Sleep disturbances that occur with nocturnal reflux may have serious consequences for the well-being of patients and their ability to perform well the next day.

F01a.jpg (13575 bytes) In the recent past, sleep’s implications for the physiology and pathogenesis of disease have been ignored. With the evolution of sleep laboratories, an awareness of the relationship between sleep and various gastrointestinal phenomena has been rapidly emerging. Most notable has been burgeoning interest in the relationship between sleep-related gastroesophageal reflux (GER) and the development of esophageal and aerodigestive complications such as esophagitis, chronic cough, exacerbation of bronchial asthma, and pulmonary aspiration. Work examining the relationship of sleep and GER has captured the attention of gastroenterologists and primary care physicians involved in the treatment of this common, perplexing problem. Sleep results in a significant alteration in basic physiology that can profoundly affect responses to GER.

Sleep is experienced by all mammalian species and is associated with remarkable behavioral and physiological changes. Sleep is a ubiquitous biological need for which the ultimate function, other than restoring behavioral alertness, remains unknown. Accordingly, attempts to understand the basic pathophysiology of GER and its consequences require an understanding and examination of sleep-related reflux events, acid clearance, and arousal responses.

Sleep itself can be divided into five separate stages determined by the simultaneous monitoring of the electroencephalogram, electro-oculogram, and electromyelogram, according to internationally accepted criteria. The basic criteria of sleep staging and the fundamental physiology of sleep are outlined elsewhere.1

Sleep is not merely a passive process; the activation of a variety of brain mechanisms is needed to initiate the onset of sleep. Stage 1 sleep is generally regarded as the transition between waking and sleep. Stages 2, 3, and 4 are generally combined into one entity referred to as non–rapid-eye-movement (NREM) sleep. REM or dreaming sleep occurs at intervals of approximately 90 minutes during a normal night of sleep. The occurrence of REM sleep is controlled and regulated by specific brainstem nuclei that include the locus ceruleus and several nuclei located in the pontine tegmentum.1,2

Physiologically, NREM sleep is characterized by general slowing of autonomic function, with diminution of heart rate, blood pressure, and metabolic rate. In contrast to NREM, REM sleep is characterized by marked and unique physiological changes. For example, regulation of normal core body temperature is suspended in warm-blooded animals, rendering them poikilothermic.1 The mechanisms that normally control and regulate blood oxygen, carbon dioxide, and pH are essentially suspended during REM sleep. Furthermore, a complete skeletal-muscle paralysis exists during REM sleep and is generally thought to preclude physically acting out a dream.1 Thus, the physiological changes associated with sleep may influence nocturnal GER and esophageal acid clearance.

Responses to Reflux
f01b.jpg (10097 bytes)Figure 1. Postprandial reflux during waking.

It is well established that GER is a common postprandial event; in fact, it is a normal physiological response to gastric distension that induces a transient relaxation of the lower esophageal sphincter. Heartburn and regurgitation are also well established as the most common symptoms of esophageal mucosal acid contact. Since the sensation of heartburn is a waking, conscious experience (and many reflux events do not produce symptoms), the actual occurrence of GER during sleep is difficult to estimate based on symptoms alone. GER does occur during sleep, as documented by recent studies,3 but it is clearly less common than GER that occurs in the waking state. It appears that reflux occurs predominantly during NREM sleep, and very rarely during REM sleep. The most frequent occurrence of reflux after sleep onset takes place during episodes of transient arousal. It is not clear what the mechanism of this may be. Classic studies conducted by DeMeester et al4 established that GER occurs less commonly during the sleeping interval, and is generally associated with a prolongation of acid clearance. As noted in Figure 1, waking reflux is generally postprandial and reflux events are rapidly cleared (in 1 to 2 minutes). During sleep, however, reflux events are more commonly associated with prolonged acid clearance (Figure 2). Subsequent studies5 from our laboratory at the University of Oklahoma have confirmed these findings in that we have demonstrated that the complications of reflux that result in discontinuity of the esophageal mucosa are generally associated with an increase in supine GER during sleep.

f01c.jpg (9467 bytes)Figure 2. Sleep-related reflux. A single event may last 15 to 20 minutes.

Sensory Response
What is occurring during sleep that leads to this marked prolongation in acid clearance? Several secretory, motor, and sensory responses are associated with acid mucosal contact in the human esophagus. Typically, acidification of the distal esophagus will produce a marked increase in salivary flow. This allows ample buffering to neutralize the acidic lining of the distal esophagus. There is also a marked increase in the rate of swallowing that allows the delivery of the potent buffer of saliva into the distal esophagus. In addition, swallowing and the subsequent primary peristaltic contractions of the esophagus allow the efficient removal of the refluxant from the distal esophagus. In addition, the esophagus has an endogenous mechanism that also produces a peristaltic response to deformation or noxious mucosal stimulation. This is called secondary peristalsis, since it does not require a preceding swallow to initiate the peristaltic response. Of course, acid mucosal contact is associated with a sensation of substernal burning that is perceived as uncomfortable and/or painful. These responses have been determined to be present in a normal waking individual, and swallowing and heartburn are generally assumed to be waking, conscious phenomena. Collectively, these responses generally result in rapid clearance of refluxed gastric contents and neutralization of the acidic mucosa.

These typical responses in the waking state are generally absent during sleep. It is clearly these alterations that result in the marked prolongation of acid clearance noted during sleep. A study6 from our laboratory has demonstrated that the simple infusion of acid into the distal esophagus during polygraphically monitored sleep results in a highly significant prolongation of acid clearance time, compared with infusion in the supine waking state. Adding to the risks associated with reflux during sleep is the fact that the swallowing rate is markedly diminished and salivary flow is essentially absent. Heartburn is clearly absent during sleep. Thus, these alterations establish a significant risk for the prolongation of acid mucosal contact during sleep. In a series of studies using a rabbit esophageal model, Johnson and Harmon7 have documented that the back diffusion of hydrogen ions into the esophageal mucosa is directly related to the duration of esophageal acid-contact time. The longer the acid-contact time, the greater the back diffusion of hydrogen ions. Short, rapidly cleared episodes of GER would appear to be relatively benign, while more prolonged episodes of GER are associated with greater risk of mucosal damage. An additional risk of prolonged acid mucosal contact relates to the higher risk of the proximal migration and eventual spillover of refluxed gastric contents into the tracheobronchial tree. A recent study8 from our laboratory relates directly to the risk of sleep in facilitating the proximal migration of very small volumes of acid infused into the distal esophagus. In this study, small (1-mL and 3-mL) volumes of acid were instilled into the distal esophagus during supine waking and sleep. We noted that none of the waking volunteers showed evidence of proximal migration of 1 mL of acid. During sleep, however, 40% of the same individuals showed evidence of the proximal migration of 1 mL of acid infused during polygraphically determined NREM sleep. Thus, it can be concluded that sleep itself induces considerable risk of prolonged acid mucosal contact, and it facilitates the occurrence of proximal migration of acid, enhancing the probability of pulmonary aspiration.

Studies9 from our laboratory have determined that the potential complications of sleep-related esophageal acid mucosal contact are mitigated by the occurrence of an awakening from sleep, or arousal response. We have determined that acid clearance is inversely related to the amount of wakefulness during the acid clearing. Individuals who tended to sleep through episodes of esophageal acid infusion had longer acid-clearance times, and those who had a rapid arousal response with prolonged awakening had shorter acid-clearing times. Maintaining sleep in response to an episode of GER would appear to be quite maladaptive. This creates a paradox: to provide an appropriate response to GER during sleep, a brief awakening from sleep is required. This arousal need only be for a short time, but it appears to be necessary to avoid the ultimate consequences of sleep-related GER. A sleep disturbance results in a more adaptive response to GER.

Nighttime GER can lead to the development of esophagitis, as well as to other respiratory complications such as exacerbation of asthma symptoms and chronic cough. These complications appear to be related primarily to the presence of significant supine acid-contact time during sleep. Nighttime reflux, with its associated delayed esophageal acid clearance, also may be a risk factor for respiratory symptoms, although the pathophysiology of this is not well established. In one study,10 for example, a large percentage of patients with idiopathic pulmonary fibrosis were found to have GER. Aspiration was noted as the likely cause. A high percentage of patients with chronic bronchitis were found to have GER and prolonged reflux episodes.11 Several studies12-14 of patients with obstructive sleep apnea have not shown a direct correlation between GER and obstructive apneic events. For example, Ing et al13 have shown that only 18% of reflux events were associated with obstructive apnea in a group of patients with polysomnographically documented obstructive apnea. Total acid-contact time was elevated, however, in comparison with a control group of individuals without significant obstructive apnea. There does appear to be a relationship between obstructive sleep apnea and an overall increase in nighttime acid contact.12-14

Clinical Manifestations
Symptom control and quality of life remain important issues in the treatment of GER. The most common symptoms, heartburn and regurgitation, have been regarded almost exclusively as daytime phenomena, and nighttime manifestations have been largely ignored until quite recently. Two recent studies15,16 have documented the importance of nighttime symptoms and their effect on the overall quality of life of heartburn patients, as well as indicating the presence of other important extraesophageal symptoms. These studies revealed remarkably similar results with approximately 75% of those with frequent heartburn admitting to significant symptoms at night, with the overall prevalence rate for nighttime symptoms estimated at approximately 10%. These studies provide considerable evidence that the sequelae of GER appear to be more severe in patients with nighttime symptoms. Patients with nighttime symptoms have a substantially diminished quality of life compared to individuals without nighttime symptoms.16 The quality-of-life scores of patients with nighttime heartburn show significant decreases in both physical and mental components such as pain, general health, and social functioning. These patients also show diminished quality of life, compared with patients with diabetes and angina.

An important component of the decreased quality of life noted in patients with nighttime heartburn appears to come from the fact that it interferes with the quality of sleep. More than 50% of those with nighttime heartburn report that they are awakened by GER symptoms, and about 30% are awakened by coughing or choking due to regurgitation. About 40% of patients with nighttime symptoms noted that their heartburn affected their ability to function well the next day, and about 60% indicated that it affected their mood. The use of sleeping pills was also substantially increased in patients with nighttime GER symptoms.15,16

GER, especially at night, has been implicated in the etiology of a variety of aerodigestive symptoms such as wheezing, chronic cough, and hoarseness.12,17 Reflux symptoms appear to be quite prevalent in patients with asthma; in one study of asthma patients, 77% complained of heartburn, 41% experienced reflux-associated respiratory symptoms, 82% had abnormal esophageal acid-contact times, and 43% manifested esophagitis upon endoscopy.18 It has been established that nighttime reflux in asthma can induce bronchoconstriction that appears to be related to the duration of the reflux event.19 In addition, it has been shown that a reduction in asthma symptoms occurs after GER treatment, which supports the notion that reflux can exacerbate asthma.20 Additional support for the relationship between nighttime reflux and asthma comes from epidemiological studies20 that have shown that asthma and other respiratory symptoms strongly coincide in patients who have nighttime heartburn at least twice a week.21

Nighttime Heartburn
Nighttime GER symptoms not only appear to be more bothersome to patients, but are more difficult to control than daytime symptoms. While most patients with nighttime GER took medication for their problem, 45% had continuing symptoms in one study.15 Patients with symptoms of nighttime GER sometimes find relief by elevating the head of the bed, changing their sleeping position to the left side, and not eating within 3 hours of bedtime. Elevating the head of the bed appears to facilitate acid clearance rather than prevent reflux.

Clearly, proton pump inhibitors (PPIs) are the most effective acid-suppressing agents, and are therefore more likely to render gastric contents less injurious to the esophageal mucosa.22-24 For that reason, PPIs are of significant therapeutic benefit in relieving symptoms and healing esophagitis.

Although PPIs have overwhelming therapeutic efficacy in healing esophagitis and relieving symptoms, some patients do have nighttime symptoms despite powerful acid suppression and a marked reduction in GER. The reflux of gastric contents is not eliminated by acid suppression and, in some instances, the reflux of less acidic gastric contents can persist, without warning. Clinically, this may be noticed in patients who report that PPIs diminish their nocturnal heartburn, but that they continue to experience unexplained awakenings from sleep with symptoms of coughing and choking. This should be a warning to the clinician that significant nonacidic reflux may be occurring, or that there is inadequate reduction in GER during the sleeping interval. In such circumstances, the most rational approach is to take the PPI twice daily, with the second dose occurring before the evening meal.

There is considerable evidence linking nighttime reflux with severe esophageal damage, respiratory complications, and decrements in quality of life. Sleep disturbances that occur with nocturnal reflux may have serious consequences for the general well-being of patients and their ability to perform well at work or in other roles the next day. Thus, frequent nighttime GER symptoms should not be considered simply an annoyance, but a chronic ailment with insidious detrimental effects on health and quality of life. GER symptoms are more noxious during the sleeping interval and are more difficult to control. Thus, it behooves the clinician to be aware of symptoms associated with the presence of nocturnal reflux, as well as appropriate treatment modifications that may be required to treat nocturnal symptoms effectively. PPIs are the drugs of choice, and there are considerable data to suggest that these drugs effectively control both daytime and nighttime symptoms.

William C. Orr, PhD, is clinical professor of medicine, Lynn Health Science Institute, University of Oklahoma Health Sciences Center, Oklahoma City.

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