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Nocturnal asthma and gastroesophageal reflux
Nocturnal Asthma and Gastroesophageal Reflux Fabio Cibella, MD, Giuseppina Cuttitta, MD
Bronchial asthma is a complex disease involving various cyclic environmental and chronobiologic factors. In patients with asthma, nocturnal gastroesophageal reflux (GER) has been associated with triggering and worsening bronchoconstriction. There are data to suggest that the prevalence of GER is higher in patients with asthma than in the general population and that GER is directly associated with asthma severity. However, the role of GER in asthma remains controversial; some studies suggest that reflux does not mediate nocturnal asthma symptoms. This article reports the results from a study conducted in 7 adult patients affected by nocturnal asthma and moderate to severe GER disease. The relation between GER and asthma was tested by continuously and simultaneously monitoring respiratory resistances and esophageal pH. The study demonstrated a significant correlation between lower respiratory resistances and spontaneous GER. More specifically, both long (more than 5 minutes’ duration) and short (5 minutes’ or less duration) GER episodes elicited bronchoconstriction in patients with asthma who had moderate to severe GER disease. The severity and duration of bronchoconstriction were related to the duration of GER. Am J Med. 2001;111(8A): 31S–36S. © 2001 by Excerpta Medica, Inc.
From Istituto di Fisiopatologia Respiratoria C.N.R., Palermo, Italy. Requests for reprints should be addressed to Fabio Cibella, MD, Istituto di Fisiopatologia Respiratoria C.N.R., Via Trabucco 180, 90146 Palermo, Italy. © 2001 by Excerpta Medica, Inc. All rights reserved.
B
ronchial asthma is a complex disease in which many cyclic environmental and chronobiologic factors are involved. Among these, nocturnal gastroesophageal reflux (GER) has been advocated as a trigger and worsening factor for bronchoconstriction. The pathophysiologic mechanisms of bronchoconstriction induced by GER include a vagally mediated pathway that occurs when acid is present in the esophagus, heightened bronchial reactivity, and microaspiration.1 The association between asthma and GER is strongly suggested by previous reports2 that showed a high incidence of GER among asthma patients. In addition, treatment of GER in these patients improved asthma symptoms.2 In a recent survey3 performed in asthmatic outpatients attending an asthma clinic, the prevalence of GER was found to be higher in patients with asthma than in the general population and was directly related to asthma severity. Moreover, increased frequency and severity of bronchoconstriction episodes were reported during nocturnal sleep, suggesting an association between GER and nocturnal bronchoconstriction. This suggestion is in agreement with other investigations that demonstrated a strong association between GER-related symptoms and asthma. In 1982, Martin et al4 reported results obtained from a sample of pediatric patients with a personal history of nocturnal or daytime asthma. All patients were evaluated with overnight esophageal pH recordings. Notably, subjects with predominant nocturnal asthma had a reflux score higher than subjects with predominant daytime asthma. The authors concluded that a relation existed between nocturnal asthma and GER and that GER may induce nocturnal asthma in reactive patients. Different results were obtained in 1983 by Hughes et al,5 who studied 9 patients with asthma and 7 control subjects during the night in a sleep laboratory. Sleep state, esophageal pH, tidal volume (measured by the noninvasive monitoring of rib cage and abdomen movements), and oxygen saturation were monitored. The authors found no difference in the number of GER episodes between groups; moreover, none of the GER episodes elicited changes in respiratory pattern. Similar negative results were reported in 1987 by Ekstrom and Tibbling,6 who performed 24-hour esophageal pH monitoring on 42 patients with moderate or severe asthma and pathologic GER. Respiratory function was evaluated by serial measurements of peak expiratory flow. Based on the results of this study, the authors concluded that GER did 0002-9343/01/$20.00 31S S0002-9343(01)00855-5
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not play an important role as an immediate trigger factor in bronchial asthma. Supine position also has been proposed as a factor possibly contributing to the increase of GER effects on bronchoconstriction. Harding et al7 demonstrated that in the supine position, acid esophageal infusion produced an increase in specific airway resistances and that this effect was obtained in the absence of microaspiration. Moreover, while supine, patients who were subjected to acid esophageal infusion showed a prolonged worsening in specific airway resistances. This may represent a delayed bronchoconstrictor effect, suggesting a late-phase reaction that reflects inflammatory mediator release. In addition, delayed esophageal clearance during sleep may be additive to the effects of being in the supine position. All of the above-cited studies were limited by the methods used to detect bronchoconstriction during the night. These methods were based primarily on indirect indicators, such as thoracoabdominal movements or transcutaneous monitoring of oxyhemoglobin saturation4,5,8 or on functional indexes, such as peak expiratory flow measures, that required waking the patient.6 Moreover, the latter method could not measure the temporal correspondence between GER occurrence and nocturnal bronchoconstriction; furthermore, disruption of sleep also may have unpredictable effects on airway tone. These limits were overcome in a study conducted by Tan et al9 evaluating 15 subjects affected by nocturnal asthma and mild GER. The patients were submitted to nocturnal polysomnography with simultaneous and continuous measurement of lower airway resistances and esophageal pH. The study was designed to evaluate the bronchoconstrictive effects produced by spontaneous GER and intraesophageal acid infusion. No relation between spontaneous or simulated GER and nocturnal increase in respiratory resistances, either in the presence or absence of esophagitis, was found. The authors concluded that GER produced only a poor contribution to nocturnal asthma worsening. On the basis of these controversial results, a study was designed to evaluate the relation between GER and airway patency during the night by applying proper techniques in adults affected by nocturnal asthma and moderate to severe GER disease (GERD). The results of this study were published previously and are summarized herein.10
PATIENTS AND METHODS Seven adult lifelong nonsmokers (4 men, 3 women) were studied. All were affected by nocturnal asthma, with both clinical and functional diagnoses.11,12 Mean age was 39.9 years (⫾10.2 standard deviation [SD]), and mean forced expiratory volume (FEV1) (as percentage of predicted) was 67.6 (⫾20.2 SD). Patients reported a personal history suggestive of moderate to severe GERD.13 All subjects 32S
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reported awakenings associated with nocturnal asthma symptoms and GER-related symptoms. In the sleep laboratory, subjects were submitted to a standard polysomnography. In addition, the following variables were continuously and simultaneously recorded during the night: bidirectional oronasal airflow by a light tight-fitting face mask with a calibrated heated pneumotachograph (Fleisch number 1) connected to a differential pressure transducer (range, ⫾5 cm H2O; MP-45 Validyne, Validyne, Northridge, CA); volume, computed by electronic integration of airflow signal; transpulmonary pressure (Ptp) by a balloon-tipped catheter placed in the lower third of the esophagus connected to a calibrated differential pressure transducer (MP-45 Validyne; range, ⫾80 cm H2O) referenced to the mask; supraglottic pressure (Psg) at supraglottic level by a second balloon-tipped catheter positioned at a distance of 15 to 17 cm from the nares and connected to a calibrated differential pressure transducer (MP-45 Validyne; range, ⫾5 cm H2O) referenced to the mask; and esophageal pH by intraesophageal glass electrode (Proxima-Light; SensorMedics, Milan, Italy) placed 5 cm above the esophagogastric junction. The isovolume method using computer-based routines was used to compute breath-by-breath total lung resistance. The ratio between Psg and airflow was used to determine supraglottic resistance (RSG). Lower airway respiratory resistance (RLR) was expressed as cm H2O ⫻ L⫺1 ⫻ sec and was derived breath by breath as the difference between total lung resistance and RSG. Episodes of GER were evaluated in terms of decreases in esophageal pH ⬍4 and were separated based on duration. Short GER (SGER) episodes lasting 5 minutes or less and long GER (LGER) episodes lasting more than 5 minutes were evaluated. The duration of GER was expressed as natural log (lnGER duration) because of its skewed distribution. While the patients were awake and in the supine position, RLR was measured at the start of the study night (Rst). Subsequently, RLR was analyzed as means per minute along the entire study night. For each GER episode, RLR value during the minute immediately preceding the GER onset (RLRb); RLR value 1 minute after GER onset (RLR1⬘); peak RLR reached during the course of the GER episode (RLRp); end RLR at the resolution of GER episode (RLRe); ⌬RLRp as RLRp ⫺ RLRb; and ⌬RLRe as RLRe ⫺ RLRb were calculated. Because it has been suggested that GER effects on airway resistances may last until 10 minutes after the resolution of the GER episode,14 RLR 10 minutes after the resolution of episodes (RLR10⬘) also was computed.
RESULTS When all subjects were assessed, the median total experimental time (TET) was 423 minutes (range, 301 to 502 Volume 111 (8A)
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Figure 1. Mean values (⫾SD) relevant to lower respiratory resistances (RLR) in absolute values during the minute immediately preceding the gastroesophageal reflux (GER) onset (RLRb), 1 minute after the GER onset (RLR1⬘), at the peak reached during the course of the GER episode (RLRp), and at the resolution of GER episodes (RLRe). GER episodes lasting 5 minutes or less (short GER [SGER]) are shown separately from episodes lasting longer than 5 minutes (long GER [LGER]).10 NS ⫽ not significant. *P ⬍0.05; **P ⬍0.02; ***P ⬍0.0005. As reference (Rst), the first column on the left indicates the mean RLR value (⫾SD) at the beginning of study night (patients awake and in supine position).
Figure 2. Mean values (⫾SD) relevant to the difference between lower respiratory resistances (RLR) at the peak reached during the course of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRp) and to the difference between RLR at the resolution of each GER episode and at the minute immediately preceding the GER onset (⌬RLRe). GER episodes lasting 5 minutes or less (SGER) are shown separately from episodes lasting longer than 5 minutes (LGER).10 *P ⬍0.0001 vs SGER.
minutes) and the median total sleep time was 194 minutes (range, 60 to 296 minutes). Overall, 101 GER episodes were analyzed; 72 episodes were SGER (median, 1.0 minute) and 29 episodes were LGER (median, 9.0 minutes; range, 6 to 41 minutes). The median time spent in GER was 17.1% of TET (corresponding to 73 minutes). Over time, there was a trend with instantaneous in-
creases in RLR with the occurrence of GER episodes and a subsequent decrease after the resolution of GER episodes. A maximum 5-fold increase was observed during GER episodes in RLRp with respect to Rst (range, 1.2 to 5.2). Conversely, not all increases in RLR were associated with a GER episode. No statistically significant difference was found in
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Figure 3. Simple linear regression computed between the difference of lower respiratory resistances (RLR) at the peak reached during the course of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRp) and natural log of GER duration (lnGER) (P ⬍0.0001).10
Figure 4. Simple linear regression computed between the difference of lower respiratory resistances (RLR) at the resolution of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRe) and natural log of GER duration (lnGER; P ⬍0.0001).10
RLRb between SGER and LGER episodes. Conversely, RLRp was significantly higher than the respective RLRb in both SGER and LGER; RLRp was significantly higher in LGER with respect to SGER. The difference between 34S
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RLRb and RLRe was significant both in SGER (P ⬍0.05) and in LGER (P ⬍0.0005; Figure 1).10 Statistically significant differences were found between SGER and LGER episodes in ⌬RLRp and ⌬RLRe (P ⬍0.0001; Figure 2).10 A Volume 111 (8A)
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Figure 5. Simple linear regression computed between the difference between lower respiratory resistances (RLR) 10 minutes after gastroesophageal reflux (GER) episode resolution and at the minute immediately preceding the GER onset (⌬RLR10⬘) and the difference between RLR at the peak reached during the course of each GER episode and at the minute immediately preceding the GER onset (⌬RLRp; P ⬍0.0001).10
highly significant positive linear relation was found between ⌬RLRp and lnGER duration (P ⬍0.0001; Figure 3).10 A similar relationship was evident between ⌬RLRe and lnGER duration (P ⬍0.0001; Figure 4).10 A separate analysis was performed to evaluate the effects of GER episodes on RLR 10 minutes after reflux resolution. The analysis showed that RLRb and RLR10⬘ were significantly different in LGER (P ⬍0.01), whereas the difference was not significant in SGER. Overall, ⌬RLR10⬘ was linearly correlated with ⌬RLRp (P ⬍0.0001; Figure 5).10
DISCUSSION The study conducted by Cuttitta et al10 demonstrated the significant role of spontaneous GER episodes in provoking and sustaining nocturnal bronchoconstriction in subjects with nocturnal asthma and moderate to severe GERD. Not only were GER episodes strongly related to increases in RLR, the increase in RLR was maintained even after resolution of GER symptoms. In particular, a significant increase in RLR was noted after GER onset, and a rapid (even if not immediate) decrease occurred after GER termination. This may explain the negative results obtained in studies based on measures of respiratory function that were not simultaneous with GER and required waking the patient.6 The results of the Cuttitta et al10 study were in agree-
ment with the study conducted by Davis et al,8 which suggested that GER may be an important mechanism in precipitating bronchial asthma, triggering nocturnal wheezing in children when asthma is complicated by esophagitis. Further indirect evidence of the potential role played by GER in asthma was provided by Harding et al,15 who demonstrated that long-term antacid therapy improved asthma symptoms and pulmonary function. The rapid response in terms of RLR increase after GER onset is in agreement with the hypothesis of a pathogenetic mechanism based on a vagal reflex originating from irritant esophageal mucosal receptors, as suggested by the presence of heightened vagal tone in asthma patients with GERD.16 The time course of changes in resistances with development of RLR peaks when GER episodes occurred lends some support to the role played by GER duration on the degree and the time course of bronchoconstriction. This fundamental role is demonstrated by the significant difference found in RLR increase between SGER and LGER; this was true both for RLRp and RLRe. In fact, a 14% increase was found between RLRp and RLRb for SGER and 54% for LGER, both significant. Moreover, the increase between RLRe and RLRb was 11% for SGER (not significant) and 40% for LGER. Because the values of RLRb were quite similar for SGER and LGER, these results indicate that GER lasting less than 5 minutes may have a significant effect on RLR, even if the bronchocon-
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strictor effect is lessened because of the shorter duration. It is noteworthy that the RLR increase at the first minute after GER onset was similar in both SGER and LGER, supporting the hypothesis that the mechanism implicated in the rapid changes of RLR produces its effect immediately and that the final result in terms of bronchoconstriction depends on the duration of GER episodes. Moreover, the importance of GER duration is confirmed by the fact that the higher the peak, the more prolonged is the effect on airways, as expressed by higher RLR10⬘. This is in agreement with Sontag,14 who reported that pulmonary symptoms were suggestive of involvement of GER as a trigger if the symptoms occurred either during an episode of acid reflux or within 10 minutes after resolution of the GER episode. This could be associated with a slower recovery of pulmonary function after acid is cleared from the esophagus, as shown in asthmatic patients,17 or to a gravitational factor (persistence of supine position). The delayed effect of GER also could reflect a delayed bronchoconstrictor effect associated with bronchial inflammation (late-phase reaction reflecting inflammatory mediator release).7 An additional factor that may influence the relation between GER and nocturnal bronchoconstriction is represented by the severity of GERD. In fact in the only previous nocturnal study9 using continuous and simultaneous monitoring of both respiratory resistances and intraesophageal pH, the asthma patients who were evaluated were affected by mild GERD. The authors reported a total of 11 GER episodes with a mean duration of 10.4 ⫾ 2.3 minutes (range, 1.1 to 24.0 minutes) and a mean total reflux time of 19.1 ⫾ 5.7 minutes or 5.4% ⫾ 1.4 of TET (346 ⫾ 10 minutes) during the night. Conversely, in the Cuttitta et al10 study, a total of 101 GER episodes were reported and the median time spent in GER was 17.1% of TET (73 minutes).
CONCLUSION In conclusion, the presence of GER may elicit a clinically relevant nocturnal bronchoconstriction in patients with asthma. This phenomenon is related to the duration of GER episodes and to the severity of GERD. Moreover, in such patients, GER episodes of shorter than 5 minutes’ duration also may play a role in influencing airway patency.
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REFERENCES 1. Harding SM. Gastroesophageal reflux and asthma: insight into the association. J Allergy Clin Immunol. 1999;104:251– 259. 2. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebocontrolled crossover study with omeprazole. Chest. 1999; 116:1257–1264. 3. Gatto G, Peri V, Cuttitta G, Cibella F. Gastro-oesophageal reflux: prevalence in asthmatics in Italy [comment]. Dig Liver Dis. 2000;32:75. 4. Martin ME, Grunstein MM, Larsen GL. The relationship of gastroesophageal reflux to nocturnal wheezing in children with asthma. Ann Allergy. 1982;49:318 –322. 5. Hughes DM, Spier S, Rivlin J, Levison H. Gastroesophageal reflux during sleep in asthmatic patients. J Pediatr. 1983; 102:666 – 672. 6. Ekstrom T, Tibbling L. Gastro-oesophageal reflux and triggering of bronchial asthma: a negative report. Eur J Respir Dis. 1987;71:177–180. 7. Harding SM, Schan CA, Guzzo MR, et al. Gastroesophageal reflux–induced bronchoconstriction: is microaspiration a factor? Chest. 1995;108:1220 –1227. 8. Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clin Immunol. 1983;72:393–398. 9. Tan WC, Martin RJ, Pandey R, Ballard RD. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis. 1990;141:1394 –1399. 10. Cuttitta G, Cibella F, Visconti A, et al. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med. 2000;161: 177–181. 11. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987;136: 225–244. 12. Bellia V, Visconti A, Insalaco G, et al. Validation of morning dip of peak expiratory flow as an indicator of the severity of nocturnal asthma. Chest. 1988;94:108 –110. 13. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995;333:1106 –1110. 14. Sontag SJ. Pulmonary abnormalities and gastroesophageal disease. In: Richter JE, ed. Ambulatory Esophageal pH Monitoring: Practical Approach and Clinical Applications. New York: Igaku-Shoin Medical Publishers, 1991:151–166. 15. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med. 1996;100:395– 405. 16. Lodi U, Harding SM, Coghlan HC, et al. Autonomic regulation in asthmatics with gastroesophageal reflux. Chest. 1997;111:65–70. 17. Schan CA, Harding SM, Haile JM, et al. Gastroesophageal reflux–induced bronchoconstriction: an intraesophageal acid infusion study using state-of-the-art technology. Chest. 1994;106:731–737.
Volume 111 (8A)
Bronchial asthma is a complex disease involving various cyclic environmental and chronobiologic factors. In patients with asthma, nocturnal gastroesophageal reflux (GER) has been associated with triggering and worsening bronchoconstriction. There are data to suggest that the prevalence of GER is higher in patients with asthma than in the general population and that GER is directly associated with asthma severity. However, the role of GER in asthma remains controversial; some studies suggest that reflux does not mediate nocturnal asthma symptoms. This article reports the results from a study conducted in 7 adult patients affected by nocturnal asthma and moderate to severe GER disease. The relation between GER and asthma was tested by continuously and simultaneously monitoring respiratory resistances and esophageal pH. The study demonstrated a significant correlation between lower respiratory resistances and spontaneous GER. More specifically, both long (more than 5 minutes’ duration) and short (5 minutes’ or less duration) GER episodes elicited bronchoconstriction in patients with asthma who had moderate to severe GER disease. The severity and duration of bronchoconstriction were related to the duration of GER. Am J Med. 2001;111(8A): 31S–36S. © 2001 by Excerpta Medica, Inc.
From Istituto di Fisiopatologia Respiratoria C.N.R., Palermo, Italy. Requests for reprints should be addressed to Fabio Cibella, MD, Istituto di Fisiopatologia Respiratoria C.N.R., Via Trabucco 180, 90146 Palermo, Italy. © 2001 by Excerpta Medica, Inc. All rights reserved.
B
ronchial asthma is a complex disease in which many cyclic environmental and chronobiologic factors are involved. Among these, nocturnal gastroesophageal reflux (GER) has been advocated as a trigger and worsening factor for bronchoconstriction. The pathophysiologic mechanisms of bronchoconstriction induced by GER include a vagally mediated pathway that occurs when acid is present in the esophagus, heightened bronchial reactivity, and microaspiration.1 The association between asthma and GER is strongly suggested by previous reports2 that showed a high incidence of GER among asthma patients. In addition, treatment of GER in these patients improved asthma symptoms.2 In a recent survey3 performed in asthmatic outpatients attending an asthma clinic, the prevalence of GER was found to be higher in patients with asthma than in the general population and was directly related to asthma severity. Moreover, increased frequency and severity of bronchoconstriction episodes were reported during nocturnal sleep, suggesting an association between GER and nocturnal bronchoconstriction. This suggestion is in agreement with other investigations that demonstrated a strong association between GER-related symptoms and asthma. In 1982, Martin et al4 reported results obtained from a sample of pediatric patients with a personal history of nocturnal or daytime asthma. All patients were evaluated with overnight esophageal pH recordings. Notably, subjects with predominant nocturnal asthma had a reflux score higher than subjects with predominant daytime asthma. The authors concluded that a relation existed between nocturnal asthma and GER and that GER may induce nocturnal asthma in reactive patients. Different results were obtained in 1983 by Hughes et al,5 who studied 9 patients with asthma and 7 control subjects during the night in a sleep laboratory. Sleep state, esophageal pH, tidal volume (measured by the noninvasive monitoring of rib cage and abdomen movements), and oxygen saturation were monitored. The authors found no difference in the number of GER episodes between groups; moreover, none of the GER episodes elicited changes in respiratory pattern. Similar negative results were reported in 1987 by Ekstrom and Tibbling,6 who performed 24-hour esophageal pH monitoring on 42 patients with moderate or severe asthma and pathologic GER. Respiratory function was evaluated by serial measurements of peak expiratory flow. Based on the results of this study, the authors concluded that GER did 0002-9343/01/$20.00 31S S0002-9343(01)00855-5
A Symposium: Nocturnal Asthma and Gastroesophageal Reflux/Cibella and Cuttitta
not play an important role as an immediate trigger factor in bronchial asthma. Supine position also has been proposed as a factor possibly contributing to the increase of GER effects on bronchoconstriction. Harding et al7 demonstrated that in the supine position, acid esophageal infusion produced an increase in specific airway resistances and that this effect was obtained in the absence of microaspiration. Moreover, while supine, patients who were subjected to acid esophageal infusion showed a prolonged worsening in specific airway resistances. This may represent a delayed bronchoconstrictor effect, suggesting a late-phase reaction that reflects inflammatory mediator release. In addition, delayed esophageal clearance during sleep may be additive to the effects of being in the supine position. All of the above-cited studies were limited by the methods used to detect bronchoconstriction during the night. These methods were based primarily on indirect indicators, such as thoracoabdominal movements or transcutaneous monitoring of oxyhemoglobin saturation4,5,8 or on functional indexes, such as peak expiratory flow measures, that required waking the patient.6 Moreover, the latter method could not measure the temporal correspondence between GER occurrence and nocturnal bronchoconstriction; furthermore, disruption of sleep also may have unpredictable effects on airway tone. These limits were overcome in a study conducted by Tan et al9 evaluating 15 subjects affected by nocturnal asthma and mild GER. The patients were submitted to nocturnal polysomnography with simultaneous and continuous measurement of lower airway resistances and esophageal pH. The study was designed to evaluate the bronchoconstrictive effects produced by spontaneous GER and intraesophageal acid infusion. No relation between spontaneous or simulated GER and nocturnal increase in respiratory resistances, either in the presence or absence of esophagitis, was found. The authors concluded that GER produced only a poor contribution to nocturnal asthma worsening. On the basis of these controversial results, a study was designed to evaluate the relation between GER and airway patency during the night by applying proper techniques in adults affected by nocturnal asthma and moderate to severe GER disease (GERD). The results of this study were published previously and are summarized herein.10
PATIENTS AND METHODS Seven adult lifelong nonsmokers (4 men, 3 women) were studied. All were affected by nocturnal asthma, with both clinical and functional diagnoses.11,12 Mean age was 39.9 years (⫾10.2 standard deviation [SD]), and mean forced expiratory volume (FEV1) (as percentage of predicted) was 67.6 (⫾20.2 SD). Patients reported a personal history suggestive of moderate to severe GERD.13 All subjects 32S
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reported awakenings associated with nocturnal asthma symptoms and GER-related symptoms. In the sleep laboratory, subjects were submitted to a standard polysomnography. In addition, the following variables were continuously and simultaneously recorded during the night: bidirectional oronasal airflow by a light tight-fitting face mask with a calibrated heated pneumotachograph (Fleisch number 1) connected to a differential pressure transducer (range, ⫾5 cm H2O; MP-45 Validyne, Validyne, Northridge, CA); volume, computed by electronic integration of airflow signal; transpulmonary pressure (Ptp) by a balloon-tipped catheter placed in the lower third of the esophagus connected to a calibrated differential pressure transducer (MP-45 Validyne; range, ⫾80 cm H2O) referenced to the mask; supraglottic pressure (Psg) at supraglottic level by a second balloon-tipped catheter positioned at a distance of 15 to 17 cm from the nares and connected to a calibrated differential pressure transducer (MP-45 Validyne; range, ⫾5 cm H2O) referenced to the mask; and esophageal pH by intraesophageal glass electrode (Proxima-Light; SensorMedics, Milan, Italy) placed 5 cm above the esophagogastric junction. The isovolume method using computer-based routines was used to compute breath-by-breath total lung resistance. The ratio between Psg and airflow was used to determine supraglottic resistance (RSG). Lower airway respiratory resistance (RLR) was expressed as cm H2O ⫻ L⫺1 ⫻ sec and was derived breath by breath as the difference between total lung resistance and RSG. Episodes of GER were evaluated in terms of decreases in esophageal pH ⬍4 and were separated based on duration. Short GER (SGER) episodes lasting 5 minutes or less and long GER (LGER) episodes lasting more than 5 minutes were evaluated. The duration of GER was expressed as natural log (lnGER duration) because of its skewed distribution. While the patients were awake and in the supine position, RLR was measured at the start of the study night (Rst). Subsequently, RLR was analyzed as means per minute along the entire study night. For each GER episode, RLR value during the minute immediately preceding the GER onset (RLRb); RLR value 1 minute after GER onset (RLR1⬘); peak RLR reached during the course of the GER episode (RLRp); end RLR at the resolution of GER episode (RLRe); ⌬RLRp as RLRp ⫺ RLRb; and ⌬RLRe as RLRe ⫺ RLRb were calculated. Because it has been suggested that GER effects on airway resistances may last until 10 minutes after the resolution of the GER episode,14 RLR 10 minutes after the resolution of episodes (RLR10⬘) also was computed.
RESULTS When all subjects were assessed, the median total experimental time (TET) was 423 minutes (range, 301 to 502 Volume 111 (8A)
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Figure 1. Mean values (⫾SD) relevant to lower respiratory resistances (RLR) in absolute values during the minute immediately preceding the gastroesophageal reflux (GER) onset (RLRb), 1 minute after the GER onset (RLR1⬘), at the peak reached during the course of the GER episode (RLRp), and at the resolution of GER episodes (RLRe). GER episodes lasting 5 minutes or less (short GER [SGER]) are shown separately from episodes lasting longer than 5 minutes (long GER [LGER]).10 NS ⫽ not significant. *P ⬍0.05; **P ⬍0.02; ***P ⬍0.0005. As reference (Rst), the first column on the left indicates the mean RLR value (⫾SD) at the beginning of study night (patients awake and in supine position).
Figure 2. Mean values (⫾SD) relevant to the difference between lower respiratory resistances (RLR) at the peak reached during the course of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRp) and to the difference between RLR at the resolution of each GER episode and at the minute immediately preceding the GER onset (⌬RLRe). GER episodes lasting 5 minutes or less (SGER) are shown separately from episodes lasting longer than 5 minutes (LGER).10 *P ⬍0.0001 vs SGER.
minutes) and the median total sleep time was 194 minutes (range, 60 to 296 minutes). Overall, 101 GER episodes were analyzed; 72 episodes were SGER (median, 1.0 minute) and 29 episodes were LGER (median, 9.0 minutes; range, 6 to 41 minutes). The median time spent in GER was 17.1% of TET (corresponding to 73 minutes). Over time, there was a trend with instantaneous in-
creases in RLR with the occurrence of GER episodes and a subsequent decrease after the resolution of GER episodes. A maximum 5-fold increase was observed during GER episodes in RLRp with respect to Rst (range, 1.2 to 5.2). Conversely, not all increases in RLR were associated with a GER episode. No statistically significant difference was found in
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Figure 3. Simple linear regression computed between the difference of lower respiratory resistances (RLR) at the peak reached during the course of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRp) and natural log of GER duration (lnGER) (P ⬍0.0001).10
Figure 4. Simple linear regression computed between the difference of lower respiratory resistances (RLR) at the resolution of each gastroesophageal reflux (GER) episode and at the minute immediately preceding the GER onset (⌬RLRe) and natural log of GER duration (lnGER; P ⬍0.0001).10
RLRb between SGER and LGER episodes. Conversely, RLRp was significantly higher than the respective RLRb in both SGER and LGER; RLRp was significantly higher in LGER with respect to SGER. The difference between 34S
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RLRb and RLRe was significant both in SGER (P ⬍0.05) and in LGER (P ⬍0.0005; Figure 1).10 Statistically significant differences were found between SGER and LGER episodes in ⌬RLRp and ⌬RLRe (P ⬍0.0001; Figure 2).10 A Volume 111 (8A)
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Figure 5. Simple linear regression computed between the difference between lower respiratory resistances (RLR) 10 minutes after gastroesophageal reflux (GER) episode resolution and at the minute immediately preceding the GER onset (⌬RLR10⬘) and the difference between RLR at the peak reached during the course of each GER episode and at the minute immediately preceding the GER onset (⌬RLRp; P ⬍0.0001).10
highly significant positive linear relation was found between ⌬RLRp and lnGER duration (P ⬍0.0001; Figure 3).10 A similar relationship was evident between ⌬RLRe and lnGER duration (P ⬍0.0001; Figure 4).10 A separate analysis was performed to evaluate the effects of GER episodes on RLR 10 minutes after reflux resolution. The analysis showed that RLRb and RLR10⬘ were significantly different in LGER (P ⬍0.01), whereas the difference was not significant in SGER. Overall, ⌬RLR10⬘ was linearly correlated with ⌬RLRp (P ⬍0.0001; Figure 5).10
DISCUSSION The study conducted by Cuttitta et al10 demonstrated the significant role of spontaneous GER episodes in provoking and sustaining nocturnal bronchoconstriction in subjects with nocturnal asthma and moderate to severe GERD. Not only were GER episodes strongly related to increases in RLR, the increase in RLR was maintained even after resolution of GER symptoms. In particular, a significant increase in RLR was noted after GER onset, and a rapid (even if not immediate) decrease occurred after GER termination. This may explain the negative results obtained in studies based on measures of respiratory function that were not simultaneous with GER and required waking the patient.6 The results of the Cuttitta et al10 study were in agree-
ment with the study conducted by Davis et al,8 which suggested that GER may be an important mechanism in precipitating bronchial asthma, triggering nocturnal wheezing in children when asthma is complicated by esophagitis. Further indirect evidence of the potential role played by GER in asthma was provided by Harding et al,15 who demonstrated that long-term antacid therapy improved asthma symptoms and pulmonary function. The rapid response in terms of RLR increase after GER onset is in agreement with the hypothesis of a pathogenetic mechanism based on a vagal reflex originating from irritant esophageal mucosal receptors, as suggested by the presence of heightened vagal tone in asthma patients with GERD.16 The time course of changes in resistances with development of RLR peaks when GER episodes occurred lends some support to the role played by GER duration on the degree and the time course of bronchoconstriction. This fundamental role is demonstrated by the significant difference found in RLR increase between SGER and LGER; this was true both for RLRp and RLRe. In fact, a 14% increase was found between RLRp and RLRb for SGER and 54% for LGER, both significant. Moreover, the increase between RLRe and RLRb was 11% for SGER (not significant) and 40% for LGER. Because the values of RLRb were quite similar for SGER and LGER, these results indicate that GER lasting less than 5 minutes may have a significant effect on RLR, even if the bronchocon-
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strictor effect is lessened because of the shorter duration. It is noteworthy that the RLR increase at the first minute after GER onset was similar in both SGER and LGER, supporting the hypothesis that the mechanism implicated in the rapid changes of RLR produces its effect immediately and that the final result in terms of bronchoconstriction depends on the duration of GER episodes. Moreover, the importance of GER duration is confirmed by the fact that the higher the peak, the more prolonged is the effect on airways, as expressed by higher RLR10⬘. This is in agreement with Sontag,14 who reported that pulmonary symptoms were suggestive of involvement of GER as a trigger if the symptoms occurred either during an episode of acid reflux or within 10 minutes after resolution of the GER episode. This could be associated with a slower recovery of pulmonary function after acid is cleared from the esophagus, as shown in asthmatic patients,17 or to a gravitational factor (persistence of supine position). The delayed effect of GER also could reflect a delayed bronchoconstrictor effect associated with bronchial inflammation (late-phase reaction reflecting inflammatory mediator release).7 An additional factor that may influence the relation between GER and nocturnal bronchoconstriction is represented by the severity of GERD. In fact in the only previous nocturnal study9 using continuous and simultaneous monitoring of both respiratory resistances and intraesophageal pH, the asthma patients who were evaluated were affected by mild GERD. The authors reported a total of 11 GER episodes with a mean duration of 10.4 ⫾ 2.3 minutes (range, 1.1 to 24.0 minutes) and a mean total reflux time of 19.1 ⫾ 5.7 minutes or 5.4% ⫾ 1.4 of TET (346 ⫾ 10 minutes) during the night. Conversely, in the Cuttitta et al10 study, a total of 101 GER episodes were reported and the median time spent in GER was 17.1% of TET (73 minutes).
CONCLUSION In conclusion, the presence of GER may elicit a clinically relevant nocturnal bronchoconstriction in patients with asthma. This phenomenon is related to the duration of GER episodes and to the severity of GERD. Moreover, in such patients, GER episodes of shorter than 5 minutes’ duration also may play a role in influencing airway patency.
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REFERENCES 1. Harding SM. Gastroesophageal reflux and asthma: insight into the association. J Allergy Clin Immunol. 1999;104:251– 259. 2. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebocontrolled crossover study with omeprazole. Chest. 1999; 116:1257–1264. 3. Gatto G, Peri V, Cuttitta G, Cibella F. Gastro-oesophageal reflux: prevalence in asthmatics in Italy [comment]. Dig Liver Dis. 2000;32:75. 4. Martin ME, Grunstein MM, Larsen GL. The relationship of gastroesophageal reflux to nocturnal wheezing in children with asthma. Ann Allergy. 1982;49:318 –322. 5. Hughes DM, Spier S, Rivlin J, Levison H. Gastroesophageal reflux during sleep in asthmatic patients. J Pediatr. 1983; 102:666 – 672. 6. Ekstrom T, Tibbling L. Gastro-oesophageal reflux and triggering of bronchial asthma: a negative report. Eur J Respir Dis. 1987;71:177–180. 7. Harding SM, Schan CA, Guzzo MR, et al. Gastroesophageal reflux–induced bronchoconstriction: is microaspiration a factor? Chest. 1995;108:1220 –1227. 8. Davis RS, Larsen GL, Grunstein MM. Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clin Immunol. 1983;72:393–398. 9. Tan WC, Martin RJ, Pandey R, Ballard RD. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis. 1990;141:1394 –1399. 10. Cuttitta G, Cibella F, Visconti A, et al. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med. 2000;161: 177–181. 11. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis. 1987;136: 225–244. 12. Bellia V, Visconti A, Insalaco G, et al. Validation of morning dip of peak expiratory flow as an indicator of the severity of nocturnal asthma. Chest. 1988;94:108 –110. 13. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995;333:1106 –1110. 14. Sontag SJ. Pulmonary abnormalities and gastroesophageal disease. In: Richter JE, ed. Ambulatory Esophageal pH Monitoring: Practical Approach and Clinical Applications. New York: Igaku-Shoin Medical Publishers, 1991:151–166. 15. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med. 1996;100:395– 405. 16. Lodi U, Harding SM, Coghlan HC, et al. Autonomic regulation in asthmatics with gastroesophageal reflux. Chest. 1997;111:65–70. 17. Schan CA, Harding SM, Haile JM, et al. Gastroesophageal reflux–induced bronchoconstriction: an intraesophageal acid infusion study using state-of-the-art technology. Chest. 1994;106:731–737.
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