(Chest. 2002;121:1806-1811.)
© 2002
American College of Chest Physicians
Airway Dehydration*
A Therapeutic Target in Asthma?
Edward Moloney, MB;
Siobhan O’Sullivan, PhD;
Thomas Hogan, MD;
Leonard W. Poulter, DSc and
Conor M. Burke, MD, FCCP
* From the Departments of Respiratory Medicine (Mr. Moloney and Drs. O’Sullivan and Burke) and Anaesthesiology (Dr. Hogan), James Connolly Memorial Hospital, Dublin, Ireland; and the Department of Immunology, Royal Free Hospital School of Medicine (Dr. Poulter), London, UK.
Correspondence to: Conor M. Burke, MD, FCCP, Department of Respiratory Medicine, James Connolly Memorial Hospital, Dublin 15, Ireland; e-mail: respcmb{at}iol.ie
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Abstract
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Background: Airway dehydration triggers exercise-induced bronchoconstriction in virtually all patients with active asthma. We are not aware of any investigations of airway dehydration in patients with naturally occurring asthma exacerbations. We wish to investigate whether airway dehydration occurs in acute asthmatic patients in the emergency department, and its functional significance.
Methods: In a pilot study on 10 asthmatic patients and 10 control subjects in the emergency department, respiratory rate was counted manually, and relative humidity of expired air was recorded using an air probe hygrometer. In parallel laboratory studies carried out over 2 consecutive days, 19 asthmatics and 10 control subjects were challenged initially with dry air, and on the second day with humidified air. FEV1 and humidity measurements were made immediately before and after the tachypnea challenges.
Results: In the emergency department, the asthmatic group was more tachypneic (p < 0.0001) and their expired air was drier (p < 0.0001) than the control group. Following a dry-air tachypnea challenge in the laboratory, which caused dehydration of the expired air in all subjects, half of the asthmatics, but none of the control subjects, demonstrated a fall of > 10% in FEV1 from baseline. This bronchoconstriction was prevented by humidifying the inspired air; tachypnea with no water loss did not affect lung function in asthmatic subjects.
Conclusions: Dehydration of the expired air is present in asthmatic patients in the emergency department. The bronchoconstriction triggered by dry-air tachypnea challenge in the laboratory can be prevented by humidifying the inspired air. Airway rehydration merits further investigation as a potential adjunct to acute treatment of asthma exacerbations.
Key Words: acute asthma • bronchoconstriction • dehydration • humidification
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Introduction
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Airway dehydration triggers bronchoconstriction in exercise in virtually all patients with active asthma.1
2
3
4
5
Furthermore, eucapnic voluntary hyperventilation using dry air is similar to exercise and methacholine challenge in provoking bronchoconstriction in asthmatic subjects.6
7
8
9
Epidemiologic studies10
11
have demonstrated a high prevalence of asthma in Nordic skiers, who habitually inhale cold, dry air.
Despite these observations that suggest that airway dehydration may be mechanistically important in triggering bronchoconstriction, we are not aware of any investigations of airway dehydration in patients with naturally occurring asthma exacerbations in the emergency department. This study investigates this possibility in acute asthmatic subjects in the emergency department, and describes the establishment of a novel dry-air tachypnea challenge to directly test the relationship between airway dehydration and bronchoconstriction.
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Materials and Methods
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Accident and Emergency Department Studies
Subjects:
Ten acutely ill, consecutive asthmatic subjects (5 men; mean age, 29.2 years; confidence interval [CI], 18.2 to 39.6 years) and 10 nonasthmatic control subjects attending the emergency department at the same time, with noncardiorespiratory symptoms (6 men; mean age, 32.1 years; CI, 27.8 to 36.4 years) were recruited into this study. Patients with bronchitis, emphysema, or other known lung diseases were excluded, and all had normal chest radiographic findings. All subjects gave informed consent, and the local hospital ethics committee approved the study.
Procedures:
Respiratory rate was counted manually, and peak flow readings were measured using a standard portable vitalograph. The first 150 mL of an expired breath, to reflect predominantly anatomical dead space air, was trapped in a polyethylene container, and relative humidity was measured using an air probe hygrometer (Hygromer; Rotronic; Basserdorf, Switzerland). Tidal volume and oxygen saturations were measured in all subjects, by a CO2SMO+ respiratory profile monitor (Novametrics Medical Systems; Miami, FL). All measurements were made immediately on the subjects’ arrival in the emergency department and before administration of any treatment, including oxygen therapy.
Laboratory Studies
Subjects:
Nineteen asthmatic subjects (9 men; mean age, 26.9 years; CI, 20.8 to 33.1 years) with mild asthma as defined by the American Thoracic Society, and 10 nonasthmatic control subjects (4 men; mean age, 24.7 years; CI, 23.1 to 26.2 years) participated in this study. All subjects had a baseline FEV1 > 70% predicted. Of the 19 asthmatic subjects, 13 subjects received maintenance low-dose inhaled corticosteroid therapy and as-required inhaled short-acting ß-agonist therapy, while the remaining 6 subjects received inhaled short-acting ß-agonist therapy alone. Subjects did not receive any medication for 12 h prior to the session, and none had a respiratory infection or asthma exacerbation in the 6-week period prior to the study.
Procedures:
All subjects underwent a bronchial provocation protocol using nebulized buffered isotonic histamine phosphate (Medicare Ltd; Dublin, Ireland), as previously described.12
Briefly, the target 20% drop in FEV1 was calculated using the FEV1 recorded after three technically correct maneuvers after administration of nebulized saline solution. The initial dose of histamine was 0.03 mg/mL, and this was doubled at successive stages until the target drop in FEV1 was achieved. The provocative dose of histamine required to reduce the FEV1 by 20% was determined by linear interpolation of the concentration-FEV1 response curve.
Two weeks later, and immediately prior to the tachypnea challenge, baseline spirometry was performed, using a computerized Gould 2400 system (SensorMedics; Yorba Linda, CA). The best of three valid FEV1 measurements was considered as the baseline value. There were two study days, each separated by at least 48 h. On the first study day, each subject, wearing a nose clip, breathed dry air at room temperature through a mouthpiece attached to the subject connection of a Y-shaped circuit for 10 min. The Y-shaped circuit had inspiratory and expiratory limbs, and a subject connection with a dead space of 15 mL. The circuit had demand-flow, nonrebreathing performance characteristics. Dry air was fed into the system from a medical compressed air cylinder. The subject connection was fitted with a differential pressure pneumotachograph and a solid-state mainstream infrared CO2 sensor. The respiratory rate, end-tidal CO2, and tidal volume were monitored continuously and recorded at 30-s intervals by a CO2SMO+ respiratory profile monitor (Novametrics Medical Systems). Subjects breathed at 50% of their calculated resting normal tidal volume in order to produce tachypnea and were coached to maintain a respiratory rate that maintained end-tidal CO2 within normal limits (38 to 42 mm Hg). No supplemental CO2 was added to the circuit. On the second study day, subjects breathed in a similar pattern as described above, but the inspired air was fully humidified at 37°C (Fisher and Paykel Healthcare Ltd; Auckland, New Zealand). After each challenge, subjects recovered breathing ambient laboratory conditions and FEV1 was measured immediately, and after 5, 10, 20, and 30 min. Exhaled air humidity measurements were made immediately before and immediately after the 10-min tachypnea challenges, as described above.
Analyses of Data
Where data were shown to be normally distributed, group mean values were compared by using Student t test and considered significantly different if the p value was < 0.05. Values are expressed as means and CI, unless otherwise stated. Differences between groups were assessed by one-way analysis of variance. Calculations of geometric mean values of the provocative dose causing a 20% fall in FEV1 were performed on log-transformed raw data. Tachypnea-induced bronchoconstriction was determined as the maximal percentage change in FEV1 from baseline. The statistical calculations were controlled by the use of a validated statistical software package for personal computers (GraphPad Prism; GraphPad Software; San Diego, CA).
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Results
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Accident and Emergency Department Studies
The asthmatic group was more tachypneic (mean respiratory rate, 27.9 breaths/min; CI, 25.3 to 30.5 breaths/min) than the control group (mean, 12.6 breaths/min; CI, 10.5 to 14.7 breaths/min; p < 0.0001; Fig 1
, top, A). There was also a significant difference in tidal volume (p = 0.0043) and peak flow measurements (p < 0.0001) between the asthmatic and control groups (Fig 1 , center, B). No difference in oxygen saturations was observed between the asthmatic group (mean, 96.7%; CI, 95.4 to 98%) and the control group (97.8%; CI, 97.3 to 98.2%; p = 0.08). Based on the relative humidity of the first 150 mL of exhaled air measurements (Fig 1
, bottom, C), the expired air in the asthmatic group (78.2%; CI, 76.3 to 80.1%) was significantly drier than the control group (86.3%; CI, 84.5 to 88.1; p < 0.0001), with no difference in expired air temperature between the asthmatic group (32.7°C; CI, 32.4 to 33°C) and the control group (33°C; CI, 32.9 to 33%; p = 0.1). There was a nonsignificant trend toward correlation (p = 0.067, r = - 0.599) between the respiratory rate and the relative humidity of the exhaled air in the asthmatic group (data not shown).
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Figure 1.. Mean (SEM) respiratory rate (top, A), tidal volume and peak flow (center, B), and relative humidity and expired-air temperature (bottom, C) measured in 10 asthmatic subjects presenting to the emergency department with acute bronchoconstriction (open bars) and 10 control subjects presenting to the emergency department for nonrespiratory causes (filled bars).
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Laboratory Studies
Nineteen stable asthmatic subjects and 10 nonasthmatic control subjects were subjected to a dry-air tachypnea challenge. Nine of the 19 asthmatic subjects, but none of the control subjects, responded with a > 10% drop in FEV1 values from baseline following this challenge (Fig 2
). The mean maximum drop in FEV1 was 12.1% in the asthmatic responder group vs 4.5% in the asthmatic nonresponder group (p < 0.0001). There was no significant change in FEV1 from baseline in the control group, with a mean maximum change of 1.8% (Fig 2)
. During the tachypnea challenges, there was no difference in tidal volume (p = 0.27), respiratory rate (p = 0.25), and end-tidal CO2 levels (p = 0.18) recorded between the groups (Table 1
), and no difference in minute volume recorded between responders, nonresponders, and control subjects (p = 0.88; Table 1
). Comparison between the responder and nonresponder asthmatic subjects, revealed an immediate difference in FEV1 after the dry-air tachypnea challenge (p = 0.0074), which was maximal 5 min after challenge (p = 0.0004), and remained significant up to 20 min (p = 0.0069), but was no longer significant at 30 min after challenge (p = 0.1163; Fig 3
, top, A). The responders had significantly greater bronchial hyperreactivity to inhaled histamine (mean, 0.7 mg/mL; CI, 0.1 to 1.3 mg/mL) vs nonresponders (mean, 3.7 mg/mL; CI, 1.6 to 5.9; p = 0.009), and Global Initiative for Asthma symptom scores: responders, 1.9 mg/mL (CI, 1.4 to 2.3 mg/mL) vs nonresponders, 1.2 mg/mL (CI, 0.9 to 1.5 mg/mL; p = 0.03). The dry-air tachypnea challenge caused a similar reduction in the relative humidity of the exhaled air from baseline values in all groups (Fig 3
, center, B), and also a similar reduction in the expired air temperature from baseline (mean, 32.9°C; CI, 32.8 to 33°C) to postchallenge values (mean, 32.4°C; CI, 32.1 to 32.8°C), with no difference between the groups (p = 0.96; data not shown). To investigate whether the drying of the airways during the tachypnea challenge was responsible for the drop in FEV1 in the responder group, eight of the nine responders were subjected to a humidified-air tachypnea challenge. The ninth subject was excluded due to ß-agonist use on the morning of the challenge. This experiment revealed that humidifying the air used during the tachypnea maneuver abolished the drop in FEV1 at all times over the 30-min postchallenge period (Fig 3
, bottom, C). When the air used during the tachypnea challenge was humidified, no drop in humidity from baseline values was observed in the exhaled air immediately after the tachypnea maneuver (data not shown). Together, these results show that while the dry-air tachypnea maneuver consistently results in reduced humidity of exhaled air, this is only associated with reduced FEV1 in those asthmatic subjects with more severe symptoms and bronchial hyperreactivity to histamine.
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Figure 2.. Following a dry-air tachypnea challenge in 19 asthmatic subjects and 10 control subjects in the laboratory, the mean maximum drop in FEV1 was calculated. Nine of the asthmatic subjects responded to the challenge (> 10% drop in FEV1), while 10 of the asthmatic subjects demonstrated a similar FEV1 response to the control group. R = responder asthmatic subjects; NR = nonresponder asthmatic subjects; C = control subjects.
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Figure 3.. Top, A: mean (SEM) FEV1 changes over time following a dry-air tachypnea challenge in asthmatic responders (filled squares), asthmatic nonresponders (open triangles), and control subjects (filled triangles). Center, B: mean (SEM) relative humidity percentage changes over time following a dry-air tachypnea challenge in asthmatic responders (filled squares), asthmatic nonresponders (open triangles), and control subjects (filled triangles). Bottom, C: mean (SEM) FEV1 changes over time following a dry-air tachypnea challenge in asthmatic responders (filled squares) and in the same responder subjects following a humidified-air tachypnea challenge (open circles).
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Discussion
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Our data demonstrate dehydration of expired air in patients with acute asthma in the emergency department. We analyzed the first 150 mL of the expirate to reflect "airway" air (ie, air mainly originating from the bronchi and bronchioles, the site of asthma) rather than "alveolar" air. Under normal circumstances, the human airway becomes progressively drier as inspiration proceeds because inspired air is drier than peribronchial fluid. The inspired air is progressively humidified along the airways, and alveolar air is fully saturated with water vapor.13
14
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During expiration, the airway water loss is replenished as the fully saturated alveolar air moves proximally through the airways.16
17
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Thus the initial expirate, comprising anatomic dead space air, which has not had the benefit of alveolar humidification, is drier than the rest of the expired "alveolar" air.19
Our data are consistent with other reports19
in showing dehydration of the initial expirate, which was present in the control subjects as well as the asthma subjects. However, we further demonstrate significantly greater dehydration of expired air in the asthma subjects than in the control subjects. We are not aware of any similar data in respect of naturally occurring asthma exacerbations.
The bronchoconstrictor impact of fluid loss from the airway has been recognized for many years. Exercise-induced bronchoconstriction, a feature of 70 to 80% of asthmatics,20
is triggered by drying of the bronchial epithelium due to airway water loss from the tracheobronchial tree.1
2
3
4
5
During exercise, the ventilation rate increases, and thus the respiratory tract needs to condition much larger volumes of air over a much shorter time during exercise compared with rest, and airway dehydration occurs with subsequent exercise-induced bronchoconstriction.1
2
3
4
5
The finding in 19771
that inhaling fully humidified air at body conditions could prevent exercise-induced bronchoconstriction demonstrated the importance of water loss from the airways, and has led to a better understanding of the etiology of this condition. Furthermore, clinicians have long recommended swimming as the exercise least troublesome to asthmatic patients because of the humidity of the inspired air, a phenomenon that is supported by comparative studies of diverse sporting activities.21
22
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Eucapnic voluntary hyperventilation maneuvers, designed to simulate exercise-induced bronchoconstriction in the laboratory, demonstrate that airway fluid loss has a similar bronchoconstrictor effect to histamine.6
7
8
9
Other workers demonstrate the release of histamine, a potent bronchoconstrictor, and other proinflammatory bronchoconstrictor mediators, including cysteinyl-leukotrienes,24
from mast cells and other airway cells under hyperosmolar conditions.25
26
27
These considerations underline the bronchoconstrictor potential of airway dehydration.
Our data demonstrate an increased respiratory rate and increased minute volume in the asthma patients in the emergency department. This respiratory pattern is the most likely explanation for the drier exhaled air in the asthma group. The drier expirate of our asthmatic patients is not related to administration of oxygen, or any other therapy, as all our measurements were made prior to treatment. The well-preserved oxygen saturation of all our patients permitted the necessary measurements of respiratory rate, tidal volume, peak flow, and expiratory humidity, before treatment, without any risk to patients (see "Materials and Methods"). Since the control measurements were also made on patients in the emergency department at the same time, any factors such as anxiety relating to attendance in the emergency department do not explain the observed differences in humidity between asthmatic and control subjects.
We describe a novel dry-air tachypnea challenge in the laboratory that caused dehydration of the expired air in all of the asthmatic and control subjects. Our results show that dry-air tachypnea could result in bronchoconstriction in asthmatic subjects. Interestingly, this phenomenon was most obvious in those patients with more severe bronchial hyperreactivity and higher Global Initiative for Asthma symptom scores. Furthermore, when the tachypnea challenge was repeated using humidified air, the bronchoconstriction effect was abolished. It therefore appears that airway dehydration, and not the tachypnea maneuver per se, caused the observed drop in FEV1 following this challenge. Although we recognize that the decrease in FEV1 following the tachypnea challenge was relatively modest, our asthma group had mild stable disease that was well controlled on treatment. Furthermore, while hypocapnia is a known bronchoconstrictor,28
29
30
by maintaining end-tidal CO2 within normal limits without the confounding factor of CO2 rebreathing in our subjects, we have effectively ruled out hypocapnia as contributing to the observed bronchoconstriction.
Our laboratory data and other reports,1
2
3
4
5
establish that airway dehydration alone can cause bronchoconstriction. Given the relationship between baseline bronchial hyperreactivity and responsiveness to dry-air tachypnea, it is possible that airway dehydration could provoke greater bronchoconstriction in patients with greater bronchial hyperreactivity and more severe asthma. Thus, airway dehydration, initially caused by the tachypnea and increased minute ventilation associated with acute asthma, could precipitate a vicious cycle, resulting in further bronchoconstriction, more severe asthma, and greater airway dehydration.
Humidification of the inspired air-oxygen mixture is not currently recommended in the guidelines for the treatment of acute asthma. Many patients receive some form of humidification, such as bubble through humidification of added oxygen at room temperature. This has limited effect on the overall humidity of the inspired mixture. For example, 40% oxygen in air is made up of approximately three parts air to one part oxygen; therefore, humidification of the oxygen alone, and only to room temperature, is of limited effect on the overall humidity of the inspired mixture. Full effective humidification, would require humidification of all inspired air and oxygen at 37°C.
In summary, we demonstrate significant airway dehydration in acute asthma. In addition, our laboratory results demonstrate the bronchoconstrictor potential of airway dehydration in asthmatic subjects in clinically stable condition. These considerations suggest that active airway rehydration merits further investigation as a potential adjunct to acute treatment of asthma exacerbations.
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Acknowledgements
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We thank Mr. Derek Barton and Dr. Peter O’Connor and their staff at the Accident and Emergency Departments of James Connolly Memorial Hospital Dublin, and the Mater Hospital Dublin, respectively.
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Footnotes
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Abbreviation: CI = confidence interval
Received for publication June 15, 2001.
Accepted for publication December 12, 2001.
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References
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Abstract
Introduction
