Rapid-Onset Asthma Attack^*

Materials and Methods

Subjects and Design

This study includes data from a prospective cohort study performed at the ED of the Hospital Central de las FF.AA. in Montevideo, Uruguay. This department sees > 60,000 patients annually, with about 1,200 visits per year for adult patients with acute asthma. We studied all adult subjects with acute asthma who attended to the ED over a 1-year period. All patients met the diagnosis criteria of asthma of the American Thoracic Society.²³ The inclusion criteria were as follows: (1) age from 18 to 50 years; (2) FEV₁ and a peak expiratory flow (PEF) of < 50% of predicted value; (3) absence of history of chronic cough, and cardiac, hepatic, renal, or other medical disease, or pregnancy; and (4) an expressed willingness to participate in the study, with written informed consent obtained. The Hospital Ethics Committee approved the study.

Protocol

After initial assessment, all patients were treated with albuterol, four puffs at 10-min intervals (100 μg per actuation), delivered by a metered-dose inhaler and a spacer device (Volumatic; Allen & Hansburys; Greenford, UK). Each dose was followed by a deep inhalation from the spacer device. The protocol involved 3 h of this treatment (1,200 μg of albuterol every 30 min). After this time, all patients with a poor response received hydrocortisone, 500 mg IV. The protocol included the administration of O₂ if arterial oxygen saturation (Sao₂) decreased to < 92%. Aminophylline was excluded in all patients. The patients were independently assessed and treated by physicians, all of whom were unaware of the previous duration of attack and pulmonary function. All subjects completed the protocol. The decision to discharge or admit a patient to the hospital was made at the end of protocol by senior ED staff without knowledge of previous patient group allocation. Patients were discharged from the ED according to the following criteria: if accessory muscle use had abated, if wheezing was judged to be minimal or completely resolved, if dyspnea abated, and if FEV₁ or PEF was > 60% of predicted. The physicians prescribed oral prednisone, 60 mg for 7 days, for all discharged patients, or IV steroids for those who were admitted.

Measurements

Patients or relatives were asked about relevant aspects of asthma history and outpatient therapy. To determine the duration of onset of present attack, patients were asked to indicate the onset of wheeze, cough, shortness of breath, or some combination of these symptoms; also, a decline in the PEF, if available, was noted. When possible, the patient’s relatives were asked to confirm information regarding the duration of symptoms before ED presentation. Severe asthma attacks were classified in accord with Kolbe et al⁵ as an ROAA (< 6 h) or an SOAA (≥ 6 h). That definition was selected to distinguish from previous definitions of sudden-onset asthma attacks (respiratory arrest or failure within 11/2 h,⁸ or 3 h,³ after the onset of attack). The following variables were measured in each patient immediately before starting treatment, and at 30, 60, 90, 120, 150, and 180 min: FEV₁, PEF, respiratory rate, heart rate, accessory muscle use, dyspnea, wheezing, and Sao₂. PEF was measured with a mini-Wright peak flowmeter (Clement Clarke; Harlow, UK). The highest of three values was recorded. FEV₁ was measured using a Vitalograph Compact spirometer (Vitalograph; Maids Moreton House; Buckingham, UK). Three successive maximal expiratory curves were recorded at each assessment, and the highest value was selected, according to the criteria of the American Thoracic Society.²⁴ Heart rate was measured from continuous ECG. Sao₂ was measured with a finger oximeter (N-180 Pulse Oximeter; Nellcor; Hayward, CA). Accessory-muscle use was defined as visible retraction of the sternocleidomastoid muscles.²⁵ Dyspnea was defined as the patient’s own assessment of breathlessness. Wheezing was defined as musical or whistling breath sounds heard with a stethoscope during expiration. These clinical factors were graded in a scale from 0 to 3 in which 0 denoted absent, 1 denoted mild, 2 denoted moderate, and 3 denoted severe. Finally, a score for severity was produced for each patient using the National Asthma Education and Prevention Program (range 1 to 4; mild intermittent to severe persistent).²⁶

Statistical Methods

All data were analyzed with an SPSS 10.0 for Windows software package (SPSS; Chicago, IL). Changes in FEV₁ and PEF were evaluated using repeated-measures analysis of variance (ANOVA), with one between-subject factor (rapid-slow) and one within-subject factor (time). One-way repeated-measures ANOVA was used to compare baseline values for each variable, after assessing both normality of distributions and homoscedasticity. When the F value indicated significant differences among group means, post hoc pairwise multiple comparisons were performed using the Newman-Keuls test. Baseline data of the two treatments were compared by t test for normally distributed independent samples or the Mann-Whitney U test for nonnormally distributed continuous variables. χ² with Yates correction or Fisher’s Exact Test was used for categorical variables. Clinical factors graded on a scale of 0 to 3 were reported as medians and interquartile ranges. A p value of < 0.05 using a two-tailed test was taken as being of significance for all statistical tests. Mean values ± SD were calculated for continuous variables. Ninety-five percent confidence intervals (CIs) and relative risks were calculated with standard formulas.²⁷

Results

Four hundred three patients (mean age, 33.6 ± 11.0 years) with acute exacerbations of asthma were enrolled in the trial (Table 1 ). On the basis of previously determined criteria, only 41 patients (11.3%) were classified as having a ROAA (< 6 h). Rapid-onset asthma patients did not differ from slow-onset asthma patients with respect to age, weight, chronic asthma severity, season of presentation, heart and respiratory rates, wheezing, dyspnea, PEF, Sao₂, accessory muscle use, and previous use of β-agonists, steroids, and theophylline. On the contrary, the two groups differed with respect to sex: male patients comprised 53.6% of the ROAA group, but only 36.3% of the SOAA group (p = 0.03). The two groups presented differences with regard to trigger factor. In ROAA patients, the exacerbation was less likely to be attributed to respiratory tract infection (12.1% vs 38.1% for SOAA patients; p = 0.001), and more likely to have no identifiable cause (51.4% vs 19.1% for SOAA patients; p = 0.0001). There were no differences among other categories of triggers, including allergens (ingested food or medications), medication noncompliance, weather, and emotional or endocrine factors. Finally, ROAA patients had lower pulmonary function at presentation (FEV₁, 0.7 L vs 0.9 L for SOAA patients) (mean difference, − 0.13; 95% CI, − 0.22 L to − 0.04 L).

The relationship between the cumulative doses of albuterol and the change in PEF and FEV₁ were analyzed (Fig 1 , 2 ). Mean PEF improved significantly over baseline values for both groups (p < 0.001). The magnitude of improvements in PEFs over baseline values was significant at all times of treatment (p < 0.01). The two-way repeated-measures ANOVA showed a significant difference between groups (p = 0.03). At the end of treatment, ROAA patients had an overall 48.0 L/min (95% CI, 14.1 to 81.8 L/min) greater improvement in PEF than SOAA patients. The ANOVA suggested that the difference between groups increased with time (p = 0.0001). The mean percent of predicted PEF values at 180 min was 64.5 ± 19.3% (337.6 ± 102.9 L/min) in the ROAA group and 56.0 ± 17.2% (289.6 ± 95.1 L/min) in the SOAA group. The same pattern held for changes in FEV₁. The improvement over baseline was significant in both groups (p < 0.01). There was a significant difference between both groups (p = 0.02). Compared with the SOAA group, the ROAA group had better FEV₁ at 180 min (mean difference, 0.31 L; 95% CI, 0.08 to 0.54 L). The mean percent of predicted FEV₁ values at 180 min was 53.3 ± 19.2% (1.67 ± 0.69 L) in the SOAA group and 61.0 ± 22.0% (1.98 ± 0.79 L) in the ROAA group. Also, the difference between groups increased with time (p = 0.001).

At the end of protocol (3 h), ROAA patients demonstrated less accessory muscle use (median ± interquartile range, 0.0 ± 1.0 vs 0.5 ± 1.0 for SOAA patients; p < 0.05) and a higher Sao₂ (1.91%; 95% CI, 0.61 to 3.22%). At the end of treatment, 4.9% of patients (2 of 39) in the ROAA group and 19.1% of patients (69 of 293) in the SOAA group were admitted to the hospital (p = 0.04). SOAA patients showed an increased risk of hospital admission (relative risk, 3.89; 95% CI, 1.01 to 15.0). On the contrary, there was no difference between groups in heart rate (mean difference, 0.3 beats/min; 95% CI, − 5.7 to 6.3 beats/min). Despite continuous ECG recording, there were no signs of arrhythmia in either group.

Discussion

The purpose of this study was to determine the frequency of ROAAs and SOAAs in adult patients with acute, severe asthma who presented to an ED, and to establish whether ROAA patients differ from SOAA patients in terms of clinical and spirometric characteristics. Data from this prospective cohort study showed that the prevalence of ROAAs was 11.3%. Men comprised 53.6% of the ROAA patients but only 36.4% of the SOAA patients. Upper respiratory tract infection was reported as the trigger more commonly in SOAA patients, and ROAA patients were more likely to have an unidentifiable trigger. We found no evidence that sensitivity to specific aeroallergens or ingested substances or environmental factors predisposes patients to ROAAs. Finally, at presentation, ROAA patients had lower pulmonary function measurements.

These findings were in concurrence with Kolbe and coworkers,⁵ who performed a cross-sectional study on 316 patients aged 15 to 49 years who were admitted to the hospital with acute, severe asthma and found that only 8.5% were classified as having rapid-onset asthma (< 6-h duration), again with a preponderance of male patients. Patients were interviewed within 24 to 48 h of hospital admission to determine the duration of attack. Similarly, Woodruff et al,⁶ in a retrospective cohort study of 225 patients with severe (PEF of ≤ 40% of predicted) acute asthma (18 to 64 years old) who were seen in an ED, reported 17% of patients as having “sudden onset” asthma (≤ 3 h). These patients with sudden-onset asthma were less likely to have reported an upper respiratory tract infection and, as in our study, were more likely to have no unidentifiable trigger. No PEF baseline data were included. Recently, Barr et al,²⁸ in a large, multicenter, prospective study of patients with severe, acute asthma (PEF < 50%), found a rate of ROAA occurrence of 14%. ROAA patients were more likely to be triggered by respiratory allergens, exercise, and psychosocial stress, and less likely to be triggered by upper respiratory infections. In addition, these patients demonstrate greater improvement with therapy. Unlike our study, treatment of patients was managed at the discretion of treating physicians.

ROAA occurrence rates differ widely among studies. Arnold and colleagues,² in a prospective study of patients with acute asthma admitted to the hospital, estimated that in 46% of cases the speed of onset was < 24 h and in 13% of cases it was < 1 h. The duration of attack was determined from clinical history. This study also reported an association between age and duration of attack: rapid-onset attacks occurred more frequently in younger patients. Our study did not find a similar association with age.

Our trial sample presented the typical features of adult patients with severe asthma who presented for care to an ED without life-threatening exacerbations. On the contrary, most studies^{3561112131415161718192021222930} regarding the speed of onset of acute severe asthma include selected retrospective reports of patients free of asthma symptoms who develop acute severe asthma and respiratory arrest or failure (sudden-onset asthma attacks/sudden-asphyxic asthma/near-fatal asthma), sometimes with fatal consequences (sudden-onset fatal asthma). Wasserfallen et al³ studied 34 patients intubated for acute asthma and found that 29.4% of patients had “rapid decompensation.” However, the duration of attack was established by “a history of extremely rapid deterioration, out of a clear blue sky” leading to intubation and mechanical ventilation within 3 h after the onset of the first symptoms. These authors concluded that sudden-onset asthma was more frequent in young men and was characterized by more severe acidosis and hypercapnia.

Likewise, Kallenbach et al³¹ studied 81 patients with acute severe asthma in whom mechanical ventilation was required, and concluded that a “hyperacute” attack duration (< 3 h from onset of attack to intubation) was associated with an increased risk of near fatality. Martin and coworkers²⁹ examined 30 cases of near-fatal asthma attacks in children < 15 years old and found a low prevalence of rapid-onset attacks (17%). As in our study, the information was obtained from a standardized interview and questionnaire that was completed with subjects/parents.

The third objective of our study was to determine whether ROAA patients differ from SOAA patients in terms of response to treatment. In accord with previous work,³⁰ our data suggest that 400 μg (four puffs) of albuterol at 10-min intervals delivered with a metered-dose inhaler and a spacer device is an effective treatment that produces a dose-related bronchodilator response in patients with acute severe asthma. However, we found two different therapeutic responses to treatment patterns: ROAA patients have rapid deterioration followed by a more rapid response to treatment and a lower hospital admission rate than SOAA patients. Similarly, other studies have found a positive correlation between the duration of attack and the duration of the required mechanical ventilation³⁴⁸³¹: SOAA patients required more-prolonged mechanical ventilation than that observed in ROAA patients.

Conclusion

Data from this study support the notion that ROAAs constitute a distinct but uncommon acute asthma presentation, with predominance of male patients. Upper respiratory tract infection was not believed to be a trigger in these patients. The SOAA group was more likely to have an upper respiratory tract infection, to respond less to ED treatment, and to require hospitalization. Thus, we have identified a subgroup of patients who appear to have common characteristics with sudden-onset near-fatal/fatal asthma patients.