Risk Factors for Near-fatal Asthma

A Case–Control Study in Hospitalized Patients with Asthma

MARK O. TURNER, KUKU NOERTJOJO, SVERRE VEDAL, TONY BAI, SUSAN CRUMP,
and J. MARK FITZGERALD
Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

We prospectively recruited patients admitted to the hospital with severe asthma to comprehensively
evaluate the association of historical and physiologic features with the risk of near-fatal asthma
(NFA). A case–control study design was used. All patients admitted with NFA (cases) were identified
prospectively and compared with asthma patients admitted during the same period without respira-
tory failure (controls). Nineteen cases (age: 40.2 6 12.0 yr) (mean 6 SD) and 80 controls (age: 36 6
13.5 yr) were enrolled. Duration of asthma, gender, smoking status, ethnicity, and prevalence of
atopy were similar in the case and control groups. More than 80% of patients in both groups re-
ported worsening symptoms for more than 48 h before admission, and more than 50% were worse
for longer than 7 d. There was no difference in degree of airways obstruction or bronchial hyperre-
sponsiveness (PC20). Perception of dyspnea was similar in the cases and controls, but among cases
the males had greater impairment than the females (Borg score: 1.9 6 1.4 versus 3.9 6 1.2: p 5
0.05). Univariate analysis identified a history of previous mechanical ventilation (OR: 27.5; 95% CI:
6.60 to 113.7), admission to the intensive care unit (ICU) (OR: 9.9; 95% CI: 3.0 to 32.9), history of
worse asthma during January and February (OR: 3.5; 95% CI: 1.0 to 11.8), and use of air-conditioning
(OR: 15.0; 95% CI: 1.3 to 166) as risk factors for NFA. Of concern was the dependence of most pa-
tients (59.8%) on the emergency department (ED) for initial care, and the small number of cases
(16%) in which patients visited a physician before admission to the hospital. We have confirmed risk
factors identified previously in retrospective studies of fatal and NFA, and have also shown that hos-
pitalized patients with asthma, irrespective of severity of their asthma, share several characteristics,
especially in terms of their failure to respond to worsening asthma. Turner MO, Noertjojo K, Vedal
S, Bai T, Crump S, FitzGerald JM. Risk factors for near-fatal asthma: a case–control study in
hospitalized patients with asthma. AM J RESPIR CRIT CARE MED 1998;157:1804–1809.

There has been concern in recent years regarding rising rates
of asthma morbidity and mortality (1–3). The reasons for this
are unclear. Case–control studies using retrospectively col-
lected data have suggested that excess use of short-acting b-ago-
nists (4, 5) and underuse of inhaled corticosteroids (6) may be
associated with this phenomenon, although more recent data
suggest that patterns of b-agonist use may be a marker of
more severe asthma rather than a causal factor (6). Recently,
near-fatal asthma (NFA) has been used as a surrogate marker
of patients at risk of fatal asthma (5–8). Because of retrospec-
tive data collection from chart review in previous studies, the
types and numbers of risk factors that could be evaluated were
limited. We prospectively enrolled asthma patients admitted
to our hospital to more comprehensively assess risk factors for
severe life-threatening asthma. We used hospitalized patients
with asthma as a control group, to better evaluate possible risk
factors for NFA rather than merely risk factors for hospital-
(Received in original form August 21, 1997 and in revised form February 6, 1998)
Presented in part at the American Thoracic Society Meeting; May 1993, Boston, MA.
Correspondence and requests for reprints should be addressed to Dr. J. Mark
FitzGerald, Respiratory Clinic, Vancouver General Hospital, 2775 Heather St.,
Vancouver, BC V5Z 3J5, Canada. E-mail: markf@unixg.ubc.ca
Am J Respir Crit Care Med Vol 157. pp 1804–1809, 1998
Internet address: www.atsjournals.org
ization for severe asthma. The primary risk factors for NFA to
be evaluated in this study were: (1) relative overuse of b-ago-
nists; (2) relative underuse of inhaled corticosteroids; (3) a
prior history of mechanical ventilation; and (4) poor percep-
tion of bronchoconstriction. Our a priori hypotheses included
the following: (1) NFA patients were more likely to be taking
lower doses of inhaled corticosteroids and using more b-ago-
nists; (2) a prior history of NFA would be a strong predictor of
a current episode of respiratory failure; (3) NFA patients
would more likely be atopic; and (4) NFA patients would be
more likely to have impaired perception of dyspnea. We also
evaluated patient responses to deteriorating asthma.
METHODS
We prospectively identified all patients admitted to the Vancouver
General Hospital with a primary diagnosis of acute asthma, as well as
patients admitted to St. Paul’s Hospital with NFA for 19 mo from 1991
to 1993. Patients requiring mechanical ventilation or with a PaCO2 >
45 mm Hg met our a priori case definition for respiratory failure, and
were classified as subjects with NFA. Patients between the ages of 18
and 55 yr who had a confirmed diagnosis of asthma were eligible.
Clinical and demographic data were obtained through the use of
structured questionnaires during a personal interview. The epidemio-
logic data were obtained from responses to the European Health Sur-
Turner, Noertjojo, Vedal, et al.: Risk Factors for Near-fatal Asthma 1805

TABLE 1 TABLE 3
CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF PULMONARY FUNCTION TESTS AND BRONCHIAL
STUDY PARTICIPANTS HYPERRESPONSIVENESS (MEAN 6 SD)

Cases (n 5 19) Controls (n 5 80) Cases Controls

Age, yr 40.2 6 12.0 36.0 6 13.5 Initial:

Gender FEV1: n 8 51
Male, % 8 (42.1) 26 (32.5) Absolute, L 0.89 6 0.32 0.99 6 0.32
Female, % 11 (57.9) 54 (67.5) % Predicted 27.5 6 12.7 30.3 6 9.8
Race: Caucasian, % 7 (36.8) 46 (57.5) PEF: n 8 73
Smoking status, % Absolute, L/min 144 6 108 148 6 64
Nonsmokers 5 (26.3) 29 (36.3) % Predicted 29.0 6 20.8 32.7 6 14.7
Ex-smokers 7 (36.8) 27 (33.8) Before discharge:
Current smokers 7 (36.8) 24 (30.0) FEV1: n 14 39
Cigarette smoking, pack-yr 12.1 6 14.9 8.8 6 14.7 Absoute, L 1.86 6 0.80 2.36 6 0.87
Occupational status: employed, % 13 (68.4) 64 (80.0) % Predicted 59.3 6 18.0 66.6 6 22.7
Duration of asthma, yr 15.0 6 11.4 14.3 6 12.4 PEF: n 15 65
Atopy, % 15 (83.3) 52 (68.4) Absoute, L/min 353 6 106 346 6 108
History of severe asthma % Predicted 73.0 6 25.0 86.7 6 62.7
ER visits, %* 8 (42.1) 46 (59.0) Methacholine inhalation test: n 10 44
Hospital admissions, %* 9 (47.4) 22 (27.8) PC20, mg/ml, geometric mean 0.20 6 2.97 0.54 6 6.97
ICU admissions, %† 12 (63.2) 14 (17.5) Timing of PC20 after discharge, wk 6.2 6 3.8 5.4 6 3.8
Mechanical ventilation, %† 11 (57.9) 7 (8.8)

* During the year before the study event.

†
p , 0.05. dose of MCh, subjects were asked to rate their sensation of dyspnea at
each MCh dose, using the modified Borg scale (11), a validated instru-
ment for assessing perception of dyspnea. Skin-prick tests were done
with a panel of common allergens (Bencard Ltd.). A positive result
vey Questionnaire (9). Data obtained included duration of asthma, was defined as a reaction of > 3 mm to one or more allergens. All pa-
previous history of NFA, duration of the current attack, and pre- tients gave written consent to participate in the study, and the study
scribed therapy. Compliance with prescribed therapy was assessed by protocol was approved by the University of British Columbia and the
a question about whether the patient was taking his or her prescribed relevant hospital ethics committees.
medications. We recorded smoking status and occupational history,
and precipitating factors for the current asthma attack. Arterial blood-
gas measurements, chest radiography results, and electrocardiography Statistical Analysis
results at the time of arrival in the emergency department (ED) were Subjects were grouped and analyzed as those who were mechanically
recorded from admission hospital records. If the patient was already ventilated or had a PaCO2 > 45 mm Hg (NFA cases) and those who
endotracheally intubated, the first available arterial-blood-gas measure- were hospitalized with severe asthma without ventilatory failure (con-
ment was used. The results of lung-function testing performed in the trols). Patients were only enrolled once during the study period. Data
recovery phase of hospitalization were recorded, and patients were of- was analyzed using SPSS statistical software (SPSS Inc., Chicago, IL).
fered the opportunity to return for a methacholine (MCh) inhalation Clinical characteristics of cases and controls were compared through
challenge test after discharge. MCh testing was done with standard Student’s t test for continuous variables, and proportions were com-
methodology (10). In addition to measuring FEV1, after each doubling pared with chi-square tests. Where appropriate, we applied Bonfer-
roni’s correction for multiple comparisons. Risk factors for NFA were
evaluated by logistic regression in univariate and multivariate analy-
TABLE 2 ses. NFA was the dependent variable, and a stepwise model was used
to assess clinically relevant and statistically significant variables identi-
CLINICAL SIGNS, CHEST RADIOGRAPHY FINDINGS,
fied in the univariate analyses. We did not include a history of previ-
ARTERIAL-BLOOD-GAS MEASUREMENTS, AND
ous ICU admission or mechanical ventilation in the same multivariate
MEDICATION USE BY STUDY PARTICIPANTS
models because of collinearity. All data are expressed as mean and
Cases (n 5 19) Controls (n 5 80) SD unless otherwise specified. Statistical tests were two sided, and sig-
nificance was accepted at p , 0.05.
Heart rate, beats/min* 124 6 22 103 6 17
Respiratory rate, breaths/min 26 6 16 25 6 4
Accessory muscle use, n (%) 8/9 (88.9) 34/57 (59.6)
Chest radiographs, % n 5 18 n 5 65
Normal 1 (5.6) 26 (40.0)
Hyperinflated† 12 (66.7) 16 (24.6)
Atelectasis 0 (0.0) 1 (1.5)
Pneumothorax 0 (0.0) 3 (4.6)
Infiltrates/pneumonia 2 (11.1) 6 (9.2)
Others 3 (16.7) 13 (20.0)
Arterial blood gases
pH, range* 7.24 (6.92–7.43) 7.38 (7.35–7.62)
PaCO2, mm Hg (range)* 70.1 (47–127) 35.5 (15–44)
Medication use, n (%)
b2 agonists 19 (100) 75 (94)
Inhaled steroids 16 (89) 57 (72)
Compliant‡ 4 (29) 15 (28)
Prednisone 7 (37) 20 (25)
Ipratropium 3 (16) 14 (17)

* p , 0.05.
†
p , 0.001. Figure 1. Duration of symptoms among cases and controls during
‡
Assessed by interview with patient. the period prior to hospitalization.
1806 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Figure 2. Mean daily dose of inhaled b-agonists prescribed, dose usually taken, dose typically taken dur-
ing asthma exacerbations, and dose taken for the 24 h prior to the study hospital admission. SEM 5 stan-
dard error of the mean; mcg 5 micrograms.
RESULTS
We enrolled 99 patients during the study period, 80 in the con-
trol group and 19 cases of NFA. Ten patients with NFA were
mechanically ventilated. There were no deaths, although one
patient with NFA suffered hypoxic brain injury. There were
no significant differences in the case and control groups with
respect to demographic variables, smoking status, duration of
asthma, or presence of atopy (Table 1). Cases were more
likely than controls to have had prior ICU admissions and
prior mechanical ventilation (p , 0.001).
Clinical characteristics, chest-radiographic findings, arte-
rial-blood-gas measurements, and medication use by the study
subjects are presented in Table 2. Inhaled b-agonists were
used by 95% (76 of 80) of controls and by all cases before ad-
mission. Salbutamol was used by 95% (72 of 76) of controls
and by 90% (17 of 19) of cases. Fenoterol was used by only
three patients (two controls and one case). Cases were more
likely than controls to be prescribed prednisone at the time of
admission and to have had prescriptions for theophylline
(53% of cases versus 27% controls, p , 0.05). Oral corticoste-
roids had been used more frequently in the past by cases
(95%, versus 71% of controls, p , 0.05). Of patients who had
used oral corticosteroids previously, 22% had had one treat-
ment course, 24% had had between two and four courses, and
54% had been treated five or more times.
There was a significantly greater prevalence of hyperinfla-
tion on the chest radiograph for NFA patients. Spirometry
done at admission and before hospital discharge, and follow-
up PC20 MCh results, are shown in Table 3. Although the PC20
for MCh did not differ for cases and controls, there was a sig-
nificant difference for perception of dyspnea between male
VOL 157 1998
and female cases (p , 0.05). Male cases had less perception of
dyspnea (Borg score: 1.9 6 1.4 at PC20, compared to 3.9 6 1.2)
than did female cases. However, there was no overall gender
difference between cases and controls in perception of dyspnea.
Duration of symptoms before hospital admission is shown
in Figure 1. The majority of subjects had worsening asthma
symptoms for more than 48 h (85% of cases and 82% of con-
trols), and more than 50% of subjects in each group had wors-
ening asthma for longer than 7 d. There was no difference in
the occurrence of specific symptoms such as cough, wheezing,
and chest tightness. Control subjects were more likely to re-
port a sensation of a sour taste in the mouth at night (p 5
0.05). Less than one third (31%) of all patients had a history of
hospital admission within the year before the study admission,
although 57% had been to the ED with acute asthma at least
once; 21% of patients had made three or more ED visits.
Subjects’ Responses to Worsening Asthma
Only 43% of patients contacted either the family physician
(n 5 40) or the ED for advice about worsening asthma (n 5
3); 39 subsequently visited their family physician, and one at-
tended an allergist. Control patients were more likely to visit
their physicians before eventually being admitted to the hospi-
tal (46% versus 16% of cases; p 5 0.02). The first contact with
the health-care system was the ED for 60% of patients.
All patients who had had physician contact before hospital
admissions were asked to recall the advice and instructions
given to them. Ten patients (nine controls and one case) were
advised to increase their bronchodilator use. Only 11 subjects
(all controls) were instructed to increase their use of inhaled
corticosteroids. Nine controls and one NFA case had a peak
Turner, Noertjojo, Vedal, et al.: Risk Factors for Near-fatal Asthma 1807

Figure 3. Mean daily dose of inhaled corticosteroids prescribed, dose usually taken, dose typically taken
during asthma exacerbations, and dose taken in the 2 wk prior to the study hospital admission. SEM 5
standard error of the mean; mcg 5 micrograms.

flow meter at home, but none was asked to make a measure- DISCUSSION
ment with it. One patient in the control group was instructed
The design of this case–control study of hospitalized asthma
to call an ambulance, and of the 13 patients instructed to go to
patients allowed us to more accurately identify risk factors for
the ED, 12 were controls.
NFA, and to do so in a more standardized way than has previ-
The usual daily dose of b-agonist and inhaled corticosteroids,
ously been possible. Our findings confirmed results in previ-
and the patient responses to exacerbations, are shown in Fig-
ous studies (12, 13) that identified a history of prior mechani-
ures 2 and 3. Controls used larger doses of b-agonists in the
cal ventilation and ICU admissions for severe asthma as
24 h before admission (p 5 0.040), Figure 2. There was a trend
strong predictors for NFA. These data emphasize the impor-
for cases to use less inhaled corticosteroid, but this was not
tance of history taking to assess asthma severity, and of risk
statistically significant.
stratification to aggressively manage patients at risk for NFA.
Prescriptions for oral corticosteroids and theophylline were
Electrocardiography Results
more common for NFA patients in our study. This is not sur-
There were no life-threatening arrhythmias at the time of pre- prising, since these medications are likely markers for more
sentation. The most common electrocardiographic pattern was severe asthma (5, 14). We found that most patients had evi-
sinus tachycardia. dence of worsening asthma over a period of 2 to 7 d before
hospitalization, rather than sudden rapid deteriorations. There-
Multivariate Analyses
Multivariate analysis showed significant differences between
groups (Table 4). The magnitude varied somewhat, depending
upon the variables included in each model. A history of ICU
admission, previous mechanical ventilation (OR: 99.2; 95% TABLE 4
CI: 8.7 to `) and having air conditioning at home were signifi- MULTIVARIABLE LOGISTIC-REGRESSION ANALYSIS
cant risk factors. A history of prescriptions for prednisone or Model OR 95% CI p Value
theophylline and a history of asthma being worse in January
and February were associated with increased risk in the Ever been prescribed theophylline versus none 4.7 0.8–24.9 0.07
Age > 40 yr old versus , 40 years old 3.6 0.7–19.7 0.13
univariate analysis, but in the multivariate analysis only prior Ex-smokers versus non-smokers 0.6 0.0–8.1 0.60
prescription for theophylline was significant (OR: 11.3; 95% Current smokers versus non-smokers 3.3 0.5–24.8 0.24
CI: 1.1 to 116 in the model with a history of mechanical venti- Ever been admitted to ICU versus no 19.3 3.5–105.7 , 0.001
lation only). The compliance data and medication doses for in- Asthma attack in January or February versus
haled b-agonists and inhaled corticosteroids were not signifi- other months 1.9 0.4–8.6 0.41
cant in either univariate or multivariate analyses. Having air conditioning at home versus none 18.8 1.4–256.7 0.03
1808 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
fore, for most asthma patients who are hospitalized, there is a
window of opportunity to implement more aggressive therapy
and follow-up with the objective of preventing progression to
fatal or near-fatal events.
A potential criticism of any study such as this is always the
selection of a control group. We selected hospitalized patients
with asthma as the control group, to isolate the variables of in-
terest: risk factors for NFA in severely asthmatic individuals.
A control group of community asthma patients could have
been another option. Because most of these patients would
have mild asthma, and would never have been hospitalized,
using a community control group would probably increase the
observed magnitude of association for NFA risk factors. How-
ever, the ability to discern between risk factors for NFA and
simple hospitalization for severe asthma would be possible
only with a three-way comparison between groups. The signif-
icant historical and clinical characteristics that we identified
with this study design also allow for their practical application
when assessing risks for asthmatic patients in the ED. The
prospective accrual of patients was advantageous for standard-
izing data collection and minimizing dependence on data ex-
traction from chart review. The reliability of the information
obtained from both cases (15) and controls is also improved,
and allowed us to better determine the individual responses to
a severe attack.
Although 89% of the cases were prescribed inhaled corti-
costeroids, the compliance with therapy with these medica-
tions was poor (29%), and was almost identical to that in the
control group (28%). Cases were more likely to be prescribed
higher doses of b-agonists and lower doses of inhaled cortico-
steroids than the controls (Figures 2 and 3). Several case–con-
trol studies have implied (4–6, 16) that excessive use of b-ago-
nists is associated with NFA and asthma deaths, especially in
the absence of inhaled corticosteroids (6). This risk appeared
especially to be associated with a rapid increase in b-agonist
use (16). Our findings do not support this hypothesis, but
show that increasing use of b-agonists reflects increasing se-
verity of asthma in the period prior to presentation with NFA.
The final common pathway leading to death in patients
with asthma has been uncertain. Several studies have reported
an association between the use of inhaled b-agonists and
asthma deaths (4, 16). It was hypothesized that administration
of high doses of b-agonists was associated with cardiotoxicity
and hypokalemia, causing a predisposition to malignant car-
diac arrhythmias (17). We confirm and extend Molfino’s ob-
servations in his retrospective study (18) by showing no seri-
ous arrhythmias in patients admitted through the ED with
NFA, and in particular, none in those requiring intubation.
Molfino and colleagues studied relatively few patients, and
there was no control group of severe asthma patients without
respiratory failure. Our data reinforce and emphasize that
asthma patients die of hypoxic respiratory failure. Therapy for
acute severe asthma should focus on using supplemental oxy-
gen, with aggressive bronchodilation with b-agonists and early
administration of corticosteroids (19).
Atopy is a risk factor for more severe asthma (20). In a re-
port from the midwest of the United States, sensitization to
the aeroallergen Alternaria alternata (21) was associated with
respiratory failure in asthma. We found no difference in be-
tween our cases and controls in the degree of atopy. This lack
of difference was consistent even when we examined absolute
wheal size (data not shown).
Home exposure to air conditioning was a strong risk factor
for NFA. This, to our knowledge, is the first time that such ex-
posure has been identified as a risk factor. However, these
data should be interpreted with caution, given the small num-
VOL 157 1998
ber of subjects in our study. The observed association may be
directly related to air conditioning or may be an indirect result
of increased exposure to aeroallergens because air-conditioned
homes are better sealed and insulated. A recent report from
Bavaria showed that children in homes with wood-burning and
coal stoves were less likely to be atopic than were children in
homes using other heating sources, such as forced air (22). Cases
in our study were more likely to report their asthma to be worse
in the months of January and February. This finding also sug-
gests that indoor exposures may contribute to poorer asthma
control and to episodes of NFA. Patients with NFA reported
more exposure to dusty conditions (data not shown), which again
supports environmental exposures as important risk factors for
NFA.
Our findings suggest a gender difference between male and
female NFA cases in perceiving dyspnea. Although our num-
bers are small, this observation is supported by other work
suggesting that males may be at greater risk because of precip-
itous declines in lung function (23). In a recent ED study, we
showed that males are more likely to have severe airflow ob-
struction than are females at the time of presentation (FEV1
% predicted: 49 6 20% [mean 6 SD] in females, versus 33 6
15% in males; p , 0.001) (24). Kikuchi and colleagues (25)
have identified differences in perception among NFA pa-
tients, non-NFA patients, and controls, but they did not report
a gender difference. These observations have important impli-
cations for developing strategies to prevent deaths from acute
asthma.
The overall reliance on crisis management in the ED for
NFA patients (59.8% of patients in the present study), and the
lack of specialist involvement in the outpatient care of these
patients, are important features to emphasize. Controls showed
a greater trend toward increased doses of medication than did
cases in response to worsening asthma. However, the general
lack of self-management skills in our patients, combined with
suboptimal medical advice, is consistent with other reports
(26, 27) that patients are not confident about changing therapy
when asthma control deteriorates. Ideally, asthma education
should address these needs and encourage a greater partner-
ship of patients with their primary care physicians (28, 29).
Unfortunately, we had little success in trying to educate the
NFA patients identified in this study (30), and these results
also highlight the need to develop new strategies capable of
changing behavior (31).
A retrospective study in France has shown reduced survival
in asthma patients with an NFA episode who were older than
40 yr of age, and also an independent association of NFA with
smoking (32). Only 10 (52.6%) of our NFA patients were
older than 40 yr, which may account for our inability to show
age-related risk for this group. We also found a relatively high
proportion of smokers in both of our study groups. Of interest
in this regard is a recent report suggesting that current smok-
ing may reduce the efficacy of inhaled corticosteroids in asth-
matic individuals (33).
Not surprisingly, patients in our study who had more se-
vere asthma (NFA cases) were more likely to show hyperin-
flation on their chest radiographs. It has been hypothesized
that hyperinflation, as measured by increased lung volumes
during the recovery phase, may be a marker for life-threaten-
ing asthma (1). However, these data await confirmation by
prospective studies designed to test this hypothesis. The many
clinical similarities between hospitalized patients and those
who have had an episode of NFA confirms our experience in
imaging the airways of these patients. We found no difference
in airway caliber among patients with severe asthma and those
with NFA, but when compared with nonhospitalized commu-
Turner, Noertjojo, Vedal, et al.: Risk Factors for Near-fatal Asthma
nity-control asthmatic individuals (34), the airway caliber of
NFA patients did differ.
In summary, our findings confirm and extend previous ob-
servations of the characteristics of patients with NFA. A his-
tory of mechanical ventilation or ICU admission for acute
asthma is a strong risk factor for NFA. Patients with NFA do
not present with life-threatening cardiac arrhythmias. We
have shown that males with NFA, when compared with fe-
male cases, have a reduced perception of dyspnea. Although a
number of guidelines designed to improve the management of
asthma patients (35) have been published, there remains the
challenge of implementing them (36) in high-risk patients, and
especially of overcoming patient and physician barriers (28) to
effective asthma education. Our findings clearly identify a fail-
ure of patients to respond to worsening asthma as a potential
area for major physician and patient intervention.
Acknowledgment : The writers would like to acknowledge the funding sup-
port of Glaxo Wellcome. The data collection and analysis were done com-
pletely independently.
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