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Dr. Orr is President and Chief Executive Officer of the Lynn Health Science Institute.
Correspondence to: William C. Orr, PhD, Lynn Health Science Institute, Suite 130, 5300 N. Independence, Oklahoma City, OK 73112
It is generally accepted that sleep represents a period of abnormal or unstable respiration, largely manifest as either obstructive or central apnea. Recognition of the clinical significance and ubiquity of these phenomena has driven the widespread proliferation of sleep laboratories largely dedicated to studying sleep apnea. The clinical presentation of obstructive sleep apnea (OSA) is well-known to clinicians and includes obesity, snoring, and daytime hypersomnolence. The article in this issue of CHEST (see page 158) by Gislason and colleagues has drawn our attention to another sleep-related phenomenon that may also be exacerbating and/or contributing to sleep-related breathing disorders, ie, gastroesophageal reflux (GER). They have shown a strong relationship between respiratory symptoms and sleep-related heartburn, and they have shown in other publications1 2 the relationship of sleep-related heartburn to symptoms of OSA such as snoring and obesity. It would appear from this research, and other outcomes that have been published from the European Community Respiratory Health Survey, that sleep-related GER may be another one of those "things that go bump in the night." In the current article, the authors establish a strong coincidence of asthmatic and other respiratory symptoms occurring in individuals who report symptoms of GER (ie, heartburn and belching) occurring at least 1 to 2 nights per week. A strong correlation, however, or even a robust odds ratio does not establish a causal relationship. Are there data available that would suggest that these events may have an underlying common cause or linkage?
Clearly, there is a body of literature accumulating suggesting a relationship between GER and asthma. In studies by Sontag and colleagues,3 4 they have established a very high incidence of GER (confirmed via 24-h pH monitoring) in a large group of unselected asthmatics, and they have also demonstrated that 39% of asthmatics were shown to have esophagitis. The clinical relevance of these findings and the physiologic mechanisms have been studied. There are numerous studies that show that the treatment of asthmatic patients, particularly those who seem to have refractory and/or nocturnal symptoms, can be improved by the administration of standard acid-suppression therapy to treat GER.5 Adding credence to this clinical approach are numerous studies6 7 that have shown a bronchoconstrictive response to distal esophageal acid mucosal contact. In fact, there are data to suggest that other respiratory symptoms and disorders of the upper airway can be linked to the occurrence of GER.8 With symptoms other than asthmatic symptoms, the rational is not as clear-cut, and it would seem that higher risk is associated with the prolongation of acid clearance during sleep. Studies9 10 11 from our laboratory have shown that the risk of this is greater during sleep secondary to the suppression of normal clearance mechanisms, such as salivation and swallowing. In fact, in a recent study11 from our laboratory, we have documented that the proximal migration of minute amounts of acid infused into the distal esophagus is significantly facilitated during sleep.
From a purely clinical prospective, it would seem rational to assume that in individuals with difficult-to-manage asthmatic symptoms, and the occurrence of nocturnal heartburn, treatment with acid-suppressing drugs such as proton pump inhibitors would have a salubrious effect on asthmatic symptoms. Although the report by Gislason and colleagues does not specifically address daytime heartburn symptoms, it does support the previously reported data12 that suggest that nocturnal heartburn is a useful clinical symptom in determining the presence of esophageal disease. However, one should not succumb to the easy logic that the absence of heartburn rules out or precludes GER as a potential contributor to asthmatic symptoms. Harding and colleagues13 have shown as many as 63% of asthmatics without reflux symptoms have significant GER. Accordingly, Gislason and colleagues have noted that individuals from this random population who had nocturnal heartburn were more than twice as likely to have a valid diagnosis of asthma compared to those who did not. These differences remained significant after appropriate adjustments for gender, age, body mass index (BMI), and other symptoms related to sleep-disordered breathing such as snoring. In the current study and two related studies1 2 published by the same group of investigators, they have described nocturnal GER as an independent risk factor for snoring, daytime sleepiness, and a variety of sleep complaints, including difficulty initiating sleep, nocturnal awakenings, and early morning awakenings.
How could GER be related to such an apparent diversity of respiratory and neurobehavioral symptoms? In attempting to establish any relationship between symptoms of GER, or the actual occurrence of GER, and other symptoms such as snoring and chronic cough, it should be recognized that heartburn is a very common symptom that can easily overlap with a variety of other symptoms by chance alone. Establishing a cause-effect relationship among phenomena that occur commonly is quite difficult and requires a sophisticated statistical approach. That is, snoring and heartburn are obviously extremely common, and would therefore be expected by chance alone to occur in a fairly significant portion of any randomly selected population. In their study, the authors report that all the differences noted, except for the relationship between GER and morning cough, were significant after adjusting for possible confounding factors such as gender, age, smoking, BMI, and symptoms related to sleep-disordered breathing. Another somewhat more precise approach, not utilized in this study, would be to analyze the concurrent occurrence of two symptoms in time, such as wheezing and the occurrence of GER. This would require a signal detection analysis to assess whether the occurrence of these two (or any two) symptoms are occurring together with a frequency greater than chance.14
GER is a phenomenon that has been believed to be largely caused by an incompetent lower esophageal sphincter. Thus, a defective lower esophageal sphincter (< 10 mm Hg) would much more easily allow the retrograde flow of gastric contents under a circumstance of a somewhat enhanced pressure gradient between the abdominal cavity and the thoracic cavity. Thus, given the extreme negative pressures created by airway obstruction in patients with OSA, it would be a reasonable assumption that this patient population would be at considerable risk for the occurrence of nocturnal GER and its attendant complications. In addition, obesity would also be a putative risk factor by enhancing the pressure gradient via increased intra-abdominal positive pressure. Since obesity is also clearly a risk factor for OSA, and the current study, as well as the others by this research group, has established a clear relationship between symptoms of nocturnal GER and those commonly associated with OSA (snoring and daytime sleepiness), it would be postulated that there is a strong relationship between the occurrence of obstructive apneic events during sleep and the concomitant occurrence of GER. Furthermore, the resolution of GER by treating patients with continuous positive airway pressure would add further credence to this hypothesis.15
Several studies16 17 have been done to assess the simultaneous occurrence of GER and OSA, with negative results. No study employed an appropriate signal detection analysis referred to above. In one study by Graf and colleagues,16 OSA was determined only by a drop in the oxygen saturation by approximately 4%. Using this as an identifier for OSA, they simultaneously monitored esophageal pH in order to detect episodes of GER. They found no significant difference between mild and severe groups of OSA in terms of percentage of esophageal acid contact time, and they concluded that there was no obvious relationship between obstructive events and GER. They did, however, note that 80% of their patients showed an increase in GER. This study has the additional flaw of not adequately identifying all episodes of OSA, since determining OSA events only by the determination of reductions in oxygen saturation by 4% will not identify a number of relatively mild obstructive events. A similar study by Penzel et al17 utilized more traditional polysomnography to determine episodes of OSA. In their study, they identified the occurrence of 69 episodes of sleep-related GER, and 38 of these were noted to occur during polysomnographically documented sleep. Virtually all of these were associated with polygraphically identified arousal responses. Although they indicated that GER has a very high incidence in the OSA population, they could not establish any significant relationship between GER and OSA events. Thus, the pressure gradient hypothesis discussed herein is not supported by either of these studies. In a somewhat more definitive study, Ing and colleagues18 studied a group of patients with polysomnography documented OSA compared to a group of control subjects, with regard to the simultaneous occurrence of obstructive events and GER as monitored by esophageal pH. They found that patients with OSA have significantly more GER events than control subjects, but only slightly more than half of the reflux events were noted to be temporally related to apneas or hypopneas. They subsequently subjected both groups to continuous positive airway pressure treatment that resulted in a reduced reflux event in both groups. Reflux therapy with a histamine-2 blocker reduced arousal responses but had no effect on the apnea-hypopnea index in patients with OSA. The authors concluded that GER does not appear to be caused by OSA but may be involved in the pathogenesis of arousal responses. The latter is a particularly important clinical observation, since studies9 10 from our laboratory have suggested that arousal responses are critical in the clearance of acid infused into the distal esophagus during sleep.
Although obesity would appear to be a condition that overlaps both OSA and GER, Gislason and his colleagues have shown that GER appears to be a risk factor independent of BMI. Furthermore, one study19 has shown no effect of weight loss on the occurrence of GER. Again we have the overlapping of occurrence of two very common medical conditions, which does not appear to show any obvious cause-effect relationship.
The study by Gislason and colleagues did not address two respiratory complications of GER that have considerable clinical relevance. Chronic cough, for example, is a common clinical problem that has been related to GER.20 Although this is a complicated and difficult area in which to establish a cause-effect relationship, there are some suggestive data. Jacob et al,21 for example, have shown that a patient with laryngopharyngitis can be distinguished from a group of patients with esophagitis by the increase in proximal esophageal acid contact time during sleep. Furthermore, some studies have shown that in patients with symptoms of chronic cough and GER, prolonged acid suppression therapy will markedly improve chronic cough (see Irwin and Zawacki20 for a review of this topic). Secondly, pulmonary aspiration is certainly the most serious and dangerous complication of sleep-related GER. Depressed consciousness is clearly a risk factor for pulmonary aspiration, and it has been demonstrated22 that the risk of pulmonary aspiration is substantially increased under conditions of depressed consciousness. Lastly, an interesting study has recently been published by Tobin and colleagues,23 which shows that in patients with idiopathic pulmonary fibrosis, significant proximal esophageal acid exposure can be documented during the sleeping interval.
In conclusion, Gislason and colleagues have provided some extremely interesting and provocative data that suggest that a common and relatively benign event such as GER occurring in the waking state can become a significant and potentially dangerous condition when it occurs during sleep. This extends our knowledge of sleep as a significant and important phenomenon in understanding not only the importance of sleep-related GER, but our overall understanding of the myriad of manifestations of sleep-related breathing disorders.
References
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