients may have
a silent chest if there is insufficient alveolar ventilation and airflow for wheezes to occur. In these patients, the development of
wheezes generally indicates improved airflow. Localized wheezing or crackles on chest auscultation may represent mucus plugging or atelectasis, but they should prompt consideration of pneumonia, pneumothorax, endobronchial lesions, or a foreign body.
Most asthmatics are tachycardic on presentation. Successful
treatment of airflow obstruction is usually associated with a decrease in heart rate (although some improving patients remain
tachycardic because of the chronotropic effects of bronchodilators). Grossman (25) found that in patients hospitalized with SA
heart rate decreased from an average of 120 beats/min on admission to 105 beats/min after 24 h of successful therapy. The
usual rhythm is sinus tachycardia although supraventricular arrhythmias are not uncommon. Josephson and colleagues (26)
found atrial, ventricular, or combined arrhythmias in nine of 44
episodes of SA in 41 patients. Supraventricular arrhythmias were
present in seven of the nine patients and ventricular arrhythmias
in eight of the nine patients. Patients with arrhythmias were older,
TABLE 1
COMPLICATIONS OF ACUTE ASTHMA
Pneumothorax
Pneumomediastinum
Subcutaneous emphysema
Pneumopericardium
Myocardial infarction
Mucus plugging
Atelectasis
Theophylline toxicity
Electrolyte disturbances (hypokalemia, hypophosphatemia, hypomagnesemia)
Myopathy
Lactic acidosis
Anoxic brain injury
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
averaging 34 yr of age compared with 26 yr of age in patients without rhythm disturbances.
Clinical signs of right and left heart failure such as a third heart
sound, jugular venous distention, and pedal edema suggest primary heart disease. Yet, SA alone can cause exam and electrocardiographic findings of right heart strain, which resolve within
hours of response to therapy (25, 27). Transient electrocardiographic findings include right axis deviation, clockwise rotation,
and evidence of right ventricular hypertrophy. Jugular venous distention is also seen when dynamic hyperinflation or tension pneumothorax limit venous return to the right heart.
The possibility of myocardial ischemia should be considered
in older patients with concomitant coronary artery disease. Patients with SA are at increased risk of myocardial oxygen supply/demand imbalance when large decreases in intrathoracic pressure
increase LV afterload and possibly decrease coronary blood flow
(28). High doses of beta-agonists, theophylline, and hypoxemia
may also adversely affect the balance between oxygen supply
and demand.
Measurement of Airflow Obstruction
Objective (though effort-dependent) physiologic measurements
of the degree of airflow obstruction can be made by bedside determination of PEFR or FEV.. Direct measurements are necessary because physician estimates of PEFR are off by more than
20% in greater than 50% of cases-with errors equally distributed
between overestimates and underestimates of the actual PEFR
(29). In most patients it is easier to measure PEFR than FEV., although even this maneuver is difficult for severely dyspneic patients to perform. In these patients, it is wise to defer measurement since deep inhalation may worsen bronchospasm (30) and,
in rare cases, precipitate respiratory arrest (31). Still, objective measurement of the severity of airflow obstruction is safe in most patients. In general, PEFR or FEV. less than 30 to 500/0 of predicted
or of the patient's personal best (usually corresponding to a PEFR
less than 120 Umin and a FEV. less than 1 L) indicates severe
exacerbation (32). Knowledge of the degree of fixed airflow obstruction and the patient's personal best PEFR or FEV. is helpful
in interpreting these tests in the acute setting.
Response to Therapy
Several studies have demonstrated that failure of initial therapy
to improve expiratory flow predicts a more severe course and need
for hospitalization (33-35). Accordingly, measurement of the
change in PEFR or FEV. over time may be one of the best ways
to assess patients acutely and predict need for hospital admission. Rodrigo and Rodrigo (10) studied 194 consecutive patients
who presented to the emergency department for treatment of acute
asthma. They demonstrated that early response to treatment was
the most important predictor of outcome. Patients who were discharged earliest from the hospital were those with the greatest
improvement in FEV. after 30 min of treatment. Similarly, Stein
and Cole (35) found that the change in PEFR after 2 h of bronchodilator treatment predicted the need for hospital admission.
In their study of corticosteroid use in the emergency room treatment of acute asthma, 91 emergency room visits resulted in 77
discharges and 14 admissions. Peak expiratory flow rate on entry
(which was approximately 250 Umin for the group) did not predict need for admission. On the other hand, after 2 h of treatment
patients ultimately discharged from the emergency room had a
significantly greater PEFR (about 330 Umin) than did patients requiring admission (in whom PEFR had not changed significantly
from entry). The predictive value of changes in PEFR before 30
min of treatment have elapsed may be misleading. Martin and
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1995
coworkers (36) found that the change in PEFR 20 min after subcutaneous epinephrine did not predict clinical outcome in patients
with asthma.
Arterial Blood Gases
Although arterial blood gas determinations have little or no role
in the assessment of the patient with mild to moderate asthma,
they are of use in the setting ot SA. When FEV. is less than 1 L
or PEFR is less than 120 L/min we recommend arterial blood gas
determinations to document the degree of hypoxemia and to determine the patient's acid-base status. Patients in the early stages
of SA often exhibit mild hypoxemia and respiratory alkalosis. If
respiratory alkalosis is present for hours to days, there may be
compensatory renal bicarbonate wasting, which may manifest later
as a non-anion-gap metabolic acidosis. As the severity of airflow
obstruction increases, Paco, generally increases because of patient exhaustion and inadequate alveolar ventilation and/or an increase in physiologic dead space. Hypercapnia usually does not
occur unless the FEV. is less than 25% of predicted (37). Although
its presence indicates severe disease and the possible need for
mechanical ventilation, hypercapnia alone is not an indication for
intubation. Hypercapnic patients may respond to aggressive drug
therapy, and they may have clinical courses similar to those of
normocapnic patients (27,38). Also, the absence of hypercapnia
does not exclude the possibility of severe airflow obstruction and
impending respiratory arrest (39).
Mountain and colleagues (40) detected metabolic acidosis in
28% of 229 consecutive episodes of acute asthma in 170 patients
requiring hospitalization. Metabolic acidosis was more likely to
occur in men and in patients with more severe airflow obstruction
and hypoxemia. The anion gap in their study patients ranged between 8 and 23 mEq/L (average, 15B mEq/L). Although blood lactate was not measured in this study, it is likely that lactic acidosis
was the cause of the elevated anion gap (40, 41). The mechanism(s) of lactic acidosis in SA have yet to be fully described. There
is evidence that lactic acidosis arises from the use of parenteral
beta-adrenergic agonists and resolves when these drugs are
stopped (42). Other possibilities include increased work of breathing resulting in anaerobic metabolism, tissue hypoxia, intracellular alkalosis, or decreased lactate clearance by the liver (which
conceivably could develop from passive congestion of the liver
in the setting of high intrathoracic pressures). Further studies are
clearly needed to understand the pathogenesis of lactic acidosis
in acute asthma.
Repeat blood gas sampling is usually not necessary to determine whether a patient is deteriorating or improving. In most cases,
valid clinical judqments can be made based on serial physical
examinations with attention to patient posture, use of accessory
muscles, diaphoresis, estimates of air movement during chest auscultation, and PEFR determinations. Patients who on these
grounds are deteriorating to the point of respiratory arrest should
be intubated whether or not Paco2 is rising. Cbnversely, patients
who are more comfortable should continue with pharmacologic
therapy despite an elevated Paco2.ln mechanically ventilated patients, however,serial blood gas measurements are helpful to guide
ventilatory management (see below).
Radiographic Studies
As for arterial blood gas analysis, chest radiography has little role
in the assessment and management of patients with mild to moderate asthma. In addition, a number of studies have demonstrated
that the yield of unselected chest radiography is low even in acutely
ill asthmatics treated in the emergency department or requiring
hospitalization, with findings that influenced treatment revealed
State of the Art
in only 1 to 50/0 of studies (43-46). Findley and Sahn (43) reviewed
chest radiographs in 90 episodes of acute asthma occurring in
60 patients. Fifty films were interpreted as normal, 33 as demonstrating hyperinflation, and six as showing minimal interstitial markings unchanged from previous radiographs. Only one patient with
allergic bronchopulmonary aspergillosis demonstrated an alveolar infiltrate. Zieverink and colleagues (44) found abnormalities
on chest radiographs in only 2.2% of 528 films taken in 122 asthmatics seen in the emergency room setting. White and colleagues
(47) evaluated initial chest radiographs in 54 adult patients admitted to hospital after failing to respond to a 12-h course of bronchodilator therapy in the emergency department. These investigators noted an incidence of "major radiographic abnormalities"
in 20 (34%) cases, which they felt significantly impacted on management. However, the majority of these findings (there were 13
of them) were classified as focal parenchymal opacities or increased interstitial markings, common indicators of focal atelectasis in patients with asthma.
On the basis of these data, chest radiographs are likely indicated only in patients presenting with signs or symptoms of
barotrauma (e.g., chest pain, mediastinal crunch, subcutaneous
emphysema, cardiovascular instability, or asymmetric breath
sounds), clinical findings suggestive of pneumonia (e.g., fever,
bronchial breath sounds, or hypoxemia not corrected with low flow
supplemental oxygen) (see below), other localizing signs on chest
examination (e.g., decreased breath sounds from mucus plugging,
foreign body, or atelectasis), or when it is not clear that asthma
is the cause of respiratory distress (e.g., measurements of airflow
obstruction do not correlate with apparent severity of dyspnea).
Admission Criteria
When repeat assessment demonstrates a good response to initial therapy in the emergency department, discharge home with
close follow-up is acceptable. Patients in this group should report
significant improvement in shortness of breath, have improved
air movement on physical examination, and FE~ or PEFR greater
than or equal to 70% of predicted (48). Observation for a minimum of 30 min after the last dose of beta-agonist is recommended
to ensure stability prior to discharge. Before discharge, these patients should be provided with written medication instructions as
well as a written plan of action to be followed in the event of worsening symptoms. Follow-up appointments should be made prior
to discharge whenever possible.
Patients with findings of severe airflow obstruction (use of accessory muscles of respiration, PP > 12 mm Hg, diaphoresis, inability to recline, hypercapnia, or PEFR < 40% of predicted) who
demonstrate a poor response to initial therapy (less than 10% increase in PEFR) or who deteriorate despite therapy should be
promptly admitted to an intensive care unit. Other indications for
immediate admission to an intensive care unit include respiratory arrest, an altered mental status, and cardiac toxicity (tachyarrhythmias, angina, or myocardial infarction). We also recommend
intensive care unit admission for patients who present initially with
mild or moderate airflow obstruction but who deteriorate in the
emergency room despite therapy.
An incomplete response to treatment may be defined as the
persistence of wheezing or shortness of breath and a PEFR or
FE~ between 40 and 700/0 of predicted (48). Patients in this group
require ongoing treatment either in the emergency room or in the
general medical ward (as long as the wards are adequately staffed
to provide frequent inhalation treatments and perform frequent
clinical assessments). In general, we treat patients for as long as
6 h in the emergency room before deciding on disposition. This
1299
length of time generally allows for assessment of the initial response to corticosteroids and, for those who are discharged home,
decreases the risk of relapse and return to the emergency room.
Kelsen and colleagues (16)showed that in patients treated for 2 h
or less there was a 500/0 relapse rate, but if treatment continued
for an additional 2 to 4 h, the relapse rate dropped to 4%. If by
6 h, the patient has demonstrated a good response to treatment,
and close follow-up can be established, discharge home is recommended. For those who continue to have an incomplete response,
admission to the general medical ward is recommended. Other
factors that influence the decision to admit or discharge include
the medication regimen prior to the emergency room visit. Patients who have deteriorated despite the use of oral corticosteroids
at home (see below) should be considered for admission, whereas
patients who were not optimally treated prior to the emergency
room visit (i.e., patients not receiving oral corticosteroids) may be
expected to have a better outcome if they receive a course of corticosteroids (49). Other factors that favor admission over discharge
include a harmful home environment where triggers such as allergens and smoke may result in further deterioration, and the
need for directly observed therapy in noncompliant or psychosocially disturbed patients.
PHARMACOLOGIC MANAGEMENT
Standard Therapies
Beta-agonists. Inhaled beta-agonists are the drugs of choice to
treat smooth muscle-mediated bronchoconstriction in acute
asthma (see Table 2). Their onset of action is rapid and their side
effects are generally well tolerated. Albuterol and metaproterenol
are the most frequently used agents in adults. Many experienced
clinicians and respiratory therapists choose albuterol because it
has a slightly longer duration of action and more beta-2 selectivity than does metaproterenol, resulting in less cardiac stimulation (50-52). Long-acting beta-agonists such as salmeterol are
not indicated in the treatment of acute asthma because of their
slow onset of action.
Larger and more frequent doses are needed in acute asthma
because the dose-response curve and duration of activity of these
drugs are affected adversely by the degree of bronchoconstriction (53). The effects of smooth muscle contraction on the lumen
diameter are also potentiated by airway narrowing (resulting from
airway wall inflammation and edema). Finally, airway narrowing
and the cooperation and breathing pattern of the patient may reduce delivery of drugs administered by inhalation. Commonly, initial treatment consists of 2.5 mg of albuterol (0.5 ml of a 0.5% solution in 2.5 ml normal saline) by nebulization every 20 min for
60 min (three doses) followed by treatments hourly during the first
several hours of therapy. Fewer doses can be given in patients
with less severe airflow obstruction who demonstrate a good response to therapy. Conversely, inhaled treatments can be given
continuously to severely obstructed patients until an adequate clinical response is achieved or adverse side effects limit further administration (e.g., excessive tachycardia, arrhythmias, or tremor).
Prior use of inhaled beta-agonists at home should not limit their
use in the emergency department unless adverse effects are identified (54). Many patients demonstrate a response to inhaled betaagonists in the emergency room despite prior use (without benefit) at home. Possible explanations for this response include the
use of higher or more frequent drug doses and ensuring proper
inhaler technique.
Recent data suggest that in nonintubated patients metereddose inhalers (MOls) combined with a spacing device are just as
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
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TABLE 2
DRUGS USED IN THE TREATMENT OF STATUS ASTHMATICUS
Standard therapies
Albuterol
Epinephrine
Corticosteroids
Oxygen
Anticholinergics
Theophylline
Unproved alternative therapies
Magnesium sulfate
Heliox
effective as nebulizers, and they are quicker and cheaper to use
(55-57). Even in patients with severe disease, Idris and colleagues
(55) showed four puffs of albuterol (0.36mg) delivered with a spacer
to be as effective as 2.5 mg of albuterol by nebulization. Similarly,
Turner and coworkers (58) demonstrated equal efficacy between
three puffs of metaproterenol delivered via a spacer and 15 mg
of metaproterenol by nebulization in the treatment of acute airflow obstruction. Still, many clinicians prefer handheld nebulizers
because fewer instructions are needed, less coordination is required, and less supervision is necessary.
Many questions remain regarding optimal delivery of inhaled
beta-agonists to intubated, mechanically ventilated patients, including the comparative efficacy of MOls and nebulizers, optimal
ventilator settings to use during drug delivery, ideal site on the
ventilator circuit for connection of the nebulizer, and maximal acceptable drug dosages (59). There is a consensus, however, that
whether MOls or nebulizers are used, higher drug dosages are
required to achieve a physiologic effect than in non intubated patients. In mechanically ventilated patients, many machine and host
factors (which vary widely) significantly decrease the delivery of
inhaled agents to the lower respiratory tract. Macintyre and colleagues (60) demonstrated that only 2.9% of a radioactive aerosol delivered by a small-volume nebulizer was deposited in the
lungs of mechanically ventilated patients. Similar to treatment
styles in nonintubated patients, many respiratory therapy staff
members have shifted to use of MOls via an adapter directly attached to the inspiratory limb of the ventilator circuit or via a spacer
device on the inspiratory limb for treatment of intubated patients.
0.5 ml of 0.5% solution (2.5 mg) in 2.5 ml
normal saline by nebulization or four puffs by
MOl with spacer every 20 min x 3; for
intubated patients, titrate to physiologic effect
or side effects (see text).
0.3 ml of a 1:1,000 solution subcutaneously every
20 min x 3; terbutaline is favored in pregnant
patients when parenteral therapy is indicated.
Use with caution in patients older than 40 yr
of age and in patients with coronary artery
disease.
Methylprednisolone 60 to 125 mg given
intravenously every 6 h or prednisone 30 to
40 mg orally every 6 h.
1 to 3 Umin by nasal cannula; titrate using
pulse oximeter.
Ipratropium bromide 0.5 mg by nebulization
hourly or four to 10 puffs by MOl with spacer
every 20 min x 3. Or: glycopyrrolate 2 mg by
nebulization every 2 h x 3.
5 mg/kg intravenously over 30 min loading dose
in patients not receiving theophylline
followed by 0.4 mg/kg/h intravenous
maintenance dose. Check serum level within
6 h of loading dose. Watch for drug
interactions and disease states that alter
clearance rates (see text).
1 9 intravenously over 20 min, repeat in 20 min
(total dose, 2 g); if hypomagnesemic, dose
adequately to normalize serum levels.
80:20, 70:30, or 60:40 helium:oxygen mix by
tight-fitting, nonrebreathing face mask. Higher
helium concentrations are needed for
maximal effect.
This shift in drug delivery technique has been based largely upon
demonstration of efficacy in lung models or by radioactive-labeled
drug studies in patients such as those in the study of Macintyre
and coworkers (60-69). This practice, however, has been recently
questioned. Manthous and colleagues (70) compared the efficacy
of albuterol delivered by MOl via a simple inspiratory adapter with
nebulized albuterol in mechanically ventilated patients. Using the
peak-to-pause pressure gradient at a constant inspiratory flow as
a measure of airway resistance, they found no effect (and no side
effects) from as many as 100 puffs (9.0 mg) of albuterol delivered
by MOl. Albuterol delivered by nebulizer to a total dose of 2.5 mg
reduced the inspiratory flow-resistive pressure 18%; nebulized
albuterol at cumulative doses of 7.5 mg led to further reductions
in this pressure in eight of 10 patients, but it led to toxic side effects in four of the eight. The investigators concluded that nebulized albuterol provided objective physiologic improvement, whereas albuterol administered by MOl through an ,endotracheal tube
adapter had no effect, and that nebulizer treatments can and
should be titrated to higher-than-conventional doses using toxic
side effects and physiologic response to guide therapy. In the accompanying editorial (71), Newhouse and Fuller noted that the
"major importance of this study is its potential for raising the awareness of physicians to the need to study aerosol delivery systems
as thoroughly as they study the pharmacologic agents themselves,
since both are equally important determinants of the therapeutic
response:' Promising in this regard is the use of MOls with spacing chambers to deliver bronchodilator during mechanical ventilatory support (72).
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1301
Accordingly, it is difficult to make recommendations for fixed
dosing of these drugs in intubated patients. Nebulized drug is efficacious in the majority of patients, although MOls are likely to
be effective if used with an appropriate spacing device. Whichever
route is used, drug dosages should be titrated to either a beneficial physiologic response as judqed by a fall in the airway peakto-pause gradient under constant inspiratory flow conditions (see
Figure 1) (73) or to the development of toxic side effects such as
worsening tachyarrhythmias. Our own approach is to prescribe
albuterol2.5 mg by nebulization and measure the change in the
airway peak-to-pause pressure. If there is a significant fall in this
gradient (l.e., 15% or greater), we continue to deliver this drug
dose hourly until there is clear-cut evidence of improving airflow
obstruction (see below). At that time fewer doses can be given.
If a significant fall in the peak-to-pause gradient is not demonstrated, we deliver additionaI2.5-mg doses of albuterol by nebulization until a significant decrease in the peak-to-pause gradient
is demonstrated or toxic side effects occur. In this situation, it is
particularly important to exclude other causes of high peak airway pressure that are resistant to bronchodilator therapy such as
a kinked or plugged endotracheal tube.
In recently extubated patients, MOls can be used successfully
in most patients. Tenholder and coworkers (74) demonstrated a
70% success rate for conversion of recently extubated patients
from nebulized therapy to MOls. Unsuccessful conversions were
seen mainly in patients with neuromuscular disease unable to actuate the MOl properly and in patients with dementia or an inability to understand instructions. Failure to convert to MOl use was
not related to the degree of airflow obstruction.
SUbcutaneously administered epinephrine or terbutaline sulfate carry no advantage over inhaled beta-agonists unless patients
are unable to cooperate (such as those with an impaired sensorium or those in cardiopulmonary arrest) (75-77). Subcutaneous
therapy should be considered, however, in patients not respond-
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Figure 1. Simultaneous plots of tidal volume and airway pressure in a
mechanically ventilated patient. The airway peak-to-plateau gradient is
determined by temporarily occluding inspiratory flow (usually with an inspiratory pause). Under conditions of constant inspiratory flow and absence of patient effort, this gradient it is a useful parameter to gauge airway resistance and bronchodilator efficacy. (From reference 73, with
permission.)
ing adequately to inhaled beta-agonists. In 60% of patients not
responding to 2 h of inhaled metaproterenol, Appel and colleagues
(78) found expiratory flow increased after subcutaneous administration of epinephrine. Subcutaneously administered epinephrine
may also be tried in intubated patients not responding adequately
to inhaled therapy, although the benefits and risks of this approach
have not been well studied. If parenteral beta-agonists are used,
care must be taken to avoid hypokalemia, lactic acidosis, and
cardiac arrhythmias. In dire circumstances, especially if there is
no intravenous access, epinephrine may be delivered effectively
down the endotracheal tube.
Known cardiac disease and age greater than 40 yr are relative
contraindications to parenteral therapy. Patients older than 40 yr
of age have more sinus tachycardia, premature ventricular contractions, and atrial arrhythmias (79). Older patients without a history of recent myocardial infarction or angina, however, tolerate
subcutaneously administered epinephrine reasonably well.
There is no advantage to giving the more beta-2-specific agent,
terbutaline sulfate, which may in fact result in greater tachycardia
for the same degree of bronchodllation than does epinephrine
(80). The pregnant patient represents an exception to this tenet.
Because epinephrine has been associated with congenital malformations and may decrease uterine blood flow (81), terbutaline
is the preferred beta-agonist if one must be given parenterally.
Note that terbutaline may inhibit uterine contractility at term.
The available data do not support the routine use of intravenous (IV) infusion of beta-agonists in the treatment of patients with
SA. Several studies (82-85) have demonstrated inhaled therapy
to be equal to or better than IV therapy in treating airflow obstruction, and less likely to cause cardiac toxicity (mainly tachycardia).
Indeed, continuous IV infusion of isoproterenol has resulted in
fatal myocardial necrosis (86). Bloomfield and coworkers (84) compared salbutamol given as a 0.5 mg IV injection over 3 min with
a 0.50/0 solution of salbutamol by intermittent positive-pressure
breathing for 3 min in a double-blind crossover trial during 22 episodes of asthma. Both treatments significantly improved PEFR,
but the inhaled route resulted in greater improvement in pulsus
paradoxus and less tachycardia than the IV route. Salmeron and
coworkers (85) compared the effects of nebulized.albuterol (5 mg
administered twice during the first hour of treatment) with intravenously administered albuterol (0.5 mg over 60 min) in 47 patients with severe acute asthma as defined by a PEFR less than
150 Umin. The mean increase in PEFR at 1 h was greater in the
group treated with inhaled albuterol (107 Umin versus 42 Umin
in the IV group). Inhaled therapy was also associated with a greater
fall in Paco, and less beta-agonist-induced hypokalemia. On the
other hand, Cheong and colleagues (87) found that 4 h of continuous salbutamol (0.72 mg/h) resulted in a greater PEFR than
did 5 mg salbutamol nebulized at 30 and 120 min. However, the
greater increase in PEFR was modest (25% in the IV group versus
14% in the inhaled group), and this improvement was at the cost
of more tachycardia. Also, it could be argued that had higher doses
of inhaled salbutamol been given (as is common in clinical practice), there may have been no difference in PEFR response between the two groups.
In our practice, we rarely use intravenously administered betaagonists in the treatment of SA. On an individual basis, however,
intravenously administered beta-agonists may be considered in
the treatment of patients (preferably younger than 40 yr of age)
who have not responded to lnhaied or subcutaneous therapy, and
in whom respiratory arrest is imminent or in whom persistent severe airflow obstruction is associated with alarming levels of lung
hyperinflation during mechanical ventilation (see below).
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
A number of recent studies have established a correlation between the long-term use of inhaled beta-agonists and asthma morbidity and mortality (88-90). Patients who use beta-agonists the
most are those at greatest risk of asthma death; but whether betaagonists are the cause of death or a marker of disease severity
is yet to be established. In a recent report (91), Suissa and coworkers showed that the "risk of asthma death began to escalate
drastically at about 1.4canisters per month of inhaled beta-agonisr
and that the association between beta-agonist use and asthma
mortality was confined primarily to the overuse of these drugs.
In response to these concerns, the Executive Committee of the
American Academy of Allergy and Immunology recently published
their position on the use of inhaled beta-agonists in asthma (92).
In their report they concluded that (1)heavy (more than one canister per month) beta-agonist use is a marker for severe asthma,
(2) heavy or increased use of beta-agonists warrants additional
therapy such as the use of corticosteroids, (3) beta-agonists may
make asthma worse, but the available data do not allow for a definitive conclusion regarding this controversy, and (4) patients currently using beta-agonists should slowly withdraw nonessential
doses so that medication is used only as needed before exercise
or as a rescue medication during "breakthrough" asthma symptoms. It is important to note, however, that concerns regarding
the long-term safety of regularly used beta-agonists do not apply
to the use of these medications during acute attacks. These drugs
continue to be the medications of choice to treat bronchial smooth
muscle contraction during attacks-and they should not be withheld or underdosed because of concerns regarding the safety of
regular use. Beta-agonists are not, however, sufficient alone to
treat patients with acute asthma exacerbations. Patients with slowly
progressive disease have significant airway inflammation that
needs to be treated specifically with anti-inflammatory agents. Corticosteroids also potentiate the effects of beta-agonists on smooth
muscle relaxation, which may be particularly important in patients
with sudden asphyxic asthma.
Corticosteroids. Corticosteroids treat airway wall inflammation,
potentiate the effects of beta-agonists on smooth muscle relaxation, decrease beta-agonist tachyphylaxis, and decrease mucus
production (9t-95). Ideally, intensifying a patient's anti-inflammatory regimen should begin whenever the patient's usual medical regimen fails to control symptoms. Unfortunately, many patients (and their physicians) fail to intervene early or aggressively
in the course of worsening asthma, and airway wall inflammation
is allowed to proceed unchecked. Invariably, whether patients are
using corticosteroids or not when they arrive in the emergency
room, they have received inadequate doses (see below).
Despite recent controversy about the routine use of steroids
in the emergency department (35), most available data support
a corticosteroid benefit in this setting, and there is evidence that
failure to treat with corticosteroids contributes to asthma deaths
(96). Benefits of steroids were recently confirmed by meta-analysis
(97) in which more than 700 articles were reviewed to identify 30
randomized, controlled trials suitable for analysis. The investigators concluded that steroids given in the emergency department
significantly reduce the rates of admission and the number of future relapses in the first 7 to 10 d. It did not matter whether steroids
were given orally or intravenously (although IV therapy is preferred
in patients at risk for intubatton), as long as a minimum of 30 mg
of prednisone (or its equivalent) was given every 6 h. Lower doses
were less effective, and there was no obvious benefit to giving
higher doses. McFadden (98) recently analyzed the available data
on steroids in asthma and recommended 150to 225 mg/d of prednisone (or its equivalent) to reach maximal therapeutic benefit.
VOL 151
1995
He recommended either 40 mg of intravenously administered
methylprednisolone every 6 h or prednisone 60 mg given orally
every 6 to 8 h for 36 to 48 h depending on the patient's condition.
Haskell and coworkers (99) showed that patients receiving 125
mg of solumedrol intravenously every 6 h improved more rapidly
than did patients receiving 40 mg of drug, although there was no
difference in ultimate improvement. Both the 125-mg and 40-mg
doses were superior to 15 mg every 6 h in terms of rate and absolute improvement. Littenberg and Gluck (100)enrolled 97 patients
with acute asthma in a double-blind, placebo-controlled, randomized trial of methylprednisolone 125 mg given intravenously
on presentation to the emergency room in addition to other standard treatments. Only nine of 48 (190/0) of patients treated with
methylprednisolone were hospitalized as compared with 23 of 49
patients (47%) in the control group.
Further studies are needed to establish the best dose and dosing frequency of corticosteroids in SA. Currently available data
do support the common approach of giving 60 to 125 mg methylprednisolone intravenously every 6 h during the initial 24 h of treatment. We administer the first dose immediately in the emergency
department since benefits are not seen clinically for hours (93)
(whether or not patients were receiving oral steroids prior to their
arrival). Improving patients are switched to prednisone in doses
ranging from 60 to 80 mg daily (in single or divided doses), which
is then continued until peak flows return to baseline values. Oral
steroids are usually required for the next 10 to 14 d as guided by
peak expiratory flow readings. Of note, we continue inhaled
steroids in patients receiving systemic steroids to avoid confusion
about restarting inhaled preparations during oral steroid taper, and
because they may be some benefit to treating inflammation from
both the luminal and blood sides. Patients with oral candidiasis
are excluded from this practice.
Care must be taken during administration of systemic corticosteroids to identify and treat steroid-induced side effects.
Problems that may be encountered include hyperglycemia, hypertension, hypokalemia, alterations in mood (including anxiety, insomnia, and frank psychosis), metabolic alkalosis, and peripheral hand or leg edema. When used concurrently with paralytic
agents, systemic corticosteroids also appear to playa causative
role in the development of myopathy in acute severe asthma (see
below section on use of paralytic agents for a more complete discussion).
Oxygen. Obstruction of peripheral airways by airway wall inflammation, mucus, and bronchoconstriction causes ventilation/perfusion mismatch (low V/O) and hypoxemia. True shunt in
acute asthma averages only 1.5% of the pulmonary blood flow
(101), so correction of hypoxemia requires only modest enrichment
of inspired oxygen (1 to 3 Llmin by nasal cannula). McFadden
and Lyons (39) found only 5% of patients with acute asthma (all
younger than 45 yr of age) had an initial Pa02 of 55 mm Hg or
less at low altitude, suggesting that routine administration of supplemental oxygen to this patient population overtreats the majority
of patients. There is a rough correlation bet~een the degree of
airflow obstruction as measured by the FE~ or PEFR and hypoxemia (37, 39). However, there is no cut-off value for either measurement that accurately predicts significant hypoxemia. The routine administration of low-flow supplemental oxygen is an entirely
safe practice that is recommended if continuous pulse oximetry
is not available or comorbid conditions (such as coronary artery
disease) exist. When low-flow supplemental oxygen by nasal cannula does not maintain saturation greater than 90% by pulse oximetry, we recommend an arterial blood gas measurement to
confirm hypoxemia and to correlate pulse and arterial blood satu-
State of the Art
rations. Refractory hypoxemia is rare and should lead to a search
for additional pathologic features such as pneumonia, aspiration,
acute lobar atelectasis, and barotrauma. Hypoxemia resulting from
peripheral airway obstruction may occur sooner and/or resolve
later than airflow rates, which reflect predominantly large airway
function (102). Benefits of oxygen therapy include improved oxygen delivery to peripheral tissues (including respiratory muscles),
reversal of hypoxic pulmonary vasoconstriction, and airway bronchodilation. Oxygen also protects against the modest fall in Pa02
often seen after beta-agonist administration resulting from pulmonary vasodilation and increased blood flow to low 'I/O units
(103, 104).
Anticholinergics. The available data generally support the use
of anticholinergic agents in patients with acute asthma. Still, these
drugs should not be thought of as first-line agents. They produce
less bronchodilation at peak effect than beta-agonists and achieve
a somewhat more variable clinical response, indicating that
cholinergic mechanisms playa variable role in patients with acute
asthma. Anticholinergics may be particularly useful in patients
with bronchospasm induced by beta-blockade (105)or in patients
with severe airflow obstruction (FE~ < 25% predicted) (106).
Three drugs are currently available in the United States: atropine sulfate, ipratropium bromide, and glycopyrrolate. Atropine
sulfate is the least desirable of these drugs, and it is not recommended in the treatment of acute asthma. Although atropine improves airflow in acute asthma (107), it is inferior to metaproterenol
as a sole drug and does not produce further improvement in patients who have already received metaproterenol (108). Atropine
is well absorbed from the airways because of its tertiary amine
structure, and it thus causes unwanted systemic effects. It may
also impair mucociliary clearance.
Ipratropium bromide and glycopyrrolate, on the other hand,
can both be recommended in the treatment of patients not responding adequately to beta-agonists and steroids. Their quarternary amine structures limit absorption from the airway, minimizing systemic effects, and these drugs are not thought to impair
mucociliary clearance. Ipratropium bromide augments the bronchodilating effect of beta-agonists in acute asthma (109-111), an
effect that is not explained by inadequate dosing of beta-agonists
(112). Bryant and Rogers (111) demonstrated that ipratropium bromide 0.25 mg by nebulizer plus 5 mg of nebulized albuterol resulted
in greater improvement in FE~ than albuterol alone. In this study,
a significant response to ipratropium bromide was detected within
1 min of administration, and the mean time to highest FE~ was
only 19 min, a much faster time course than is usually seen in
patients with chronic stable disease. One in 25 patients in this
study had a paradoxical bronchoconstrictive response to ipratropium, which contrasts with prior reports that as much as 20% of
patients with acute asthma may demonstrate a bronchoconstrictor response (113). In this patient, administration of a preservativefree solution prevented the paradoxical response. Fitzgerald (114)
randomized 324 asthmatics in the emergency department to
ipratropium bromide 0.5 mg combined with salbutamol 3.0 mg or
salbutamol 3.0 mg alone. Mean FE~ at 45 and 90 min trended
higher with combined therapy, but values did not reach statistical
significance. Fewer patients were admitted to hospital from the
combined group.
The optimal dose of ipratropium bromide is not known. Most
investigators have used doses between 0.25 and 0.5 mg by nebulization in nonintubated patients who would require more than 10
puffs by MOl (0.018 mg/puff) if delivery to the airways was equivalent. Ipratropium bromide is now available in the United States
as a premixed unit-dose inhalation solution for nebulization (0.5
1303
mg diluted with saline). Nebulized glycopyrrolate has not been
studied extensively in acute asthma. When compared with nebulized metaproterenol, nebulized glycopyrrolate has been shown
to produce the same bronchodilator response with fewer side effects (115).
Available data do not allow for strong recommendations regarding the use of anticholinergics in acute asthma. Our own approach
is to use ipratropium bromide or glycopyrrolate as second-line
agents in patients not responding adequately to beta-agonists and
steroids. We give four to 10 puffs of ipratropium bromide by MOl
with a spacing device every 20 min, or 0.5 mg ipratropium bromide inhalation solution by nebulization over 10 to 15 min hourly.
Alternatively, ipratropium bromide inhalation solution unit-dose
vial (0.5 mg in 2.5 ml) may be used in conjunction with albuterol
concentrate (2.5 mg in 0.5 ml). Glycopyrrolate 2 mg in 2.5 ml of
normal saline may be administered by an updraft nebulizer over
20 min every 2 h. We generally do not continue inhaled anticholinergics for more than three doses unless there is evidence
of a clinical response as determined by subjective improvement
in symptoms or by an increase in PEFR.
Theophylline. As monotherapy, theophylline is inferior to betaagonists in the emergency-room treatment of asthma. Rossing
and colleagues (116) randomized 48 patients with acute asthma
to treatment with nebulized isoproterenol, subcutaneously administered epinephrine, or theophylline given intravenously (all
delivered as monotherapy). The mean improvement in FE~ after
60 min of treatment was greater in patients treated with isoproterenol or epinephrine than in patients given theophylline. Additionally, the mean duration of therapy required prior to discharge was
significantly longer in the theophylline group. Other studies have
demonstrated that the addition of theophylline to beta-agonists
in the first few hours of treatment does not confer additional benefit, and that the use of theophylline increases the incidence of
tremor, nausea, anxiety, palpitations, and heart rate (117-119). In
a recent prospective, double-blind, randomized, and placebocontrolled trial of 44 patients 18 to 45 yr of age, Murphy and coworkers (118) found that when theophylline was added to other
standard medications, there was no additional improvement in
PEFR over 5 h of therapy, and that patients treated with theophylline had more tremor, nausea or vomiting, and palpitations.
On the other hand, Pierson and colleagues (120) demonstrated
that in children treated with theophylline, ventilatory function had
improved after 1 and 24 h of treatment without adverse effects.
Huang and coworkers (121) conducted a randomized, placebocontrolled, double-blind study of 21 adults treated intravenously
with theophylline added to frequent nebulizations of albuterol and
intravenously administered steroids. The rate of improvement in
FE~ during the first 3 h was faster in patients receiving theophylline than in patients receiving placebo, and this difference persisted over the 48 h of study. Also, in a recent study (122), intravenously administered theophylline was found to confer additional
benefit on inhaled beta-agonists and parenteral steroids in the
first 4 h of therapy.
Emergency-room administration of theophylline may also result in fewer hospitalizations-even if airflow rates are not different from patients receiving placebo (123). This finding raises the
possibility that theophylline benefits patients in ways distinct from
bronchodilation (124) such as through anti-inflammatory effects
(125, 126)or effects on respiratory muscle function. Kelly and Murphy (127) point out that even when benefit is not detected in the
first few hours of therapy, theophylline may improve lung function
after 8 to 24 h of therapy. They believe that it is inappropriate to
extrapolate data from short-term studies performed in the emer-
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
gency room to hospitalized patients with SA in whom administration of theophylline has been demonstrated to be beneficial at 24 h
(120, 128). Milgrom (129) also pointed to a possible delayed benefit in the use of theophylline in hospitalized patients with acute
asthma.
Taken in sum, the available data do not allow for strong conclusions regarding the use of theophylline in acute asthma. Indeed, Littenberg (130) analyzed 13 trials of theophylline use in
the emergency-room treatment of asthma and concluded that there
was inadequate evidence to support or reject the use of theophylline in this setting. Further definitive trials are needed to
determine the role of theophylline in both the short-term and the
long-term management of asthmatics in acute exacerbation. While
debate continues (131, 132) and until more data are available, our
approach is to add theophylline to patients with a poor or incomplete response to treatment with beta-agonists and corticosteroids.
We prefer IV dosing to limit oral intake in patients who may go
on to intubation, although there is no difference in efficacy between IV and oral therapy. The loading dose of theophylline is
5 mg/kg (6 mg/kg aminophylline) by peripheral vein over 30 min
in patients not receiving theophylline followed by a continuous
infusion of 0.4 mg/kg/h (0.5 mg/kg/h aminophylline). In patients
receiving theophylline, serum levels should be checked on arrival
to the emergency room before additional theophylline is given.
If the level is within the therapeutic range, a continuous infusion
may be started, or the oral preparation may be continued.
Several investigators (121, 133-135) have demonstrated that
theophylline can be used safely if attention is paid to serum drug
levels and to factors that increase serum levels. Serum levels
should be checked within 6 h of IV loading to avoid toxic levels
and to guide further dosing. We aim for levels between 8 and 12
Ilg/ml to avoid toxicity. Factors that decrease theophylline clearance and thereby increase risk of toxicity include: congestive heart
failure, liver failure, and a number of medications, including ciprofloxacin, macrolide antibiotics, and cimetidine.
Unproved Alternative Therapies
Magnesium sulfate. Intravenously administered magnesium sulfate has been reported to be a useful adjunctive therapy in patients with acute asthma refractory to treatment with inhaled betaagonists (136-142). This benefit has been described in patients
with normal serum magnesium levels, although hypomagnesemia has been reported in 500/0 of patients with acute asthma (143).
If magnesium is beneficial in acute asthma, the mechanism is
unknown. One possibility is that magnesium inhibits calcium channels of airway smooth muscle, thus interfering in calcium-mediated
smooth muscle contraction (144). Magnesium also decreases
acetylcholine release at the neuromuscular junction, which may
interfere with bronchoconstriction from parasympathetic stimulation. Magnesium reduces histamine-induced (145) and methacholine-induced (146) bronchoconstriction in asthmatics, and it
also affects respiratory muscle force generation (147).
Studies reporting a magnesium benefit in acute asthma suffer from the small number of patients studied. Many are anecdotal. One patient in acute hypercapnic respiratory failure has been
described in whom 1 g magnesium sulfate delivered intravenously
over 15 min was associated with dramatic improvement midway
into infusion, thereby preventing intubation and mechanical ventilation (148). Sydow and colleagues (149) gave high doses of magnesium sulfate (10to 20 g) over 1 h to five mechanically ventilated
asthmatics. They demonstrated a significant decrease in peak airway pressure (43 to 32 em H20) and in inspiratory flow resistance.
Despite serum magnesium levels as great as three times normal,
VOL 151
1995
the only significant side effect was moderate systemic hypotension in two of the five patients.
However, the two largest prospective studies failed to show a
benefit from the use of magnesium in acute asthma. One hundred twenty consecutive emergency department patients with
acute asthma unresponsive to inhaled albuterol received 2 g magnesium sulfate intravenously if they presented on odd days and
no magnesium if they were seen on even days (150). Physicians
were not blinded, but respiratory therapists and patients were unaware of the study. There were no differences in hospitalization
rates, duration of emergency department treatment, or changes
in PEFR between treated and untreated patients. Tiffany and coworkers (151) conducted a randomized, double-blinded, placebocontrolled trial of 48 patients given magnesium or placebo if their
initial PEFR was less than 200 Llmin and failed to double after
two albuterol treatments. Patients were randomized to three
groups: 2 g magnesium sulfate given intravenously over 20 min
followed by an infusion of 2 g/h for 4 h, 2 g magnesium sulfate
given intravenously followed by placebo infusion, or a placebo
loading dose and infusion. In this study, magnesium sulfate did
not improve FE~ or PEFR over approximately 4 h of measurement. The investigators concluded that "IV administered magnesium sulfate does not provide clinically meaningful improvement in pulmonary function test results when used in addition to
standard bronchodilator therapy in patients with moderate to severe asthmatic exacerbations:' They pointed out, however, that
there may be patients in whom their conclusions may not apply
such as less severely ill patients not receiving high-dose betaagonists or more severely ill (Le., ventilated) patients. They also
raised the possibility that the sex of the patient may playa role
since estrogen has been reported to augment the bronchodilator
effect of magnesium (152). Indeed, there was a trend toward female responsiveness in this study, and in one other study demonstrating a magnesium effect, 25 of 34 patients were women (136).
In general, magnesium sulfate is a safe drug, particularly in
doses not greater than 2 g given intravenously over 20 min (150),
a dose that increases serum levels to about twice the original level
(141). Most studies have not reported major complications of magnesium administration. Still, care must be taken to avoid magnesium intoxication, particularly in patients with impaired renal
function. The loss of deep tendon reflexes and hypotension have
been reported in magnesium intoxication. Minor complications
include flushing and mild sedation.
The available data do not support the routine use of magnesium
sulfate in the treatment of SA. Further definitive studies are needed
to clarify efficacy and to identify possible subsets of patients for
whom this agent may be beneficial. In our practice, we consider
magnesium sulfate in patients who have failed treatment with other
standard agents because it is generally safe and inexpensive. We
give 1 g intravenously over 20 min and repeat 20 min later (unless the patient is hypomagnesemic, in which ease normalization
of serum levels should be achieved). All patlents receiving magnesium should have levels followed and be observed closely for
toxic side effects.
Heliox. Heliox is a blend of helium and oxygen with a gas density less than that of air. It is generally available in mixtures of
80:20 helium:oxygen, 70:30, and 60:40. It can be delivered through
a tight-fitting nonrebreathing face mask in nonintubated patients
and through the inspiratory limb of the ventilator circuit in mechanically ventilated patients. Because this gas mixture is less dense
than air, airway resistance is decreased in bronchi with turbulent
flow regimes. This may decrease work of breathing and delay inspiratory muscle fatigue until concurrent definitive bronchodila-
State of the Art
tor/anti-inflammatory therapy becomes effective. Manthous and
colleagues (153) observed a significant decrease in pulsus paradoxus and significant increase in peak flow in patients with acute
asthma breathing heliox for 15 min as compared with control subjects. To the extent that pulsus paradoxus reflects the inspiratory
fall in pleural pressure, and that the inspiratory drop in pleural
pressure is related to inspiratory airway resistance (Raw), the
reduction in pulsus paradoxus during heliox administration indicates a substantial reduction in inspiratory Raw. Heliox also
resulted in a 35% increase in peak flow, which signals a similar
reduction in expiratory Raw. Taken together, these effects of heliox
may diminish muscle fatigue and lung hyperinflation. If these
favorable results are confirmed, heliox may prove to be a useful
bridge to effective bronchodilator/anti-inflammatory therapy.
Gluck and colleagues (154)administered a 60:40 blend of heliox
to seven intubated asthmatics. Within minutes, heliox decreased
peak airway pressure by a mean of 33 cm H2 0 and Paco2 by a
mean of 35.7 mm Hg.lf heliox is used during mechanical ventilatory support, it is important to recognize that recalibration of gas
blenders and flow meters to this low-density gas will be required
to obtain accurate measures of oxygen concentration or tidal volume. Although these results are promising, further studies regarding the efficacy of heliox in SA are clearly indicated before this
gas can be recommended in the routine management of patients
with acute asthma.
Antibiotics. Because respiratory tract infections that trigger
asthma are usually viral, there is no role for the routine use of
antibiotics. Antibiotics are frequently prescribed for these patients
based on an increase in sputum volume and purulence. However,
sputum that looks purulent typically contains an abundance of
eosinophils and not polymorphonuclear leukocytes, a distinction
that can be made only after microscopic inspection of the specimen. Indeed, transtracheal aspirates obtained from adults thought
to have acute "infective" asthma demonstrated culture results similar to those from normal control subjects (155). Graham and coworkers (156) conducted a randomized, double-blind study of
amoxicillin and placebo in 60 adult patients admitted to hospital
with acute exacerbations of asthma. They did not demonstrate
differences in improvement between groups for length of hospltalization, patient's self assessment, or spirometry.
Patients for whom antibiotics are indicated include those with
fever and sputum containing polymorphonuclear leukocytes, those
with clinical findings of pneumonia, and those with signs and
symptoms of acute sinusitis. We also favor the use of antibiotics
in patients who, on clinical grounds, have clinical findings suggestive of mycoplasmal or chlamydial infection.
MECHANICAL VENTILATION
For patients who have received pharmacologic treatment in the
emergency room or inpatient setting, intubation should be considered if there is clinical deterioration. As previously stated, the
general appearance of the patient is the primary determinant of
need for ventilatory support. Changes in posture, alertness,
speech, extent of accessory muscle use, and respiratory rate can
all indicate worsening respiratory failure that does not need blood
gas or peak flow confirmation. Fatiguing patients and patients with
altered mental status should be intubated whether or not PaC02
is rising; and patients who are more comfortable, better able to
speak, and less attentive to the task of breathing should continue
with medical therapy despite an elevated Paco2 • Ultimately, the
decision to intubate is made by a clinician's estimate of the ability
of a patient to maintain spontaneous respiration until bronchodi-
1305
lator/anti-inflammatory therapy takes hold. Immediate intubation
is indicated for patients arriving in the emergency room in cardiopulmonary arrest, near cardiopulmonary arrest (e.g., patients unable to speak and/or gasping for air), coma, or significant obtundation.
Noninvasive Ventilation
Noninvasive face mask mechanical ventilation may be an option
for short-term ventilatory support in patients with hypercapnic ventilatory failure who are (1)not responding adequately to pharmacologic intervention and (2) not thought by the physician to be in
need of immediate intubation and mechanical ventilation. Patients
who are encephalopathic or in need of airway protection to manage secretions should not be considered for this form of ventilatory support. Advantages of noninvasive over invasive ventilatory
support may include decreased need for anesthesia, sedation and
paralysis, decreased incidence of nosocomial pneumonia, decreased incidence of otitis and sinusitis, and improved patient comfort (157). Potential disadvantages include increased risk of aspiration of gastric contents secondary to gastric insufflation, facial
pressure necrosis, and less control of the patients'ventilatory status
when compared with invasive ventilation (157). Shivaram and colleagues (158) studied 21 patients in SA with a mean PEFR of 144
Llmin. They showed that nasal CPAP of 5 or 7.5 cm H20 significantly decreased respiratory rate and dyspnea compared with
placebo (CPAP mask without positive-pressure therapy) perhaps
by decreasing the inspiratory work of breathing (159). Only two
patients in the study group were withdrawn from the group because of increased dyspnea during CPAP of 5 cm H20 , and there
was no evidence that these low levels of CPAP adversely affected
expiratory airflow, hemodynamics, or arterial blood gas determinations. Similarly, Mansel and coworkers (160) reported a patient
with acute, severe asthma and metabolic acidosis who was able
to forgo intubation by face mask CPAP and continuous sodium
bicarbonate infusion. Meduri and coworkers (157)evaluated face
mask pressure support ventilation in 18 patients with acute hypercapnic respiratory failure, two of whom had SA. Both patients had
failed aggressive inpatient treatment for more than 24 h and had
developed signs of respiratory muscle fatigue and hypercapnia.
Noninvasive ventilation was performed using a Puritan Bennett
7200 ventilator (Puritan Bennett Co., Carlsbad, CA). Initial ventilator settings consisted of CPAP with pressure support (details
not provided) titrated to achieve a respiratory rate less than 25
breaths/min and tidal volume greater than or equal to 7 ml/kg.
Both patients were ventilated upright using a full face mask with
a nasogastric tube on low intermittent suction to prevent gastric
insufflation. One patient was ventilated for 18 h, the other for 44 h.
Both patients demonstrated a decrease in respiratory rate and
Paco.. and neither patient required subsequent intubation.
Further studies involving larger numbers of patients are needed
before strong recommendations can be made regarding the use
of noninvasive face mask ventilation in SA. Although the above
reports are promising, in our experience this mode of ventilation
is often poorly tolerated by severely dyspneic patients who describe mask ventilation as causing claustrophobia. Still, we consider noninvasive ventilation in cooperative patients who are not
improving (or who are deteriorating) as long as they are not thought
to be in need of immediate intubation, and as long as there are
personnel available who are experienced with this form of therapy. By decreasing work of breathing, noninvasive ventilation may
lessen inspiratory muscle fatigue, buy time for concurrent pharmacologic therapy to become effective, and thereby avert the need
for intubation in some patients.
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Intubation
VOL 151
1995
See Table 3 for a summary of agents, doses, and cautions for
commonly
used sedatives in SA. In preparation for intubation, we
Once the decision has been made to proceed with intubation and
give midazolam 1 mg intravenously followed by 1 mg every 2 to
mechanical ventilation, the goal is to take rapid and complete con3 min until the patient allows positioning and inspection of the
trol of the patient's cardiopulmonary status. Intubation should be
airway. Bolus administration of morphine sulfate is avoided beperformed by the most experienced available clinician since macause
of its potential to induce systemic hypotension through a
nipulation of the upper airway may induce laryngospasm. Oral
combination of direct vasodilation, histamine release, and vagally
intubation allows for placement of a large endotracheal tube (8 mm
mediated bradycardia (162). Opioid-induced vomiting is also unor greater), which is important to suction tenacious mucus plugs
desirable in the peri-intubation period. Ketamine, an IV general
mobilized during recovery from SA and to decrease airway resisanesthetic with sedative, analgesic, anesthetic, and bronchodilattance. This latter benefit is especially important at high airflows.
ing properties (163, 164),has been used successfUlly for the emerAt a flow of 120 L1min, endotracheal tube airflow resistance is more
gency intubation of patients with SA. In four of five patients with
than twice as much with a 6.0 mm tube than with a 7.0 mm tube
SA requiring intubation in the emergency room, ketamine and sucin vitro, a difference that may be even greater in vivo (161). Nasal
cinylcholine in the peri-intubation period were associated with deintubation is probably safe in most patients, and it may be the
creased wheeZing (165).The fifth patient had been intubated and
preferred route in an awake, breathless patient anticipated to be
ventilated with a rising Paco 2 ; after ketamine, wheezing and Paco,
difficult to ventilate with a bag-valve-mask (e.g., obese patients
both decreased. The usual dose of ketamine, 1 to 2 mg/kg given
with short necks). Fiberoptic guidance is useful to facilitate nasal
intravenously at a rate of 0.5 mg/kg/min, generally provides 10 to
intubation in these semielective situations. However,there are sev15 min of general anesthesia (166)without significant respiratory
eral problems with the nasal approach, including the need for a
depression. Rapid bolus administration may result in respiratory
smaller endotracheal tube and the high incidence of nasal polyps
depression (167). Bronchospasm may improve within minutes afand.sinusitis in this patient population.
ter IV administration, but this effect generally does not last for
Sedation
more than 20 to 30 min after bolus administration (165, 168, 169).
Sedation is invariably required in awake patients to prepare for
Potential risks to ketamine use include its ability to increase heart
intubation and to allow for safe and effective mechanical ventila- . rate and arterial blood pressure because of sympathomimetic eftion. Sedation improves patient comfort, helps prevent unwanted
fects. It is therefore relatively contraindicated in patients with
respiratory efforts, facilitates procedures, and decreases oxygen
atherosclerotic vascular disease, hypertension, increased inconsumption and carbon dioxide production. Sedation may also
tracranial pressure, and preeclampsia. Another drawback to the
decrease the risk of barotrauma. Despite the frequency with which
use of ketamine is its potential to lower the seizure threshold, alsedatives are used in the leu setting, surprisingly little data are
ter mood, and occasionally cause delirium, effects that mayocavailable from which to form strong conclusions regarding which
cur in as much as one third of patients older than 16 yr of age
agents or combinations of agents are best and how to administer
(166, 169, 170). Ketamine increases laryngeal secretions and does
these agents optimally to maximize patient comfort and minimize
not block pharyngeal and laryngeal reflexes (166); thus, particuside effects. The development and validation of sedation and
lar care must be taken in the peri-intubation period to avoid larynanalgesia protocols will help in this regard.
gospasm and aspiration (171). Ketamine is broken down in the liver
TABLE 3
SEDATIVES USED IN STATUS ASTHMATICUS
Agent
Peri-intubation period
Midazolam
Ketamine
Dose
1 mg intravenously slow
push; repeat every 2 to 3
min as needed.
1 to 2 mg/kg intravenously
at a rate of 0.5 mglkglmin.
Propofol
60 to 80 mg/min intravenous
initial infusion up to 2.0
mglkg followed by an
infusion of 5 to 10 mglkglh
as needed.
Sedation for protracted mechanical ventilation
1 to 5 mg/h intravenous
Lorazepam
continuous infusion or bolus
as needed.
Morphine sulfate
1 to 5 mglh intravenous
continuous infusion; avoid
bolus.
0.1 to 0.5 mg/min
Ketamine
intravenously.
Propofol
1 to 4.5 mglkglh intravenously.
Cautions
Hypotension,
respiratory
depression.
Sympathomimetic
effects, respiratory
depression, mood
changes, delerium-type
reactions.
Respiratory depression.
Drug accumulation.
Ileus.
Sympathomimetic
effects, delerium-type
reactions.
Seizures,
hypertriglyceridemia.
State of the Art
to norketamine, which also has anesthetic properties and a halflife similar to that of midazolam (about 120 min). As such, there
is some risk for drug accumulation with continuous infusion (167).
Propofol may prove to be a useful drug in the preintubation
period, but as with ketamine, experience is limited in patients with
SA. In a recent comparative study (172) of propofol and midazolam as sedatives for asthmatics undergoing fiberoptic bronchoscopy, propofol resulted in more rapid onset and resolution of
sedation. There were no significant differences in oxygen desaturation or hemodynamic parameters between the propofol and
midazolam groups. Patients in the propofol group received initial
IV infusions of 60 to 80 mg/min up to 2.0 mg/kg until adequate
sedation was achieved followed by an infusion of 5 to 10 mg/kg/h
to maintain the desired level of sedation.
Propofol seemingly meets many of the requirements for an ideal
sedating drug in the ICU setting. Its rapid onset of action allows
for rapid titration of the level of sedation without significant cardiovascular effects; and since patients can be titrated to anesthetic
depth sedation, it may avoid the need for muscle paralysis and
its consequences (see below). The risk of drug accumulation is
low because of rapid metabolism by hepatic conjugation to inactive metabolites, which are renally excreted (173). In addition, a
recent report (174) of the use of propofol in two patients with chronic
obstructive pulmonary disease (CaPO) who developed bronchospasm after insertion of a prosthetic aortic valve suggests
propofol may have bronchodilating properties as well. It should
be pointed out, however,that propofol has no analgesic properties.
For ongoing sedation we prefer lorazepam over midazolam
mainly because of the prohibitive cost of long-term midazolam
infusion. When given by continuous infusion in mechanically ventilated patients, benzodiazepines may accumulate and require extended periods of time to clear and permit return of normal mental status (175). The addition of morphine sulfate 1 to 5 mg/h given
intravenously by constant infusion helps relieve pain and achieve
unconsciousness for the use of paralytic agents. Slow infusions
of oplolds minimize hemodynamic effects and histamine release
(which can be blocked by pretreatment with antihistamines) (162).
However, opioids decrease gut motility, cause nausea and vomiting, and depress ventilatory drive in spontaneously breathing patients. They are also slowly cleared in patients with depressed
liver or kidney function.
More extensive clinical trials of ketamine and propofol (including the use of continuous infusions) in patients with SA may prove
these agents to be acceptable alternatives to benzodiazepines
and opioids for long-term sedation. However, a growing body of
evidence suggests prolonged propofol administration may be associated with generalized seizures (176-180). Hypertriglyceridemia and increased CO 2 production have also rarely been reported
during propofol infusion since the drug is mixed in a fat-based
diluent (176, 181). Until further data are available, we do not recommend the routine use of either propofol or ketamine for long-term
sedation in SA.
The optimal level of sedation in mechanically ventilated asthmatics is not known. Many clinicians aim for a state of drowsiness and relaxation in which patients are able to open their eyes
on command, demonstrate little spontaneous movement, and
breathe in synchrony with the ventilator and at the set ventilator
rate. Ideally, sedation alone allows for control of the patient's cardiopulmonary status, and muscle paralysis is not necessary.
Paralysis
Ultimately, the decision whether or not to use a neuromuscular
blocking agent as a part of the overall therapeutic strategy is based
1307
on the clinician's judgment that paralysis is needed to maintain
stable respiratory parameters and ensure patient safety. Muscle
paralysis is indicated in patients who, in spite of sedation, continue to breathe in a desynchronized manner during mechanical
ventilation, placing themselves at greater risk of generating high
airway pressures and losing airway access. Paralysis augments
the beneficial effects of sedation to reduce oxygen consumption,
carbon dioxide production, and lactic acid generation, and it may
decrease the risk of barotrauma. Eliminating expiratory effort may
also be associated with less airway collapse (182).
The preferred paralytic agents are vecuronium and atracurium.
These nondepolarizing agents are virtually free of cardiovascular effects, although large boluses of atracurium may cause
hypotension through the release of histamine (183). The current
trend in many institutions is to use atracurium because of fewer
reports of the development of myopathy (see below). One potential disadvantage of atracurium, however, is its histamine-releasing
property, which may worsen bronchospasm. Whether this potential problem is of clinical significance in patients with SA is currently unknown. Vecuronium is largely cleared by the liver,although
two metabolites are renally excreted making it a poor choice in
patients with failure of either organ system. In such patients, atracurium is the better choice because it is eliminated by esterase degradation and spontaneous breakdown in the serum. Pancuronium,
which is metabolized in the liver and excreted by the kidney, is
an acceptable alternative to vecuronium in most cases and is less
expensive. However, its vagolytic properties are more likely to
cause tachycardia and hypotension.
Paralytic drugs may be given intermittently by bolus injection
or by continuous IV infusion. If a continuous infusion is used, the
drug should be withheld every 4 to 6 h to avoid drug accumulation and prolonged paralysis and to assess the need for ongoing
paralysis. In all cases, use of a nerve stimulator to define least
drug dosage is advisable. Muscle paralysis should be provided
only on an as-needed basis and only to unconscious patients. Ensuring unconsciousness in these patients is a challenge since
the commonly used indicator of agitation, tachycardia, may not
be reliable in patients receiving high doses of adrenergic agents.
There are a number of disadvantages to using paralytic agents,
including difficulties assessing mental status, a potentially greater
risk of developing deep venous thrombosis, and worsening of disuse muscle atrophy (184). Paralytic agents also appear to play
a causative role in the development of myopathy in acute severe
asthma. Muscle weakness may be mild and of little clinical significance or severe enough to interfere with successful liberation
from mechanical ventilation. Most patients recover completely, although some patients require several weeks of rehabilitation. In
a recent study (185) of 25 consecutive, mechanically ventilated
asthmatics (22 of whom received vecuronium), 19 demonstrated
a significant increase in serum creatine kinase (CK), and nine
(36%) had clinically detectable myopathy. Mechanical ventilation
was significantly prolonged in patients with an elevated CK whether
or not there was clinically detectable myopathy. Fluegel and colleagues (186) reviewed 90 episodes of mechanical ventilation for
SA. Profound muscle weakness occurred in 14 cases. Median CK
(measured in 10 cases) was 1,000 lUlL. Electromyograms in six
cases showed a myopathic pattern. Muscle biopsy in three cases
showed myonecrosis. All patients had received a neuromuscular
blocking agent (five received vecuronium; four, atracurium; two,
pancuronium; and three, a combination of these drugs). No patients receiving corticosteroids alone developed muscle weakness.
Indeed, there was no association between the dose of corticosteroid used and the development of myopathy. On the other hand,
1308
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
patients with myopathy received higher doses of vecuronium for
longer periods of time.
The data of Fluegel and colleagues suggest that it is the combination of corticosteroids and neuromuscular blocking agents
that increases the risk of myopathy; still, other factors may be involved, inclUding hypokalemia, hypophosphatemia, and high-dose
beta-agonists. The concern that the steroid structure of vecuronium and pancuronium increases the risk of myopathy (184, 187,
188) (and therefore that atracurium is safer) is not supported by
the data of Fluegel and colleagues.
Until further data are available, we recommend the use of paralytics only in patients who cannot be adequately controlled with
sedation alone. When paralytics are necessary, they should be
dosed using a peripheral nerve stimulator so that lower dosages
can be given. Paralytics should be held intermittently to assess
the need for ongoing paralysis, serum CK levels should be followed, and blood electrolyte and mineral concentrations should
be maintained within normal ranges (187). Although, Fluegel and
colleagues (186) found no correlation between the dose of corticosteroids and the development of myopathy, this finding needs
to be validated in future trials. For now, we recommend that excessive doses of corticosteroids (which we define as greater than
125 mg methylprednisolone or its equivalent given intravenously
every 6 h) should be avoided.
VOL 151
1995
90
80
70
·Ppk
(em H20)
60
50
40
30
·Pple •
20
4.0
llJ
~ r-f1
~
r-rr
rri
3.0
Vl1l~:~.
2.0
LUNG
VOL
(L)
1.0
Lung Hyperinflation and Barotrauma
Postintubation hypotension is common. Causative factors are lung
hyperinflation, hypovolemia, and sedation. Lung hyperinflation occurs when expiratory airflow obstruction prevents complete alveolar gas emptying. It is directly proportional to minute ventilation
(Ve) (189, 190). In the postintubation period, dangerous levels of
lung hyperinflation can develop if patients are ventilated excessively in a misguided attempt to stabilize or resuscitate. With severe airflow obstruction, even delivery of a normal or reduced Ve
may cause substantial gas trapping and hemodynamic compromise. Clinically, inspired breaths are difficult to deliver (because
of both airway obstruction and hyperinflation), breath sounds are
diminished, and neck veins are distended. Systemic blood pressure and pulse pressure fall and pulse rate rises. In the same patients, hypovolemia from increased insensible water losses and/or
decreased oral fluid intake, sedation, and muscle relaxation all
act to decrease mean systemic vascular pressure, further decreasing venous return to the heart. This pathophysiology can be
demonstrated by slowly ventilating (2 to 3 breaths/min) the patient while delivering 100% oxygen to avoid hypoxemia. Mean intrathoracic pressure will fall, and within 30 to 60 s, blood pressure will rise, pulse pressure will widen, and pulse rate will fall.
Vigorous volume challenge should follow in hypovolemic patients,
along with strategies to minimize lung hyperinflation (see below).
Note that the clinical features of lung hyperinflation mimic tension pneumothorax. Indeed, if hypoventilation does not quickly
achieve cardiopulmonary stability, consideration should be given
to the immediate placement of bilateral chest tubes. But just as
important, chest tubes should not be inserted in unstable patients
(unless clear-cut evidence of tension pneumothorax exists) until
there has been a trial of hypoventilation.
Once the patient has been adequately fluid-resuscitated, ventilator settings should be chosen that avoid excessive lung inflation. Such a strategy decreases the risk of systemic hypotension
and pneumothorax, both of which correlate directly with the degree of lung hyperinflation (190). Lung hyperinflation is minimized
by allowing an adequate time for exhalation (Te)and by ongoing
treatment of expiratory airflow obstruction. Expiratory time can
5.4
",
5.1
¥
10
4.5
"
3.2
2.9 2.3
"-
"I
16
1.7
'"
1.5
1.1
./
26
Figure 2. During controlled mechanical ventilation of patients with SA,
three inspiratory flow rates(100Llmin, 70 Llmin, and 40 LImin) were studied
during three levels of minute ventilation (VE) (10 Llmin, 16 Llmin, and 26
Llmin). Decreasing inspiratory flow at each VEshortened exhalation time
(Is) and resulted in greater lung volume at end-inspiration (VEl), lung volume at end-expiration (VEE), and plateau pressure (Pplat), but lower Ppk.
Note how increasing VE decreases ~ and adds to lung hyperinflation.
The longest ~ (5.4 s) was achieved when the highest inspiratory flow was
combined with the lowest VE and was associated with the least amount
of lung hyperinflation. (From reference 190, with permisslon.)
be prolonged by decreasing Ve by either lowering respiratory rate
(RR) or tidal volume (VT) or by minimizing inspiratory time (li) (see
Figure 2). Inspiratory time is reduced by increasing inspiratory
flow rate and using a square flow wave form. The use of ventilator
circuit with a low compressible volume (l.e., low-compliance tubing) decreases the portion of VT wasted in expanding the ventilator tubing, and thereby allows the physician to set a smaller VT
to achieve the same effective VT in the patient (191). Thus, a smaller
Ve can be set, allowing for longer 11:.
Minute ventilation is usually a more important determinant of
expiratory time than is li. To illustrate this point, consider the consequences of the following ventilator settings (192): VT, 1,000 ml;
RR, 15 breaths/min, and inspiratory flow rate, 60 Llmin. These
settings result in a li of 1 s and a 11: of 3 s (I:E ratio of 1:3). Decreasing RR to 12 breaths/min prolongs 11: to 4 s (I:E of 1:4), whereas
doubling of inspiratory flow prolongs 11: to only 3.5 (I:E of 1:7).
Decreasing RR in this example results in less lung hyperinflation
than increasing flow because there is more time to exhale the
1-L breath. Note how the I:E ratio can be misleading. In general
a low I:E ratio is desirable because it suggests a ventilator strategy
is in place that prolongs Te. In the above example, however, the
strategy that achieved a higher I:E resulted in longer 11:.
For an average-sized adult an initial Ve between 8 and 10 Llmin
State of the Art
LUNG
VOLUME
1309
TOTAL VENTILATION ......t - - - - APNEA -
..
2.5
_ ___..
...•
2.0
Tidal Vol.
VEl
FRC ........- - - -
~==__
1.5
1.0
TIME
3. One way to measure lung hyperinflation is to collect the total
exhaled volume during a period of apnea (usually 20 to 60 s). This volume, termed VEl, isthevolume ofgas atend-inspiration above FRC and
is thesum of thetidal volume (Vr) and volume at end-exhalation above
FRC (VEE). VEl above a threshold value of 20 ml/kg (1.4 L in anaveragesized adult) has been shown topredict complications ofhypotension and
barotrauma. (From reference 193, with permission.)
Figure
(achieved by a VT between 8 and 10 ml/kg and a RR between
11 and 14 breaths/min), combined with an inspiratory flow rate
of 100 Llmin, is unlikely to result in a dangerous degree of lung
hyperinflation (189, 193). However, somemeasure of lung hyperinflation is desirable to ensure that these settings are indeed safe.
One way to measurelung hyperinflation is to collect the total exhaled volume during 20 to 60 s of apnea in a paralyzed patient.
This volume, termed by Tuxen "VEl;' is the volume of gas at endinspirationaboveFRC(see Figure 3). VEl abovea threshold value
of 20 ml/kg (1.4 L in an average-sized adult) has been shown to
predict complications of hypotension and barotrauma (193). An
initial VE of less than or equal to 115 ml/kg/min, or about 8 L/min
in a normal-sized adult, resulted in a VEl greater than 20 ml/kg
in only 18% of patients (193). An initial VE of 12.5 Llmin resulted
in a VEl above the safe level in eight of 10 patients (189).
Tuxen and colleagues (189) have used VEl to regulate VE to
a safe level(that not resulting in VEl> 20 mllkg) in ventilated asthmatics. Respiratory ratewasdecreased whenVEl wasgreaterthan
20 ml/kg, and it was increased when VEl was less than 20 ml/kg.
At the beginning of mechanical ventilation, the safe level of VE
often resulted in hypercapnia, but as airflowobstruction improved,
the VE deemed safe approached the VE required for normocapnia; and when safe VE achieved a Pac02 less than 40 mm Hg,
patients were evaluated for extubation.
Additionalstudies involvinglarge patientnumbers are needed
to validatethe predictivevalue of VEl. One potentialproblem with
the use of VEl to measure lung hyperinflation is that not all trapped
gas is exhaledduring the period of apnea used for its determination. Functional residual capacity remainssubstantially elevated
even after prolonged apnea, indicating that there is noncommunicatinggas resultingfrom airwayclosure (189). Another practical consideration limiting the use of VEl is that most clinicians
and respiratory therapists are unfamiliar with its determination.
In place of VEl we prefer to follow the static or plateau pressure (Pplat), which is an estimate of average end-inspiratory alveolar pressures. This pressure is easily determined by stopping
flow at end-inspiration (commonly by settinga O.4-s end-inspiratory
pause). Duringthis pause, airwayopeningpressure fallsfrompeak
pressure(Ppk)(the sum of static and resistivepressures)to Pplat
as resistivepressurefalls to zero. Patients must be relaxed to obtain reliablemeasurements. Becausealveolarpressureincreases
as lung volume increases, measurementof Pplat correlates with
VEl (see Figure4); but unfortunatelythis correlation is often poor,
likely caused by the large variation in lung compliance seen in
these patients and the presence of noncommunicating gas (see
below) (193). Pplathas not yet beenshownto be a reliable predictor of complications, but when this easily determined pressure
is keptlessthan 30 cm H20 complicationsappearto be rare (192).
R2= 0.094
• •
•
(L)
•
• Complications
• No Complications
A
0.5
0.0
0
10
20
Pp lBt
30
40
50
(cmH20)
Relationship between Pplat and VEl in mechanically ventilated
asthmatics. Because alveolar pressure increases as lung volume increases, measurement of Pplat correlated with VEl, butthis correlation
is often poor because of the large variation in lung compliance and the
presence ofnoncommunicating gas. (From reference 193, with permission.)
Figure 4.
Auto-PEEP is another measure of lung hyperinflation. When
expiratory airflow obstruction prevents complete emptying of alveolargas,end-expiratory alveolarpressureremains positive. This
pressure is not reflected at the airway opening if the expiratory
port of the ventilator is open (which allows airwayopening pressure to approach atmospheric pressure or the level of ventilatorapplied PEEP). If the expiratoryport of the ventilatoris occluded
at end-expiration, however, central airway pressure equilibrates
with alveolar pressure, permitting measurements of auto-PEEP
at the airway opening (see Figure 5). Auto-PEEP measurements
are accurate only in relaxed patients since expiratory muscle
contraction elevates auto-PEEP without adding to dynamic
hyperinflation. Auto-PEEP has not been shown to correlate with
complications (193); there are recent data from Leatherman and
colleagues (194) demonstrating that auto-PEEP maysignificantly
underestimate the degree of lung hyperinflation in somepatientsagain suggesting the presenceof noncommunicatinggas resulting from airway closure.
Ventilator-applied PEEP should be avoided in mechanically
ventilated patientswith SA becauseit has the potential to increase
lung volume and intrathoracic pressure in sedated and paralyzed
patients (195). We also avoid applied PEEP in hyperinflated patients who are actively breathing (even though this strategy may
decrease inspiratory work of breathing) because the degree of
auto-PEEP is difficult to assess in spontaneously breathing patients,and applying PEEPabovethe level of auto-PEEP mayadd
to lung hyperinflation.
The use of high inspiratoryflow rates minimizes lung hyperinflation, but this choice is not without possible risk. High inspiratory flows increase Ppk (see Figure 2), a pressureseveralinvestigatorshavesuggestedis associatedwith risk of barotrauma(193,
196). Recent data, however, fail to show a relationship between
Ppk and complications of mechanical ventilation (193). The reason may be that Ppk does not predict alveolar pressure or the
degree of lung hyperinflation because of the pressure gradient
between the large robust airways and the alveoli. High inspiratory flow rates may also increase annular flow of mucus toward
alveoli (197) and preferentiallyfill (and hyperinflate) more normal
lung units with faster time constants. The clinical significance of
these last two possibilities is unknown.
In the most severelyobstructed patients, a VE of 8 to 10 Llmin
may result in unacceptablelung hyperinflation as judged by VEl,
Pplat, or auto-PEEP. In this circumstance, VE should be progressivelydecreased,evenif hypercapniaensues. However, decreasing VE may not increase PaC02 if decreasing lung hyperinflation
1310
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
End Inspiration
End Expiration
Normal
VOL 151
1995
Initial Settings
VT = 8-10 ml/kg
RR = 11-14/min
V = 100 LIsee
Square wave form
PEEP = 0 emH 20
Pplat < 30 cmHp
Airflow
Obstructed
Figure 6. Recommended initial ventilator settings and an algorithmic approach to mechanical ventilation in patients with status asthmaticus.
Figure 5. Measurement of auto-PEEP. Under normal conditions, alveolar pressure (Palv) closely tracks the pressure at the airway opening (Pao),
which is reported on the ventilator manometer. At end-expiration, Palv
falls to atmospheric pressure (0 cm H20 ) and is accurately reflected by
Pao. In severe airflow obstruction, Palv may increase because of gas trapping, and at end-expiration Palv has not fallen to atmospheric pressure
and does not equal Pao. If an expiratory hold maneuver is performed,
Pao will rise, reflecting the degree of gas trapping. (From reference 22,
with permission.)
decreases the dead space to tidal volume ratio (yoM) by improving perfusion to ventilated lung units. It is the product of VE and
(1-VDM) that sets alveolar ventilation; so that if alveolar ventilation increases with a drop in VE, Paco2 may actually fall assuming constant CO 2 production.
Purposeful hypoventilation is not without potential risk. Hypercapnic acidosis may cause cerebral vasodilation, cerebral edema,
decreased myocardial contractility, vasodilation with a hyperdynamic circulation, and pulmonary vasoconstriction (198). Accordingly, purposeful hypoventilation is a strategy best avoided
in patients with raised intracranial pressure (as might occur in the
setting of anoxic brain injury from cardiopulmonary arrest) and
in patients with severely depressed myocardial function. Still, purposeful hypoventilation is well tolerated by many patients as long
as PaC02 does not exceed 90 mm Hg (199) and acute increases
in Pac02 are avoided. Low values of arterial pH also appear to
be well tolerated by most patients-which raises the question as
to whether low values of arterial pH need to be treated with buffer
therapy. To date, the efficacy of increasing serum pH in the setting of purposeful hypoventilation is unknown, and there is a clear
need for additional studies addressing this issue. Our approach
is to treat patients with an arterial pH less than 7.20 with sodium
bicarbonate (200) unless there is room to increase VE as guided
by VEl or Pplat. Rapid bicarbonate infusion should be avoided
because it causes an increase in CO 2 production (and Paco, in
patients with a fixed alveolar ventilation) and intracellular acidosis. Slow infusions, on the other hand, appear to be well tolerated
(201).We stop bicarbonate infusions once the serum pH is greater
than 7.20 or at the first sign of clinical improvement to avoid rebound metabolic alkalosis.
See Figure 6 for a summary of initial ventilator settings and
an algorithmic approach to mechanical ventilation in patients with
SA. We recommend initial ventilator settings of: VT,8 to 10 mllkg;
RR, 11 to 14 breaths/min; PEEp, 0 cm H20 ; inspiratory flow rate,
100 L/min with a square flow wave form. Flo2 should be 1.0 (humidified) in the peri-intubation period, but it should be decreased
to a nontoxic level once the patient is stable. Ventilator mode is
irrelevant in the sedated and paralyzed patient since assist-control
and intermittent mandatory ventilation both provide controlled ventilation in this setting. There are no data that one ventilator mode
is better than another in patients with respiratory efforts, and the
clinician should choose the mode with which he or she is most
familiar (182). One caution is that the use of volume-cycled assist
control ventilation in the initial treatment of awake asthmatics may
be associated with increased risk of hyperinflation (202). Similar
to Tuxen and colleagues (189) and Leatherman and coworkers
(192), we accept the above settings if they achieve a Pplat less
than 30 cm H 20 and an arterial pH greater than 7.20. If Pplat is
greater than 30 cm H20 , we decrease RR until this goal is achieved.
If purposeful hypoventilation results in an arterial pH less than
7.20 and there is no room to increase VE as guided by Pplat, we
consider adding sodium bicarbonate to the maintenance infusion
while continuing to lower CO 2 production with sedation and paralysis.
Although the available data justify the use of a ventilator strategy
that limits lung hyperinflation and tolerates hypercapnia, this approach needs validation in larger clinical trials. Whether using such
a strategy will decrease the mortality of ventilated asthmatics as
well as morbidity remains unknown. Tuxelfl's group (193) has
reported zero asthma mortality (albeit in a small number of patients), but so have other groups caring for v~ntilated asthmatics
during the last 15 yr. Braman and Kaernrnerlen (196) reported no
deaths during 24 episodes of mechanical ventilation for SA between 1978 and 1987. These investigators did not provide details
regarding ventilatory strategy or arterial blood gas measurements
during ventilation, but in all cases the ventilator was preset to limit
Ppk to less than 50 cm H20 , and initial Paco2 averaged 89 mm
Hg. Darioli and Perret (199) similarly reported zero mortality during 34 episodes of mechanical ventilation for SA when Ppk was
limited to 50 cm H20 and hypercapnia was tolerated. Bellomo and
coworkers (203) also accepting of high levels of Paco., reported
one death (which was attributed to brain death prior to ventilation) during 35 consecutive cases of SA requiring mechanical ven-
State of the Art
tilation. On the other hand, reported death rates have been generally higher when mechanical ventilation was performed without
permissive hypercapnia. Scoggin and coworkers (204) reported
a 38% mortality rate during 21 episodes of SA treated with conventional mechanical ventilation during which the goal was to avoid
alveolar hypoventilation. Luksza and colleagues (205) reported
a 9% mortality rate using a strategy of adjusting VT to achieve
normocapnic ventilation. Mansel and colleagues (206) reported
a 220/0 mortality rate for asthmatics requiring mechanical ventilation between 1980 and 1988. They did not provide data regarding
ventilator settings or PaC0 2 during mechanical ventilation.
The wide range of reported death rates in ventilated patients
with SA (zero to 38%), the lack of a common approach to mechanical ventilation and pharmacologic therapy, and the concern
that disease severity may not have been similar among the various studies, preclude fair comparison of mortality rates among
studies. It is, therefore, premature to conclude that limiting lung
inflation and permitting hypercapnia decreases mortality in ventilated asthmatics. Moreover, ventilatory strategy is unlikely to impact significantly on the clinical outcome of patients with severe
anoxic brain injury. Better outpatient management is clearly
needed to prevent this complication of SA and to decrease the
number of asthma deaths prior to arrival at an acute care center.
Inhalational Anesthetics
Rarely, the above strategies do not allow for adequate ventilation
at a safe level of lung inflation, and consideration should be given
to the use of inhalational anesthesia. Both halothane and enflurane are bronchodilators that can acutely reduce Ppk and Paco2
(207, 208), but effects do not last after drugs are stopped. lnhalational anesthetics have considerable cardiovascular effects, including myocardial depression, arterial vasodilation, and arrhythmias, but hemodynamic stability can usually be maintained during
administration by skilled anesthesiologists. As mentioned previously, a blend of 60% helium and 400/0 oxygen has been studied
in seven intubated asthmatics (154). Within minutes heliox decreased peak airway pressure by a mean of 33 cm H2 0 and Paco2
by a mean of 35.7 mm Hg; one patient who responded quickly
to heliox had previously failed a trial of halothane. There has been
recent interest in the use of nitric oxide (NO) to induce bronchial
relaxation, but there has been limited experience in patients with
SA. Hogman and colleagues (209) recently reported their experience with NO in healthy volunteers, adults with airway hyperreactivity during methacholine challenge, patients with stable
asthma, and patients with COPD. They concluded that NO inhaled
at 80 ppm exerted a weak bronchodilatory effect in asthmatics
but not in patients with COPO.
Bronchoalveolar Lavage
One of the most striking findings noted in patients dying of SA
is the degree of mucus impaction of both large and small airways
(210). In refractory patients, retained secretions, not yet mobilized
by bronchodilators and corticosteroids, contribute to airflow limitation and lung hyperinflation. Unfortunately, other strategies to
mobilize mucus such as chest physiotherapy or treatment with
mucolytics or expectorants have not proved efficacious in controlled trials (211, 212). BAL, on the other hand, using either saline or acetylcysteine, may be useful to remove mucus plugs in
some patients with refractory SA (213-217). Lang and colleagues
(214) recently demonstrated that BAL improved airflow obstruction in nonintubated patients with stable but refractory acute
asthma. There were no major complications. Minor complications
included three episodes of transient hypoxemia and four episodes
1311
of worsening bronchospasm, which resolved after treatment with
subcutaneous or inhaled beta-agonists.
In intubated asthmatics, however, this procedure is more risky.
The presence of the bronchoscope within the lumen of the endotracheal tube and large airways increases expiratory airway resistance and may lead to dangerous levels of lung hyperinflation.
Temporarily decreasing VE may minimize this complication, but
it is likely to result in further increases in Paco2 • Despite these
risks, some physicians advocate a quick inspection of the airways
to remedy possible diffuse mucus impaction in patients who are
not improving after several days of mechanical ventilation. This
practice may prove to be beneficial for rare patients, but convincing data demonstrating benefit and safety of BAL in this setting
are needed before this practice can be validated. For now, BAL
should not be considered a part of the routine management of
ventilated asthmatics.
Extubation
Once airway resistance starts to fall and Paco2 normalizes, paralytic agents and sedatives should be withheld in anticipation of
extubation. If signs of worsening bronchospasm are not present,
we favor a quick return to spontaneous breathing through aT-piece
or by decreasing the respiratory rate on SIMV. The use of 5 to
8 cm H20 of pressure support helps overcome endotracheal tube
resistance. If patients tolerate a trial of spontaneous breathing,
we move quickly toward extubation. This tempo minimizes endotracheal-tube-induced bronchospasm and other risks of prolonged
intubation and mechanical ventilation. Close observation in the
ICU is recommended for an additional 24 h postextubation during which time clinicians can focus on safe transfer to the general
medical ward.
PREVENTING FUTUREEPISODES OF STATUSASTHMATICUS
After the patient has arrived on the general medical ward, the treating team should address the prevention and treatment of subsequent asthma attacks. This process starts with extensive patient
education regarding the definition of asthma, the signs and symptoms of asthma, how to control or eliminate triggers, and how to
identify and treat attacks appropriately. Patients should be provided
with written medication instructions as well as a written plan of
action to be followed in the event of worsening symptoms. A peak
flow meter should be given to all patients to help them recognize
and treat symptoms. Time should be taken to address psychosocial and financial issues that may interfere with medication compliance, and follow-up appointments should also be made prior
to discharge whenever possible.
A common goal is to treat airway wall inflammation by controlling the patient's environment and by the religious use of antiinflammatory medications. When inhaled corticosteroids are
prescribed, patients must be told not to expect immediate relief
of respiratory symptoms, as these medications are notbronchodilators. The regular use of anti-inflammatory therapy must be
stressed, and patients should demonstrate their ability to administer inhaled drugs effectively. Corticosteroid side effects
should be discussed with patients, who are often quite concerned
about the use of these drugs even for short periods of time, and
strategies should be provided that minimize the risk of these side
effects occurring. Patients inhaling corticosteroids should use a
spacing device and be counseled to rinse and spit after usage
to decrease systemic absorption and the risk of oral candidiasis.
For patients using oral preparations, exercise and nutritional gUidance should be provided to minimize weight gain and the risk of
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
hyperglycemia and hypertension. Attention should also be paid
to the prevention of steroid-induced osteopenia.
Patients should be taught how to recognize early warning signs
so that they may initiate proper treatment. In general, warning signs
of worsening airflow obstruction include a 20% drop in PEFR below predicted or personal best, and an increase in cough, shortness of breath, chest tightness, or wheeze (48). Although mild
asthma episodes (PEFR between 70 and 90% of baseline) may
be treated by a temporary increase in bronchodilator therapy, branchodilators alone are not sufficient to treat more severe attacks
(48). Indeed, beta-agonists may even confer a false sense of security and delay the administration of anti-inflammatory therapy. Accelerated use of beta-agonists should be a warning sign that airway wall inflammation has worsened and that corticosteroid
therapy should begin. Should such a strategy be followed, many
emergency room visits could be avoided. Patients with a history
of sudden asphyxic asthma should also be given an epinephrine
kit for the immediate subcutaneous use of this drug during a crisis.
SUMMARY
Despite advancing knowledge of the pathophysiology and treatment of asthma, asthma morbidity and mortality are on the rise.
To help avert this trend, clinicians and patients must focus their
attention on the early identification and treatment of asthma exacerbations. As in the words of Dr. Thomas Petty: ..... the best treatment of status asthmaticus is to treat it three days before it
occurs." (7) Still, there will be asthmatics with life-threatening attacks that require careful assessment and aggressive management. Inhaled beta-agonists, systemic corticosteroids, and oxygen remain the drugs of choice in SA. Anticholinergics playa lesser
role in the treatment of acute asthma, and debate continues regarding the efficacy of theophylline in this setting. Available data
do not support the routine use of magnesium sulfate or antibiotics in patients with SA.
Patients failing drug therapy should be considered early for
intubation and mechanical ventilation. A strategy of mechanical
ventilation that prolongs lE by limiting VE and decreasing inspiratory time, and that tolerates hypercapnia, avoids excessive lung
hyperinflation and barotrauma and should improve the outcome
of these most critically ill asthmatics. Intubated and mechanically
ventilated patients should be aggressively sedated. Paralytic
agents should be used only if adequate control of the cardiopulmonary status cannot be achieved by sedation alone. Minimizing
the use of paralytic agents may decrease risk of myopathy and
other adverse consequences of muscle paralysis. Finally, after
successful treatment of a life-threatening episode of asthma, the
treatment team should address prevention of future episodes of
SA prior to discharge.
References
1. American Thoracic Society. 1987. Standards for the diagnosis and care
of patients with chronic obstructive pulmonary disease (COPD) and
asthma. Am. Rev. Respir. Dis. 136:225-244.
2. Busse, W. W., W. F. Calhoun, and J. D. Sedgewick. 1993. Mechanism
of airway inflammation in asthma. Am. Rev. Respir. Dis. 147:S20-S24.
3. Reed, C. E. 1986. New therapeutic approaches to asthma. J. Allergy
Clin. Immunol. 77:537-543.
4. Wasserfallen, J. B., M. D. Schaller, F. Feihl, and C. H. Perret. 1990.
Sudden asphyxic asthma: a distinct entity? Am. Rev. Respir. Dis.
142:108-111.
5. Sur, S., T. B. Crotty, G. M. Kephart, B. A. Hyma, T. V. Colby, C. E. Reed,
L. W. Hunt, and G. J. Gleich. 1993. Sudden-onsetfatal asthma: a distinct clinical entity with few eosinophils and relatively more neutraphils in the airway submucosa. Am. Rev. Respir. Dis. 148:713-719.
6. Ried, L. M. 1987. The presence or absence of bronchial mucus in fatal
asthma. J. Allergy Clin. Immuno/. 80:415-416.
VOL 151
1995
7. Petty, T. L. 1989. Treat status asthmaticus three days before it occurs.
J. Intensive Care Med. 4:135-136.
8. Westerman, D. E., S. R. Benetar, P. D. Potgieter, and A. D. Ferguson.
1979. Identification of the high-risk asthmatic patient. Am. J. Med.
66:565-572.
9. Strunk, R. C. 1993. Deaths due to asthma. Am. Rev. Respir. Dis. 148:
550-552.
10. Rodrigo, G., and C. Rodrigo. 1993. Assessment of the patient with acute
asthma in the emergency department: a factor analytic study. Chest
104:1325-1328.
11. Greenberger, P. A., and R. Patterson. 1988. The diagnosis of potentially fatal asthma. N.E.R. Allergy Proc. 9:147-152.
12. Lowenthal, M., R. Patterson, P. A. Greenberger, and L. C. Grammer.
1993. The application of an asthma severity index in patients with potentially fatal asthma. Chest 104:1329-1331.
13. Rea, H. H., R. Scragg, R. Jackson, R. Beaglehole, J. Fenwick, and D. C.
Sutherland. 1986. A case-controlled study of deaths from asthma. Thorax 41:833-839.
14. Kikuchi, Y., S. Okabe, G. Tamura, W. Hida, M. Homma, K. Shirato, and
T. Takishima. 1994. Chemosensitivity and perception of dyspnea in
patients with a history of near-fatal asthma. N. Engl. J. Med. 330:
1329-1334.
15. Brenner, B. E., E. Abraham, and R. R. Simon. 1983. Position and diaphoresis in acute asthma. Am. J. Med. 74:1005-1009.
16. Kelsen, S. G., D. P. Kelsen, B. F. Fleegler, R. C. Jones, and T. Rodman.
1978. Emergency room assessment and treatment of patients with
acute asthma. Am. J. Med. 64:622-628.
17. Fitzgerald, J. M., and F. E. Hargreave. 1989. The assessment and
management of acute life-threatening asthma. Chest 95:888-894.
18. Scharf, S., R. Brown, N. Saunders, and L. Green. 1979. Effects of normal and loaded spontaneous inspiration on cardiovascular function.
J. Appl. Physio/. 47:582-590.
19. Scharf, S., R. Brown, D. Tow, and A. Parisi. 1979. Cardiac effects of
increased lung volume and decreased pleural pressure. J. Appl. Physio/.
47:257-262.
20. Permutt, S., and R. A. Wise. 1986. Mechanical interaction of respiration
and circulation. In A. Fishman, editor. Handbook of Physiology. Vol.
3. American Physiological Society. Williams and Wilkins, Baltimore.
647-656.
21. Knowles, G., and T. J. H. Clark. 1973. Pulsus paradoxus as a valuable
sign .indicatlnq severity of asthma. Lancet 2:1356-1359.
22. Corbridge, T., and J. B. Hall. 1991. Status asthmaticus in the adult: assessment, drug therapy, mechanical ventilation. Choices Respir. Manage. 21:119-126.
23. Permutt, S., and R. A. Wise. 1986. Mechanical interaction of respiration
and circulation. In A. Fishman, editor. Handbook of Physiology. Vol.
3. American Physiological Society. Williams and Wilkins, Baltimore.
647-662.
24. Shim, C. S., and M. H. Williams. 1983. Relationship of wheezing to the
severity of obstruction in asthma. Arch. Intern. Med. 143:890-892.
25. Grossman, J. 1976.The occurrence of arrhythmias in hospitalized asthma
patients. J. Allergy Clin. Immuno/. 57:310-317.
26. Josephson, G. W., H. L. Kennedy, E. J. MacKenzie, and G. Gibson. 1980.
Cardiac dysrhythmias during the treatment of acute asthma: a comparison of two treatment regimens by a double blind protocol. Chest
78:429-435.
27. Rebuck, A. S., and J. Read. 1971. Assessment and management of severe asthma. Am. J. Med. 51:788-798.
28. Scharf, S. 1985. Mechanical cardiopulmonary interactions with asthma.
Clin. Rev. Allergy 3:487-500.
29. Shim, C. S., and M. H. Williams, Jr. 1980. Evaluation of the severity
of asthma: patients versus physicians. Am. J. Med. 68: 11-13.
30. Lim, T. K., S. M. Ang, T. H. Rossing, E. P. Ingenito, and R. H. Ingram,
Jr. 1989. The effects of deep inhalation on maximal expiratory flow
during intensive treatment of spontaneous asthmatic episodes. Am.
Rev. Respir. Dis. 140:340-343.
31. Lemarchand, P., S. Labrune, B. Herer, and G. J.iHuchon. 1991. Cardiorespiratory arrest following peak expiratory floy.'measurement during
I
attack of asthma. Chest 100:1168-1169.
32. National Heart, Lung, and Blood Institute. 1991. 'National Asthma Education Program. Expert Panel Report: guidelines fot the diagnosis and
management of asthma. J. Allergy Clin. Immuno/. 88:425-433.
33. Banner, A. S., R. S. Shah, and W. W. Addington. 1976. Rapid prediction of need for hospitalization in acute asthma. J.A.M.A. 235:1337-1338.
34. Fanta, C. H., T. H. Rossing, E. R. McFadden, Jr. 1982. Emergency room
treatment of asthma: relationships among therapeutic combinations,
severity of obstruction and time course of response. Am. J. Med.
72:416-422.
35. Stein, L. M., and R. P. Cole. 1990. Early administration of corticosteroids
in emergency room treatment of acute asthma. Ann. Intern. Med.
112:822-827.
36. Martin, T. G., R. M. Elenbaas, and S. H. Pingleton. 1982. Failure of peak
State
of
the Art
expiratory flow rate to predict hospital admission in acute asthma. Ann.
Emerg. Med. 11:466-470.
37. Nowak, R. M., M. C. Tomlanovich, D. D. Sarker, P. A. Kvale, and J. A.
Anderson. 1983. Arterial blood gases and pulmonary function testing
in acute bronchial asthma: predicting patient outcomes. J.A.M.A.
249:2043-2046.
38. Mountain, R. D., and S. Sahn. 1988. Clinical features and outcome in
patients with acute asthma presenting with hypercapnia. Am. Rev.
Respir. Dis. 138:535-539.
39. McFadden, E. R., Jr., and H. A. Lyons. 1968. Arterial-blood gas tension
in asthma. N. Engl. J. Med. 278:1027-1032.
40. Mountain, R. D., J. E. Heffner, N. C. Brackett, and S. A. Sahn. 1990.
Acid-base disturbances in acute asthma. Chest 98:651-655.
41. Appel, D., R. Rubenstein, K. Schrager, and M. H. Williams. 1983. Lactic
acidosis in severe asthma. Am. J. Med. 75:580-584.
42. O'Connell, M. B., and C. Iber. 1990. Continuous intravenous terbutaline
infusions for adult patients with status asthmaticus. Ann. Allergy
64:213-218.
43. Findley, L. J., and S. A. Sahn.1980. The value of chest roentgenograms
in acute asthma in adults. Chest 5:535-536.
44. Zieverink, S. E., A. P. Harper, R. W. Holden, E. C. Klatte, and H. Brittain. 1982. Emergency room radiography of asthma: an efficacy study.
Radiology 145:27-29.
45. Blair, D. N., L. Coppage, and C. Shaw. 1986. Medical imaging in asthma.
J. Thorac. Imaging 1:23-25.
46. Sherman, S., J. A. Skoney, and K. P. Ravikrishnan. 1989. Routine chest
radiographs in exacerbations of acute obstructive pulmonary disease.
Arch. Intern. Med. 149:2493-2496.
47. White, C. S., R. P. Cole, H. W. Lubetsky, and J. H. M. Austin. 1991.
Acute asthma: admission chest radiography in hospitalized adult patients. Chest 100:14-16.
48. National Asthma Education Program, Expert Panel Report. Aug. 1991.
Guidelines for the diagnosis and management of asthma. Bethesda.
U.S. Department of Health and Human Services. Publication No.
91-3042.
49. Feil, S. B., M. A. Swartz, K. Glanz, and M. E. Francis. 1983. Efficacy
of short-term corticosteroid therapy in outpatient treatment of acute
bronchial asthma. Am. J. Med. 75:259-262.
50. Gem, J. E., and R. F. Lemanske. 1983. Beta-adrenergic agonist therapy. Immunol. Allergy Clin. North Am. 13:839-860.
51. Kennedy, M. C. S., andW. T. Simpson. 1969. Human pharmacological
and clinical studies on salbutamol: a specific beta-adrenergic bronchodilator. Sr. J. Dis. Chest 63:165-174.
52. Paterson, J. W., R. J. C. Evans, and F. J. Prime. 1971. Selectivity of
bronchodilator action of salbutamol in asthmatic patients. Sr. J. Dis.
Chest 65:21-38.
53. Kelly, H. W. 1985. New 8 2-agonist aerosols. Clin. Pharmaco/. Ther.
4:393-403.
54. Rossing, T. H., C. H. Fanta, and E. R. McFadden. 1983. Effect of outpatient treatment of asthma with beta-agonists on the response to sympathomimetics in an emergency room. Am. J. Med. 75:781-784.
55. ldrls, A. H., M. F. McDermott, J. C. Raucci, A. Morrabel, S. McGorray,
and L. Hendeles. 1993. Emergency department treatment of severe
asthma: metered-dose inhaler plus holding chamber is equivalent in
effectiveness to nebulizer. Chest 103:665-672.
56. Jasper, A. C., Z. Mohsenifar, S. Kahan, H. S. Goldberg, and S. K. Koerner.
1987. Cost-benefit comparison of aerosol bronchodilator delivery
methods in hospitalized patients. Chest 91:614-618.
57. Newhouse, M. T. 1993. Emergency department management of lifethreatening asthma: are nebulizers obsolete? Chest 103:661-663.
58. Turner, J. R., K. J. Corkery, D. Eckman, A. M. Gelb, A. Lipavsky, and
D. Sheppard. 1988. Equivalence of continuous flow nebulizer and
metered-dose inhaler with reservoir bag for treatment of acute airflow
obstruction. Chest 93:476-481.
59. Hess, D. 1991. How should bronchodilators be administered to patients
on ventilators. Respir. Care 36:399-404.
60. Macintyre, N. R., R. M. Silver, C. W. Miller, F. Schuler, and E. Coleman.
1985. Aerosol delivery in intubated, mechanically ventilated patients.
Crit. Care Med. 13:81-84.
61. O'Doherty, M. J., S. H. L. Thomas, C. G. Page, C. J. Page, D. F. Treacher,
and T. O. Nunan. 1992. Delivery of a nebulized aerosol to a lung model
during mechanical ventilation. Am. Rev. Respir. Dis. 146:383-388.
62. O'Riordan, T. G., M. J. Greco, R. J. Perry, and G. C. Smaldone. 1992.
Nebulizer function during mechanical ventilation. Am. Rev. Respir.
Dis. 145:1117-1122.
63. Crogan, S. J., and M. J. Bishop. 1989. Delivery efficiency of metered
dose aerosols given via endotracheal tubes. Anesthesiology 70:
1008-1010.
64. Fuller, H. D., M. B. Dolovich, G. Posmituck, W. W. Pack, and M. T. Newhouse. 1990. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Am. Rev. Respir. Dis. 141:440-444.
65. Bishop, M. J., R. P. Larson, and D. L. Buschman. 1990. Metered dose
1313
inhaler aerosol characteristics are affected by the endotracheal tube
actuator/adaptor used. Anesthesiology .13:1263-1265.
66. Rau, J. L., R. J. Harwood, and J. L. Groff. 1992. Evaluation of a reservoir device for metered-dose bronchodilator delivery to intubated adults.
Chest 102:924-930.
67. Taylor, R. H., and J. Lerman. 1991. High-efficiency delivery of salbutamol
with a metered dose inhaler in narrow tracheal tubes and catheters.
Anesthesiology 74:360-363.
68. Taylor, R. H., J. Lerman, C. Chambers, and M. Dolovich. 1993. Dosing
efficiency and particle size characteristics of pressurized metered-dose
inhalers in narrow catheters. Chest 103:920-924.
69. Niven, R. W., R. M. Kacmarek, J. D. Brain, and R. A. Peterfreund. 1993.
Small bore nozzle extensions to improve the delivery efficiency of drugs
from metered dose inhalers: laboratory evaluation. Am. Rev. Respir.
Dis. 147:1590-1594.
70. Manthous, C. A., J. B. Hall, G. A. Schmidt, and L. D. H. Wood. 1993.
Metered-dose inhaler versus nebulized albuterol in mechanically ventilated patients. Am. Rev. Raspir. Dis. 148:1567-1570.
71. Newhouse, M. T., and H. D. Fuller. 1993. Rose is a rose is a rose? Aerosol therapy in ventilated patients: nebulizers versus metered-doseinhalers-a continuing controversy. Am. Rev. Respir. Dis. 148:14441446.
72. Chatila, W., J. B. Hall, and C. A. Manthous. 1994. Treatment of bronchospasm by metered-dose-inhaler albuterol via spacer in mechanically ventilated patients. Am. J. Respir. Crit. Care Med. 149:A190.
73. Tobin, M. J. 1988. Respiratory monitoring in the intensive care unit. Am.
Rev. Respir. Dis. 138:1625-1642.
74. Tenholder, M. F., M. J. Bryson, R. F. Waller, and T. T. Faircloth. 1992.
Can MDls be used effectively by extubated ICU patients? J. Crit. illness 7(1):111-117.
75. Fanta, C. H" T. H. Rossing, and E. R. McFadden. 1986. Treatment of
acute asthma: is combination therapy with sympathomimetics and
methylxanthines indicated. Am. J. Med. 80:5-10.
76. Uden, D. L., D. R. Goetz, D. P. Kohen, and G. C. Fifield. 1985. Comparison of nebulized terbutaline and subcutaneous epinephrine in the treatment of acute asthma. Ann. Emerg. Med. 14:229-232.
77. Becker, A. B., N. A. Nelson, and F. E. R. Simons. 1983. Inhaled salbutamol (albuterol) vs injected epinephrine in the treatment of acute
asthma in children. J. Pediatr. 102:465-469.
78. Appel, D., J. P. Karpel, and M. Sherman. 1989. Epinephrine improves
expiratory airflow rates in patients with asthma who do not respond
to inhaled metaproterenol sulfate. J. Allergy Clin. Immunol. 84:90-98.
79. Cydulka, R., R. Davison, L. Grammer, M. Parker, andJ. Mathews. 1990.
The use of epinephrine in the treatment of older adult asthmatics. Ann.
Emerg. Med. 17:322-326.
80. Amory, D. W., S. C. Burnham, and F. W. Cheney, Jr. 1975. Comparison
of the cardiopulmonary effects of subcutaneously administered epinephrine and terbutaline in patients with reversible airway obstruction. Chest 67:279-286.
81. Rosenfeld, C. R., M. D. Barton, and G. Meschia. 1972. Effects of epinephrine on distribution of blood flow in the pregnant ewe. Am. J. Obstet. Gynecol. 124:156-163.
82. Lawford, P., B. M. J. Jones, and J. S. Milledge. 1978. Comparison of
intravenous and nebulised salbutamol in initial treatment of severe
asthma. Sr. Med. J. 1:84.
83. Williams, S. J., S. J. Winner, and T. J. H. Clark. 1981. Comparison of
inhaled and intravenous terbutaline in acute severe asthma. Thorax
36:629-631.
84. Bloomfield, P., J. Carmichael, G. R. Petrie, N. P. Jewell, and G. K. Crompton. 1979. Comparison of salbutamol given intravenously and by intermittent positive-pressure breathing in life-threatening asthma. Sr.
Med. J. 1:848-850.
85. Salmeron, S., L. Brochard, H. Mal, A. Tenaillon, M. Henry-Amar, D. Renon, P. Duroux, and G. Simonneau. 1994. Nebulized versus intravenous albuterol in hypercapnic acute asthma: a multicenter, doubleblind, randomized study. Am. J. Respir. Crit. careMed. 149:1466-1470.
86. Kurland, G., J. Williams, and N. J. Lewiston. 1979. Fatal myocardial infarction during continuous infusion of intravenous isoproterenol during therapy of asthma. J. Allergy Clin. Immunol. 63:407-411.
87. Cheong, B., S. R. Reynolds, G. Rajan, and M. J. Ward. 1988. Intravenous beta-agonist in severe acute asthma. Sr. Med. J. 297:448-450.
88. Sears, M. R., D. R. Taylor, C. G. Print, D. C. Lake, Q. Li, E. M. Flannery,
D. M. Yates, M. K. Lucas, and G. P. Herbison. 1990. Regular inhaled
beta-agonist treatment in bronchial asthma. Lancet 336:1391-1396.
89. Spitzer, W.O., S. Suissa, P. Ernst, R.t. Horowitz, B. Habbick, D. Cockcroft, J. F. Boivin, M. McNutt, A. S. BUist, and A. S. Rebuck. 1992.
The use of beta-agonists and the risk of death and near death from
asthma. N. Engl. J. Mad. 326:501-506.
90. Taylor, D. R., M. R. Sears, G. P. Herbison, E. M. Flannery, C. G. Print,
D. C. Lake, D. M. Yates, M. K. Lukas, and Q. Li. 1993. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 48:134-138.
1314
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
91. Suissa, S., P. Ernst, J. F. Boivin, R. I. Horwitz, B. Habbick, D. Cockcroft, L. Blais, M. McNutt, A. S. Buist, and W. O. Spitzer. 1994. A cohort analysis of excess mortality in asthma and the use of inhaled betaagonists. Am. J. Respir. Crit. Care Med. 149:604-610.
92. Executive Committee of the American Academy of Allergy and Immunology. 1993. Position statement. Inhaled betaz-adrenergic agonists
in asthma. J. Allergy Clin. Immunol. 91:1234-1237.
93. Barnes, N. C. 1992. Effects of corticosteroids in acute severe asthma.
Thorax 47:582-583.
94. Townley, R. G., R. Reeb, T. Fitzgibbons, and R. L. Adolphson. 1970.
The effects of corticosteroids on the beta-adrenergic receptors in bronchial smooth muscle. J. Allergy 45:118.
95. Davis, C., and M. E Conolly. 1980. Tachyphylaxis to beta adrenergic
agonists in human bronchial smooth muscle: studies in vitro. Br. J.
Clin. Pharmacol. 10:417-423.
96. Benatar, S. R. 1986. Fatal asthma. N. Engl. J. Med. 314:423-429.
97. Rowe, B. H., J. L. Keller, and A. D. Oxman. 1992. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am.
J. Emerg. Med. 10:301-310.
98. McFadden, E. R., Jr. 1993. Dosages of corticosteroids in asthma. Am.
Rev. Respir. Dis. 147:1306-1310.
99. Haskell, R. J., B. M. Wong, and J. E. Hansen. 1983. A double-blind,
randomized clinical trial of methylprednisolone in status asthmaticus.
Arch. Intern. Med. 143:1324-1327.
100. Littenberg, B., and E. H. Gluck. 1986. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N. Engl. J. Med.
314:150-152.
101. Rodriguez-Roisin, R., E Ballester, J. Roca, A. Torres, and P. D. Wagner.
1989. Mechanisms of hypoxemia in patients with status asthmaticus
requiring mechanical ventilation. Am. Rev. Respir. Dis. 139:732-739.
102. Ferrer, A., J. Roca, P. D. Wagner, F. A. Lopez, and R. Rodriguez-Roisin.
1993. Airway obstruction and ventilation-perfusion relationships in acute
severe asthma. Am. Rev. Respir. Dis. 147:579-584.
103. West, J. B. 1977. Ventilation-perfusion relationships. Am. Rev. Respir.
Dis. 116:919-943.
104. Ballester, E, A. Reyes, J. Roca, R. Guitart, P. D. Wagner, and R.
Rodriguez-Roisin. 1989. Ventilation-perfusion mismatching in acute
severe asthma: effects of salbutamol and 100% oxygen. Thorax
44:258-267.
105. Gross, N. 1988. The use of anticholinergic agents in the treatment of
airways disease. Clin. Chest Med. 9:591-598.
106. Ward, M. J., P. H. Fentem, W. H. R. Smith, and D. Davies. 1981.lpratropium bromide in acute asthma. Br. Med. J. 282:598-600.
107. Fairshter, R. D., M. P. Habib, and A. F. Wilson. 1981. Inhaled atropine
sulfate in acute asthma. Respiration 42:263-272.
108. Karpel, J. P., D. Appel, D. Breidbart, and M. J. Fusco. 1986. A comparison of atropine sulfate and metaproterenol sulfate in the emergency
room treatment of asthma. Am. Rev. Respir. Dis. 133:727-729.
109. Rebuck, A. S., K. R. Chapman, R. Abboud, P. D. Pare, H. Kreisman,
N. Wolkove, and F. Vickerson. 1987. Nebulized anticholinergic and
sympathomimetic treatment of asthma and chronic airways disease
in the emergency room. Am. J. Med. 82:59-64.
110. Kelly, H. W., and S. Murphy. 1990. Should anticholinergics be used in
acute severe asthma? Ann. Pharmacother. 24:409-414.
111. Bryant, D. H., and P. Rogers. 1992. Effects of ipratropium bromide
nebulizer solution with and without preservatives in the treatment of
acute and stable asthma. Chest 102:742-747.
112. Bryant, D. H. 1985. Nebulised ipratropium bromide in the treatment of
acute asthma. Chest 88:24-29.
113. Rafferty, P., R. Beasley, and P. H. Howarth. 1986. Bronchoconstriction
induced by ipratropium bromide in asthma: relation to bromide ion.
Br. Med. J. 293:1538-1539.
114. Fitzgerald, J. M. 1994. A study of the efficacy and safety of nebulization
therapy combining ipratropium bromide 0.5 mg with salbutamol sulphate 3.0 mg versus salbutamol sulphate 3.0 mg alone in acute asthma.
Am. J. Respir. Crit. Care Med. 149:A190.
115. Gilman, M. J., L. Meyer, J. Carter, and C. Siovis. 1990. Comparison of
aerosolized glycopyrrolate and metaproterenol in acute asthma. Chest
98: 1095-1 098.
116. Rossing, T. H., C. H. Fanta, D. H. Goldstein, J. R. Snapper, and E. R.
McFadden, Jr. 1980. Emergency therapy of asthma: comparison of
the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am. Rev. Respir. Dis. 122:365-371.
117. Siegel, D., D. Sheppard, A. Gelb, and P. F. Weinberg. 1985. Aminophylline increases the toxicity but not the efficacy of an inhaled betaadrenergic agonist in the treatment of acute exacerbations of asthma.
Am. Rev. Respir. Dis. 132:283-286.
118. Murphy, D. G., M. F. McDermott, R. J. Rydman, E. P. Sloan, and R. J.
Zalenski. 1993. Aminophylline in the treatment of acute asthma when
beta two adrenergics and steroids are provided. Arch. Intern. Med.
153:1784-1788.
119. Josephson, G. W., H. L. Kennedy, E. J. MacKenzie, and G. Gibson. 1980.
VOL 151
1995
Cardiac dysrhythmias during the treatment of acute asthma: a comparison of two treatment regimens by double blind protocol. Chest
78:429-435.
..
120. Pierson, W. E., C. W. Bierman, S. J. Stamm, and P. P. VanArsdel, Jr.
1971. Double-blind trial of aminophylline in status asthmaticus. Pediatrics 48:642-646.
121. Huang, D., R. G. O'Brien, E Harman, L. Aull, S. Reents, J. Visser, G.
Shieh, and L. Hendeles. 1993. Does aminophylline benefit adults admitted to the hospital for an acute exacerbation of asthma? Ann. Intern. Med. 119:1155-1160.
122. Lalla, S., A. Saleh, J. Faroog, G. Lombardo, M. Gudi, and N. Anandarao.
1991. Intravenous aminophylline in acute, severe bronchial asthma.
Chest 100(Suppl.):60S.
123. Wrenn, K., C. M. Siovis, F. Murphy, and R. S. Greenberg. 1991. Aminophylline therapy for acute bronchospastic disease in the emergency
room. Ann. Intern. Med. 115:241-247.
124. Milgrom, H., and B. Bender. 1993. Current issues in the use of theophylline. Am. Rev. Respir. Dis. 147:S33-S39.
125. Persson, C. G. A. 1988. Xanthines as airway antiinflammatory drugs.
J. AllergyClin.lmmunol. 81:615-617.
126. Pauwels, R. A. 1989. New aspects of the therapeutic potential of theophylline in asthma. J. Allergy Clin. Immunol. 83:548-553.
127. Kelly, H. W., and S. Murphy. 1989. Should we stop using theophylline
for the treatment of the hospitalized patient with status asthmaticus.
D.I.C.P. 23:995-998.
128. Evans, W. V., R. D. H. Monie, J. Crimmins, and A. Seaton. 1980. Aminophylline, salbutamol, and combined intravenous infusions in acute
severe asthma. Br. J. Dis. Chest 74:385-389.
129. Milgrom, H. 1993. Theophylline. Immunol. Allergy Clin. North Am.
13:819-838.
130. Littenberg, B. 1988. Aminophylline in severe, acute asthma: a metaanalysis. J.A.M.A. 259:1678-1684.
131. Newhouse, M. T. 1990. Is theophylline obsolete? Chest 98:1-2.
132. McFadden, E. R.,1991. Methylxanthines in the treatment of asthma: the
rise, the fall, andthe possible rise again. Ann.lntem. Med. 115:323-324.
133. Weinberger, M., and L. Hendeles. 1983. Slow-release theophylline: rationale and basis for product selection. N. Engl. J. Med. 308:760-764.
134. Reynolds, R. J., J. G. Buford, and R. B. George. 1982. Treating asthma
and COPD in patients with heart disease. J. Respir..Dis. 3:41-51.
135. George, R. B. 1991. Preventing arrhythmias in acute asthma. J. Respir.
Dis. 12(6):545-561.
136. Skobeloff, EM., W. H. Spivey, R. M. McNamara, and L. Greenspon.
1989. Intravenous magnesium sulfate for the treatment of acute asthma
in the emergency department. J.A.M.A. 262:1210-1213.
137. Noppen, M., L. Vanmaele, N.lmpens, and W. Schandevyl. 1990. Bronchodilating effect of intravenous magnesium sulfate in acute severe
asthma. Chest 97:373-376.
138. Rolla, G., C. Bucca, E. Caria, W. Arossa, M. Bugiana, L. Cesano, and
A. Caropreso. 1986. Acute effect of intravenous magnesium sulfate
on airway obstruction of asthmatic patients. Ann. Allergy 61:388-391.
139. Okayama, H., T. Aikawa, M. Okayama, H. Sasaki, S. Mue, and T.
Takishima. 1987. Bronchodilating effect of intravenous magnesium
sulfate in bronchial asthma. J.A.M.A. 257:1076-1078.
140. Okayama, H., M. Okayama, T. Aikawa, M. Sasaki, and T. Takishima.
1991. Treatment of status asthmaticus with intravenous magnesium
sulfate. J. Asthma 28:11-17.
141. Okayama, H., T. Aikawa , M. Okayama, H. Sasaki, S. Mue, and T.
Takishima. 1987. Bronchodilating effect of intravenous magnesium
sulfate in bronchial asthma. J.A.M.A. 257:1076-1078.
142. Bloch, H., R. Silverman, N. Mancherje, P. Arsove, S. Grant, L. Jagminas,
and S. Scharf. 1992. Magnesium sulfate is a useful adjunct to standard therapy for acute severe asthma. Chest 102(Suppl.):83S.
143. Haury, V. G. 1940. Blood serum magnesium in bronchial asthma and
its treatment by the administration of maqneslum sulfate. J. Lab. Clin.
Med. 25:340-344.
144. Spivey, W. H., E M. Skobeloff, and R. M. Levin. 1990. Effect of magnesium chloride on rabbit bronchial smooth muscle, Ann. Emerg. Mad.
19:1107-1112.
145. Rolla, G., C. Bucca, M. Bugiani, W. Arossa, and S. Spinaci. 1987. Reduction of histamine-induced bronchoconstriction,by magnesium in asthmatic SUbjects. Allergy 42: 186-188.
146. Rolla, G., C. Bucca, W. Arossa, and M. Bugiani. 1987. Magnesium attenuates methacholine-induced bronchoconstriction in asthmatics.
Magnesium 6:201-204.
147. Molloy, D. W., S. Dhingra, F. Solven, A. Wilson, and D. S. McCarthy.
1984. Hypomagnesemia and respiratory muscle power. Am. Rev.
Respir. Dis. 129:497-498.
148. McNamara, R. M., W. H. Spivey, E M. Skobeloff, and S. Jacubowitz.
1989. Intravenous magnesium sulfate in the management of acute
respiratory failure complicating asthma. Ann. Emerg. Med. 2:197-199.
149. Sydow, M., T. A. Crozier, S. Zielmann, J. Radke, and H. Burchardi. 1993.
High-dose intravenous magnesium sulfate in the management of life-
State of the Art
threatening status asthmaticus. Intensive Care Med. 19:467-471.
150. Green, S. M., and S. G. Rothrock. 1992. Intravenous magnesium for
acute asthma: failure to decrease emergency treatment duration or
need for hospitalization. Ann. Emerg. Med. 21:260-265.
151. Tiffany, B. R., W. Berk, I. K. Todd, and S. White. 1993. Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest 104:831-834.
152. Skobeloff, E. M., W. H. Spivey, and R. M. McNamara. 1992. Estrogen
alters the response of bronchial smooth muscle (abstract). Ann. Emerg.
Med. 21:647.
153. Manthous, C. A., J. B. Hall, A Melmed, M. A. Caputo, J. Walter, J. M.
Klocksieben, G. A Schmidt, and L. D. H. Wood. 1995. Heliox improves
pulsus paradoxus and peak expiratory flow in nonintubated patients
with severe asthma. Am. J. Respir. Crit. Care Med. 151:310-314.
154. Gluck, E H., D.J. Onorato, and R. Castriotta. 1990. Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 98:693-698.
155. Berman, S. Z., D. A. Mathison, D. D. Stevenson, E. M. Tan, and J. H.
Vaughan. 1975. Transtracheal aspiration studies in asthmatic patients
in relapse with "infective" asthma and in subjects without respiratory
disease. J. Allergy C/in. Immuno/. 56:205-214.
156. Graham, V. A. L., G. K. Knowles, A F. Milton, and R. J. Davies. 1982.
Routine antibiotics in hospital management of acute asthma. Lancet
1:418-420.
157. Meduri, G. U., N. Abou-Shala, R. C. Fox, C. B. Jones. K. V. Leeper,
and R. G. Wunderink. 1991. Noninvasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Chest
100:445-454.
158. Shivaram, U., AM. Miro, M. E Cash, P. J. P. Finch, A E Heurich, and
S. L. Kamholz. 1993. Cardiopulmonary responses to continuous positive airway pressure in acute asthma. J. Crit. Care 8(2):87-92.
159. Martin, J. G., S. Shore, and L. A. Engel. 1982. Effect of continuous positive airway pressure on respiratory mechanics and pattern of breathing in induced asthma. Am. Rev. Respir. Dis. 126:812-817.
160. Mansel, J. K., S. W. Stogner, and J. R. Norman. 1989. Face-mask CPAP
and sodium bicarbonate infusion in acute, severe asthma and metabolic acidosis. Chest 96:943-944.
161. Wright, P. E, J. J. Marini, and G. R. Bernard. 1989. In vitro versus in
vivo comparison of endotracheal tube airflow resistance. Am. Rev.
Respir. Dis. 140:10-16.
162. Wheeler, A P. 1993. Sedation, analgesia, and paralysis in the intensive
care unit. Chest 104:566-577.
163. Corseen, G., J. Gutierrez, J. G. Reves, and F. C. Huber. 1972. Ketamine in the anaesthetic management of asthmatic patients. Anesth.
Ana/g. 51:588-596.
164. Huber, F. C., J. Gutierrez, and G. Corssen. 1972. Ketamine: its effect
on airways resistance in man. South Med. J. 65:1176-1180.
165. L'Hommedieu, C. S., and J. J. Arens. 1987. The use of ketamine for
the emergency intubation of patients with status asthmaticus. Ann.
Emerg. Med. 16:568-571.
166. Roy, T. M., V.l. Pruitt, P. A. Garner. and M. F. Heine. 1992. The potential role for anesthesia in status asthmaticus. J. Asthma 29:73-77.
167. Strube, P. J., and P.l. Hallam. 1986. Ketamine by continuous infusion
in status asthmaticus. Anaesthesia 41:1017-1019.
168. Sarma, V. J. 1992. Use of ketamine in acute severe asthma. Acta
Anaesthesio/. Scand. 36: 106-1 07.
169. Rock, M. J., S. Reyes de la Rocha, and E. T. L'Hommedieu. 1986. Use
of ketamine in asthmatic children to treat respiratory failure refractory
to conventional therapy. Crit. Care Med. 14:514-516.
170. White, P. F., W. I. Way, and A. J. Trevor. 1982. Ketamine-its pharmacology and therapeutic uses. Anesthesiology 56: 119-136.
171. Penrose, B. H. 1972. Aspiration pneumonitis following ketamine induction for general anesthetic. Anesth. Analg. 51:41-43.
172. Clarkson, K., C. K. Power, F. O'Connell, S. Pathmakanthan, and C. M.
Burke. 1993. A comparative evaluation of propofol and midazolam as
sedative agents in fiberoptic bronchoscopy. Chest 104:1029-1031.
173. Grounds, R. M., J. M. Lalor, J. Lumley, D. Royston, and M. Morgan.
1987. Propofol infusion for sedation in the intensive care unit: preliminary report. Br. Med. J. 294:397-400.
174. Pedersen, C. M. 1992. The effect of sedation with propofol on postoperative bronchoconstriction in patients with hyperreactive airways disease. Intensive Care Med. 18:45-46.
175. Byrne, A. J., P. M. Yeoman, and P. Mace. 1984. Accumulation otmidazolam in patients receiving mechanical ventilation. Br. Med. J. 289:1309.
176. Valente, J. F., G. L. Anderson, R. D. Branson, D. J. Johnson, K. Davis,
Jr., and D. T. Porembka. 1994. Disadvantages of prolonged propofol
sedation in the critical care unit. Crit. Care Med. 22:710-712.
177. Thomas, J. S., and N. O. Boheimer. 1991. An isolated grand mal seizure 5 days after propofol anesthesia. Anesthesia 46:508.
178. Rodgers, E. M. 1991. Diprivan intensive care sedation in children. Br.
J. Anaesth. 67:505.
1315
179. McManus, K. F. 1992. Convulsions after propofol. Anaesth. Intensive
Care 20:396-397.
180. Collier, C., and K. Kelly. 1991. Propofol and convulsions, the evidence
mounts. Anaesth. Intensive Care 19:573-575.
181. Gottardis, M., K. S. Khunl-Brady, W. Koller, G. Sigl, and J. M. Hackl.
1989. Effect of prolonged sedation with propofol on serum triglyceride and cholesterol concentrations. Br. J. Anaesth. 62:393-396.
182. Slutsky, A. S. 1993. Mechanical ventilation. Chest 104:1833-1859.
183. Hunter, J. M. 1987. Adverse effects of neuromuscular blocking drugs.
Br. J. Anaesth. 59:46-60.
184. Pollard, B. J. 1993. Which drug-steroid or benzylisoquinolinium? Intensive Care Med. 19:586-S90.
185. Douglass, J. A., D. Tuxen, M. Horne, C. D. Scheinkestel, M. Weinmann,
D. Czarny, and G. Bowes. 1992. Myopathy in severe asthma. Am. Rev.
Respir. Dis. 146:517-519.
186. Fluegel, W., C. Iber, S. Davies, and J. Leatherman. 1994. Risk factors
for acute myopathy in patients with severe asthma who require mechanical ventilation. Am. J. Respir. Crit. Care Med. 149:A432.
187. Griffin, D., N. Fairman, D. Coursin, L. Rawsthorne, and J. E. Grossman.
1992. Acute myopathy during treatment of status asthmaticus with
corticosteroids and steroidal muscle relaxants. Chest 102:510-514.
188. Kaplan, P., W. Rocha, D. Sanders, B. D'Souza, and A. Spock. 1986.
Acute steroid tetraplegia follOWing status asthmaticus. Pediatrics
78:121-123.
189. Tuxen, D. V., T. J. Williams, C. D. Scheinkestel, D. Czarny, and G. Bowes.
1992. Use of a measurement of pulmonary hyperinflation to control
the level of mechanical ventilation in patients with acute severe asthma.
Am. Rev. Respir. Dis. 146:1136-1142.
190. Tuxen, D. V., and S. Lane. 1987. The effects of ventilatory pattern on
hyperinflation. airway pressures, and circulation in mechanical ventilation of patients with severe air-flow obstruction. Am. Rev. Respir.
Dis. 136:872-879.
191. Scott, L. R.. M. S. Benson, and D. J. Pierson. 1986. Effect of inspiratory
flowrate and circuit compressible volume on auto-PEEP during mechanical ventilation. Respir. Care 31:1075-1079.
192. Leatherman, J. 1994. Life-threatening asthma. Clin. Chest Med. 15:
453-479.
193. Williams, T. J., D. V. Tuxen, C. D. Scheinkestel, D. Czarny, and G. Bowes.
1992. Risk factors for morbidity in mechanically ventilated patients
with acute severe asthma. Am. Rev. Respir. Dis. 146:607-615.
194. Leatherman, J. W., S. A Ravenscraft, C.lber, and S. Davies. 1993. Does
measured auto-PEEP accurately reflect the degree of dynamic hyperinflation during mechanical ventilation of status asthma? Am. Rev. Respir.
Dis. 147:877A.
195. Tuxen, D. V. 1989. Detrimental effects of positive end-expiratory pressure during controlled mechanical ventilation of patients with severe
airflow obstruction. Am. Rev. Respir. Dis. 140:5-9.
196. Braman, S. S., and J. T. Kaemmerlen. 1990. Intensive care of status
asthmaticus: a 10 year experience. J.A.M.A. 264:366-368.
197. Sackner, M. A, andC. S. Kim. 1987. Phasic flow mechanisms of mucus
clearance. Eur. J. Respir. Dis. 71:159-164.
198. Tuxen, D. V. 1994. Permissive hypercapnic ventilation. Am. J. Respir.
Crit. Care Med. 150:870-874.
199. Darioli, R., and C. Perret. 1984. Mechanical controlled hypoventilation
in status asthmaticus. Am. Rev. Respir. Dis. 129:385-387.
200. Menitove, S. M., and R. M. Goldring. 1983. Combined ventilator and
bicarbonate strategy in the management of status asthmaticus. Am.
J. Med. 93:898-901.
201. Cooper, D. J., J. B. Calles, C. D. Scheinkestel, and D. V. Tuxen. 1993.
Does bicarbonate improve cardiac or respiratory function during respiratory acidosis and acute severe asthma: a prospective randomized
study. Am. Rev. Respir. Dis. 147:614A.
202. Marini, J. J., J. S. Capps, and B. H. Culver. 1985. The inspiratory work
of breathing during assisted mechanical ventilation. Chest87:612-618.
203. Bellomo, R., P. McLaughlin, E. Tal, and G. Parkin. 1994. Asthma requiring mechanical ventilation: a low morbidity approach. Chest
105:891-896.
204. Scoggin, C. H., S. A Sahn, and T. L. Petty. 1977. Status asthmaticus:
a nine year experience. J.A.M.A. 238:1158-1162.
205. Luksza, A. R., P. Smith, J. Coakley, I. J. Gordan, and S. T. Atherton.
1986. Acute severe asthma treated by mechanical ventilation: a 10
years' experience from a district general hospital. Thorax 41:459-463.
206. Mansel, J. K., S. W. Stogner, M. F. Petrini, and J. R. Norman. 1990.
Mechanical ventilation in patients with acute severe asthma. Am. J.
Med. 89:42-48.
207. Saulnier, F. F., A. V. Durocher, R. A Deturck, M. C. Lefebvre, and F. E.
Wattell. 1990. Respiratory and hemodynamic effects of halothane in
status asthmaticus. Intensive Care Med. 16:104-107.
208. Echeverria, M., A. W. Gelb, H. R. Wexler, D. Ahmad, and P. Kenefick.
1986. Enflurane and halothane in status asthmaticus. Chest 89:
153-154.
1316
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
209. Hogman, M., C. G. Frostell, H. Hedenstrom, and G. Hedenstrierna. 1993.
Inhalation of nitric oxide modulates adult human bronchial tone. Am.
Rev. Respir. Dis. 148:1474-1478.
210. Hogg, J. C. 1984. The pathology of asthma. Clin. Chest Med. 5:567-571.
211. Falliers, C. J., W. P. McCann, H. Chai, E. F. Ellis, and N. Yazdi. 1966.
Controlled study of iodotherapy for childhood asthma. J. Allergy
38:183-192.
212. Wanner, A, and A. Rao. 1980. Clinical indication for and effects of bland,
mucolytic, and antimicrobial aerosols. Am. Rev. Respir. Dis. 122:79-87.
213. Helm, W. H., K. M. Barran, and S. C. Mukerjee. 1972. Bronchial lavage
in asthma and bronchitis. Ann. Allergy 30:518-523.
VOL 151
1995
214. Lang, D. M., R. A Simon, D. A Mathison, R. M. Timms, and D. D. Stevenson. 1991. Safety and possible efficacy of fiberoptic bronchoscopy
with lavage in the management of refractory asthma with mucous impaction. Ann. Allergy 67:324-330.
215. Rogers, R. M., J. F. Shuman, and A. B. Zubrow. 1973. Bronchoalveolar
lavage in bronchial asthma. Chest 63(Suppl.):62S-64S.
216. Smith, D. L., and R. D. Deshazo. 1993. Bronchoalveolar lavage in asthma.
Am. Rev. Respir. Dis. 148:523-532.
217. Millman, M., F. M. Millman, I. M. Goldstein, and A. J. Mercandetti. 1985.
Use of acetylcysteine in bronchial asthma: another look. Ann. Allergy
54:294-296.