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Sleep-Associated Airway Problems in Children
Symposium on The Pediatric Airway
Sleep-Associated Airway Problems in Children John D. Mark, M.D.,* and]ohn G. Brooks, M.D.t
Airway problems during sleep are often difficult to document and may be overlooked if the child appears normal when awake. The primary and secondary symptoms of these disorders vary widely in children and may range from behavioral changes to hypoxemia with secondary right heart failure (cor pulmonale), pulmonary edema, and even death. 27 Several of the most common and important sleep-associated airway problems are the topic of this review. Other sleep-related respiratory disorders in children, such as obesity hypoventilation syndrome, 34 failure of autonomic ventilation (On dine's curse), 15 apnea of prematurity, 23 apnea of infancy, 3 and sudden infant death syndrome (SIDS), 3 · 37 although important, will not be discussed.
RESPIRATION DURING SLEEP There are several mechanisms that may cause airway problems to appear or to worsen during sleep in children. Some of the adverse pathophysiology is unique to children as a result of their immature or incompletely developed respiratory system, while other sleep problems are common to adults and children. 26 Sleep is not a homogeneous state; it comprises several stages, each with specific electroencephalographic, behavioral, and physiologic characteristics. Sleep begins with a slow wave, or quiet, stage that alternates with rapid-eye movement (REM) sleep at intervals of 60 to 90 minutes. REM sleep is associated with abrupt movements of the eyes and an irregular breathing pattern with frequent, brief (less than 10 seconds) periods of apnea. 33 Ventilatory responses to hypercapnea and arousal responses to hypercapnea, hypoxia, and airway irrita-
*Fellow and Clinical Instructor in Pediatrics, Pulmonary Division; University of Rochester, Rochester, New York t Associate Professor of Pediatrics, Director Pediatric Pulmonary Division; University of Rochester, Rochester, New York
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tion are depressed during REM sleep. There is also a decrease in skeletal muscle tone (diaphragm excluded) during sleep that is most pronounced in the REM stage. The patency of the upper airway, particularly during inspiration, is maintained by the appropriate phasic contraction of the muscles of the tongue (primarily the genioglossus), pharynx, and larynx; this overcomes the collapsing effects of negative intraluminal pressure caused by the inspiratory activity of the primary respiratory muscles, the diaphragm, and the intercostal muscles. Cranial nerves, such as the facial, recurrent laryngeal (vagus), and hypoglossal, and nerves innervating the larynx and pharynx, have sustained tonic and phasic activity cycling with respiration. The control of upper airway muscles may be normal during wakefulness, but abnormal during sleep when negative upper airway pressure due to inspiration can collapse the pharyngeal wall and allow the tongue to fall back into the airway.36 In infants and children, many structural abnormalities of the airway can produce fixed or dynamic airway narrowing or instability (Table 1) and thus predispose the child to obstructive sleep apnea or hypoventilation. Finally, individuals with blunted ventilatory responses to carbon dioxide are at significant risk for respiratory compromise during sleep, particularly when respiratory work requirements are increased as occurs during an upper or lower respiratory tract infection. 31
OBSTRUCTIVE SLEEP APNEA SYNDROME The most common significant airway problem associated with sleep in children is the obstructive sleep apnea syndrome (OSAS). 27 By Guilleminault' s criteria for diagnosing OSAS (Table 2), there must be at least 30 apneic periods (greater than 10 seconds) during a seven-hour sleep period.14 Criteria and definitions, however, vary with different investigators, and the range between normal and abnormal has not been well defined in Table 1.
Causes of Sleep-Related Airway Obstruction in Children
COMMON STRUCTURAL ABNORMALITIES
Enlarged tonsils and adenoids Choana! atresia or stenosis Nasal septal deviation Nasal hematoma or tumor Enlarged tongue Temporomandibular joint dysfunction Generalized facial abnormalities Crouzon' s syndrome Trisomy 21 Pierre-Robin (micrognathia) Larsen's syndrome Cleft palate Velopharyngeal incompetence repair
*May improve with sleep.
LESS COMMON STRUCTURAL ABNORMALITIES
Vocal cord paralysis Glottic web Goiter Subglottic stenosis* Laryngomalacia* Tracheomalacia* Vascular abnormalities* Aberrant arteries Double aortic arch NEUROMUSCULAR WEAKNESS
Hypotonic cerebral palsy Dysautonomias Myotonic dystrophy Congenital myopathy
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Table 2.
Obstructive Sleep Apnea Syndrome: Definitions and Diagnostic Criteria
Respiratory pause--less than 10 seconds Apneic period-greater than 15 seconds Central apnea-no chest wall movement or air flow Obstructive apnea-inspiratory effort without air flow Mixed apnea~ombination of central and obstructive Obstructive Sleep Apnea Syndrome---30 or more apneic periods per 7 hours of sleep
children. Prolonged respiratory pauses may be central, obstructive, or mixed; in children, the majority are obstructive secondary to one of the structural abnormalities listed. 4• 12• 13 Frank et al. 12 reviewed the cases of 32 children studied for OSAS over a three-year period and found 23 of 32 (72 per cent) had hypertrophy of the tonsils and adenoids and that 84 per cent were under eight years of age (range 2 to 14 years). The duration of symptoms prior to the diagnosis was longer than one year in all but one patient and longer than four years in 10 children (31 per cent). These findings are in agreement with other reported pediatric series of patients with OSAS. 4, 25, 2s The signs and symptoms of OSAS in children vary (Table 3), and the delay in diagnosis may be due to lack of physician awareness of the more subtle clinical changes, especially when these are only behavioral. Most typically, the parents complain of loud snoring in the child during nighttime sleep, and may even describe periods of obstruction where the child's snoring is followed by brief periods of silence with persistence of respiratory effort. The silent period is followed by a typical, loud, sonorous "breakthrough" gasp or snort and is associated with a brief arousal. Most children with OSAS sleep restlessly and assume abnormal positions, such as sleeping in a sitting position on their elbows and knees.
DIAGNOSIS A detailed history is the first step in evaluating the child with possible sleep-associated airway obstruction. The child's sleeping habits should be described; the presence of loud snoring with or without respiratory pauses, Table 3.
Signs and Symptoms in Obstructive Sleep Apnea Syndrome COMMON
Excessive daytime sleepiness or napping Loud, noisy snoring Nocturnal insomnia Nocturnal enuresis Abnormal or increased activity during sleep Frequent arousals during sleep Mouthbreathing Behavioral changes Declining school performance Hyperactivity
LESS COMMON
Disorientation on awakening Morning headaches Irritability Systemic hypertension Pectus excavatum Cardiomegaly Polycythemia Right ventricular hypertrophy on ECG
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recent onset of enuresis, abnormal sleep positions, and peculiar behaviors should be noted. A home tape recording during sleep, if possible, is helpful in determining whether "snoring" is a significant problem. Daytime symptoms, such as a decline in school performance, mood changes, "hyperactivity," weight loss, and hypersomnolence may be present. The excessive daytime sleepiness is often difficult to document because of the varied sleep patterns seen in normal children. The child who appears normal when awake provides the most difficult clinical challenge; however, a careful physical examination may help determine the site of obstruction as well as demonstrate signs of recurrent hypoxemia. Special attention should be given to the exam of the nose and throat. The presence of nasal obstruction secondary to nasal septal deviation, nasal polyps, enlarged nasal turbinates, or tumor may be seen by direct visualization. The finding of enlarged tonsils, especially if the tonsils touch each other in the midline, is a likely cause of the problem. Noisy respirations and mouth breathing provide further clues to a nasal or nasopharyngeal obstruction. Physical findings that may occur as a result of recurrent hypoxemia or cor pulmonale include a prominent second heart sound (P 2), cardiac gallop murmur, chest rales, hepatosplenomegaly, and clubbing or edema of the extremities. An ECG, systemic blood pressure measurement, and chest radiograph are routinely done to rule out right ventricular hypertrophy or strain, systemic hypertension, and cardiomegaly respectively. Whenever possible, the child should be examined while asleep or at least in the supine position. Often, if excessive daytime sleepliness is present, the child will fall asleep easily and obstructive apnea may be dramatically demonstrated. Frequently, further evaluation is necessary to locate the site of airway obstruction. In the past, instillation of 2 to 3 ml of radiopaque contrast material in the nasal passage, followed by fluoroscopy, was used in an attempt to demonstrate partial choanal atresia or stenosis (complete choanal atresia presents in the newborn period). Recently, the pediatric flexible fiberoptic nasopharyngoscope has been used with increasing frequency, since the posterior nasopharynx, adenoids, and tonsils can be directly and clearly visualized with the patient awake. Examination with the fiberoptic scope, however, may obscure airway collapse, since its presence will alter dynamic airway function. A lateral nasopharyngeal radiograph may give an indication of airway patency (Fig. 1), but, depending on the phase of respiration when obtained, may again miss airway collapse. Cinefluoroscopy during sleep, though it involves a relatively large amount of radiation exposun:;, allows the physician to directly visualize the dynamics of the upper airway and area of airway obstruction during both inspiration and expiration. This obstruction may involve forward movement of retropharyngeal soft tissue, displacement of enlarged tonsils posteriorly, narrowing between the soft palate and adenoidal tissue, or posterior displacement of the tongue or mandible. Formal sleep studies (polysomnography) are usually done after airway obstruction during sleep has been documented or strongly suspected, to clarify the type, duration, amount (episodes per hour of sleep), and severity (oxygen desaturation and ECG changes) of the apneic episodes. Polysomnography can also be helpful in determining if children with underly-
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Figure 1. A, Adenoidal hypertrophy with upper airway obstruction in a four-year-old girl. Note the narrowed airway between the adenoid shadow (A) and the soft palate (P). B, Enlarged palatine tonsils (T) in a 10-year-old boy resulting in chronic airway obstruction.
ing disorders, such as neuromuscular weakness with disordered control of airway musculature, have a significant central component to their OSAS. The polysomnography may include electroencephalography (EEG), electrocardiography (ECG) or heart rate, electromyography (EMG) of the diaphragm or chin muscles, electro-oculography (EOG) to record eye movement, a measure of nasal air flow (end tidal C0 2 analyzer or nasal thermistor), and a recording of thoracoabdominal movements (chest wall,
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abdominal wall, and the sum by inductance method or magnetometers). Blood oxygen is monitored by an ear oximeter (0 2 saturation), transcutaneous oxygen monitor, or an indwelling arterial catheter.
TREATMENT Successful treatment of OSAS in children requires removal (or bypass) of the airway obstruction. Hospitalization is often necessary to adequately monitor children while sleeping, and, if evidence of cor pulmonale is present, hospitalization is mandatory. Oxygen therapy, if used either before or after surgery, should be given cautiously, since, as in any patient with severe chronic airway obstruction, the patient may rely on hypoxic respiratory drive so that oxygen adminstration may depress ventilation. Brouillette et al. 4 reported 22 children with OSAS, all of whom underwent one or more operations to relieve or bypass the obstruction. Tonsillectomy and adenoidectomy was the most common procedure performed. Eight patients with micrognathia, generalized facial abnormalities, or repaired cleft palate required tracheostomy, as did 3 of 14 tonsillectomy and adenoidectomy patients (prior to T and A) owing to severe cardiopulmonary failure. All of these children, as in other pediatric series, 10. 12, 13, 42 improved after surgery, with less labored breathing, quieter sleep, fewer arousals during sleep, and improved growth and development. The presence of enlarged tonsils and adenoids and a history of mouthbreathing, excessive daytime sleepiness, and loud snoring, with or without respiratory pauses, in the child without other underlying medical problems are indications for tonsillectomy and adenoidectomy. Tonsillectomy and adenoidectomy is effective in relieving OSAS in approximately two thirds of all pediatric patients evaluated, and the majority of children can avoid permanent tracheostomy. A temporary tracheostomy may be necessary, however, when other surgical procedures are required to correct other congenital abnormalities, or when the child has severe cardiopulmonary failure. There are cases reported of children with normal lungs and respiratory muscles who continue to have sleep-related hypercapnea after tracheostomy.4· 20 Respiratory stimulants such as progesterone, theophylline, caffeine, and pemoline, used alone or in combination, have helped some of these children as well as children who are not candidates for surgical correction. 4· 12 Another means of nonsurgical treatment is the placement of nasopharyngeal tubes or "trumpets" during sleep. 25 Unfortunately, the tubes are irritating to the nasopharyngeal mucosa, so this is not satifactory for long-term management. In summary, OSAS has many different presentations and manifestations. Delays in diagnosis can lead to cor pulmonale, failure to thrive, and neurologic dysfunction resulting in developmental delay. Treatment in the majority of pediatric cases involves the removal of the tonsils and adenoids with resolution of obstructive sleep apnea and all secondary signs and symptoms. Increased physician awareness of these signs and symptoms of
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OSAS, especially in the child who appears normal when awake, and careful observation of the sleeping child with suspected OSAS, will expedite diagnosis and will decrease the associated morbidity and mortality. NOCTURNAL ASTHMA Asthma is the most common chronic respiratory disease of childhood, affecting 2 to 5 per cent of school-age children in the United States. 46 Of these eight million children under the age of 17 who experience episodic asthma, there is a subgroup who have acute exacerbations of airway obstruction primarily during the night, usually during sleep. 8 • 9 Various mechanisms have been proposed to explain this nocturnal exacerbation but none have been proven, including allergic exposure in the bedroom, 29, 32 variability of the blood or tissue levels of bronchodilator drugs, 8 position during sleep, 19 circadian decrease in circulating epinephrine levels, 2 and gastroesophageal reflux.lB, 38 Murray et al.32 studied 20 children with asthma using histamine bronchial challenge to measure airway hyperreactivity. Airway reactivity of one group of 10 children whose bedrooms were modified to a "dust-free" state was compared with the airway reactivity of another group of 10 children, matched for age and severity of disease, who did not change their bedrooms. The group with modified bedrooms had significantly less airway hyperreactivity than did the other group. Barnes et al. 2 measured circulating epinephrine, cyclic AMP, and plasma histamine, every four hours over a 24-hour period, in five adults with asthma and five adults with no history of asthma. Peak flow rates were also measured every four hours in the asthma group. A circadian fall in plasma epinephrine and cyclic AMP with a corresponding rise in plasma histamine was found in the asthma group; the lowest level of epinephrine and the highest level of histamine was at 4 A.M. Normal subjects showed a similar circadian variation, but the plasma histamine level was significantly lower than in the adults with asthma. The asthma group also demonstrated a decrease in peak flow rates that correlated with the increase in histamine and decrease in epinephrine. This suggests that nocturnal asthma is due to the loss of circulating epinephrine protection during the night associated with an abnormally high level of circulating histamine, resulting in bronchoconstriction. Shapiro et al. 38 studied 19 steroid-dependent asthmatic youths and found 9 of 19 to have gastroesophageal reflux (GER) by acid reflux test. Nocturnal asthma exacerbations could be secondary to reflux with aspiration or reflex bronchoconstriction from irritation of receptors in the esophagus or upper airway. However, another study, 21 comparing nine children (six with a history of nighttime cough and three with a history of heartburn) with seven children without asthma, found no significant differences in the number of reflux episodes, duration of episodes, or symptoms such as cough, wheezing, or oxygen desaturation. Although the factors involved in nocturnal asthma may be variable and are probably a combination of the proposed mechanisms in the susceptible child, the treatment is similar to that for episodic or chronic asthma. En-
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vironmental control (for example, not allowing pets in the bedroom; closing the windows at night) may improve symptoms dramatically. A very compliant and well-motivated family may attempt to modify the child's bedroom to a dust-free state; this requires vinyl cases for pillows, mattress, and box spring; frequent laundering of curtains and bed linens; removing stuffed toys, upholstered furniture, and carpet; closing hot air ducts; and daily cleaning of the floor with a damp mop. A reasonable compromise would be some combination of environmental control and asthma medication. For the child with episodic (including nocturnal) or chronic asthma, the medication most commonly used in the United States is theophylline. 30 The slow-release theophylline preparation is the treatment of choice in nocturnal asthma, since it can be taken easily (scored tablets or sprinkles) on a twice-daily dosage schedule and achieve relatively stable theophylline blood levels in most patients. It is especially important that the theophylline level be maintained in the therapeutic range (12 to 18 J.Lg/ml) if this can be achieved without significant side effects, such as hyperactivity. A starting dose of 12 to 15 mg/kg/day is used, but there is wide variability in an individual's theophylline metabolism, and, if nighttime wheezing occurs, a blood level should be obtained prior to the morning dose to assess the adequacy of nighttime protection. An alternative medication that may be used alone or in combination with theophylline is a 13 2-adrenergic sympathomimetic agent such as albuterol or metaproterenol. The metereddose inhaler (1 or 2 puffs) or oral preparations (2 to 4 mg of albuterol or 10 to 20 mg of metaproterenol) used prior to bedtime may provide relief of nocturnal exacerbations. Cromolyn (20 mg by inhaler four times a day) is thought to decrease airway hyperreactivity and prevent mast cell mediator release, and therefore may benefit the child with nocturnal asthma. Through simple environmental control and these medications, most cases of nocturnal asthma will be adequately treated. If nighttime wheezing or coughing persists despite therapeutic theophylline levels and use of 132 adrenergic agents, further studies may be necessary to pursue the possibility of gastroesophageal reflux, chronic sinusitis, allergic bronchopulmonary aspergillosis, and other causes of recalcitrant asthma. GASTROESOPHAGEAL REFLUX AND NOCTURNAL ASPIRATION Gastroesophageal reflux (GER) results from dysfunction of the lower esophageal sphincter. Refluxed gastric contents may rise only to the lower portion of the esophagus or may ascend to the pharynx and higher with vomiting. The incidence of GER in infants less than 18 months has been estimated to be 1:500 in Great Britain, 5 but reflux with aspiration causing respiratory symptoms is probably much less frequent. 16 Although most children resolve GER by 18 months of age, 18 there are certain disorders in children where GER and possible aspiration are more common. These groups at increased risk include children with central nervous system abnormalities,22 institutionalized children with mental retardation, 46 and children with tracheoesophageal fistula repair.35 Gastroesophageal reflux with
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aspiration is more likely to occur when the child is supine, particularly during sleep, but can occur in any position, especially if the child is at increased risk for GER. IS The child may present with a history of chronic cough, recurrent pneumonia, recent onset of wheezing, or failure to gain weight with developmental delay.1 1 In addition, older children may give a history of epigastric pain, substernal burning, and a "bad taste" upon awakening.' Infants who are less than six months of age may have only frightening episodes of cyanosis and apnea. 33 A history of cough or choking occurring during or immediately following a feeding is useful in making the diagnosis of GER. The evaluation for GER with aspiration includes a chest radiograph that may reveal patchy infiltrates and chronic appearing perihilar streakiness. An esophagram, noting the swallowing coordination and the presence of reflux, is one of the most helpful tests in establishing nasopharyngeal and gastroesophageal reflux. Studies of esophageal motility and sphincter pressures (manometry), extended (24-hour) esophageal pH monitoring, esophagoscopy, and esophageal biopsy are often used in addition to the esophagram, especially when surgical intervention is considered. Appropriate therapy for infants and children with symptomatic GER with aspiration begins with thickened feedings if the infant is primarily taking liquids, elevation of the head after feedings and during sleep, and taking medications such as bethanechol, which strengthens lower esophageal sphincter tone, and metaclopromide, which accelerates gastric emptying. Caution must be taken when bethanechol is prescribed, since it may produce bronchoconstriction in some children with underlying asthma. Medical management of GER with aspiration is frequently unsuccessful, particularly if there is neurologic impairment, and surgical intervention may be necessary. Since a feeding gastrostomy or jejunostomy will not stop the reflux of gastric secretions, the Nissen or Thal fundoplications have been used; if no other congenital anomalies are present, they are 90 to 95 per cent successful.!, 17
SPASMODIC CROUP Spasmodic croup occurs almost exclusively at night usually in children between the ages of one and three years. The mechanism is unclear, but it is thought to be related to an interaction of laryngotracheal bronchitis of viral etiology with an underlying allergic predisposition. 7 Since its onset is rapid and resolution often spontaneous, the pathophysiology may involve a mild noninflammatory edema within the submucosa of the subglottic area. Often, these children, who previously had been well or who had a mild upper respiratory tract infection, will awake with inspiratory stridor and a croupy, barking cough. The symptoms may disappear over several hours without specific treatment, while in more severe cases cool mist therapy is beneficial. Nebulized racemic epinephrine probably helps, but this has not been proved. If racemic epinephrine is used, it is advisable to hospitalize the child for observation, since acute deterioration one to two hours later may occur. 44 In rare circumstances for children with recurrent
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severe spasmodic croup and when medical facilities are far away, home nebulized racemic epinephrine may be used, but only to ensure improvement while the child is en route to medical care. Corticosteroids are not recommended for children with spasmodic croup.
SLEEP HYPOXEMIA IN CHRONIC LUNG DISEASE Adults with chronic obstructive pulmonary disease (COPD) have arterial oxygen desaturation during sleep, and, although the mechanisms remain uncertain, some episodes are associated with hypopnea and obstructive sleep apnea. 24 • 45 Cattarall et al. 6 studied 20 adults with severe chronic bronchitis and emphysema and found that 29 of 40 hypoxemic episodes occurred during periods of hypoventilation. Similarly, some children with obstructive pulmonary disease, such as cystic fibrosis and asthma, develop sleep hypoxemia. In a study of eight patients with cystic fibrosis, 41 one patient with mild disease showed a single fall in oxygen saturation of 10 per cent after a severe coughing episode, and two other patients had significant falls in oxygen saturation (greater than 10 per cent) during REM sleep lasting 5 to 17 minutes and occurring during more than one sleep cvcle. Similar findings (though not as dramatic) have been shown in childrPn with chronic asthma. Smith et al.39 studied 16 children with wellcorrtrolled asthma and 10 healthy control children during sleep and found botlr a greater oxygen desaturation and number of desaturations per hour of sleep in the asthmatic group. A subgroup of eight asthmatic children were studied after their asthma medications had been reduced, and again these children had further decrease in oxygen saturation, suggesting that poorly controlled or unstable asthma can be associated with significant oxygen desaturation during sleep. As in adults with COPD, the mechanisms involved in this sleep-related oxygen desaturation are unclear. The chronic inflammatory process and increased mucus production in cystic fibrosis and asthma associated with decreased mucociliary clearance during sleep may produce more airflow limitation. Tusiewicz et al. 43 postulated that patients with COPD and an increase in gas trapping will have a flattened, less efficient diaphragm. This less efficient diaphragm and the reduced intercostal muscle tone that occurs during REM sleep could result in reduced ventilation and less even distribution of inspired air with resultant hypoxemia. Nighttime oxygen desaturation and poor control of disease should be suspected in the asthmatic or cystic fibrosis patient who complains of restless sleep, frequent arousals, mornings headaches, or increased respiratory symptoms upon awakening. These children may have many of the same signs and symptoms described in the obstructive sleep apnea syndrome. A chest radiograph and ECG should be obtained to rule out cardiomegaly and right ventricular hypertrophy respectively. Treatment centers around better control in the unstable asthmatic and, although not proved, low flow nighttime oxygen in the cystic fibrosis patient with sleep hypoxemia may delay the development of pulmonary hypertension and cor pulmonale.
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28. Mangat, D., Orr, W. C., and Smith, R. 0.: Sleep apnea, hypersomnolence, and upper airway obstruction secondary to adenotonsillar enlargement. Arch. Otolaryngol., 103:38:h386, 1977. 29. Maunsell, K., Wraith, D. G., and Cunnington, A. M.: Mites and house-dust allergy in bronchial asthma. Lancet, 1:1267-1270, 1968. 30. Mathews, K. P.: Respiratory atopic disease. J.A.M.A., 248:2587-2610, 1982. 31. Moore, G., Zwillich, C. W., Battaglia, J., et a!.: Familial depression of ventilatory response to hypoxia and hypercapnia. N. Engl. J. Med., 295:861--865, 1976. 32. Murray, A. B., and Ferguson, A.: Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: A controlled study. Pediatrics, 71 :418--422, 1983. 33. Phillipson, E. A.: Breathing disorder during sleep. Basics of RD, 7:18-23, 1979. 34. Riley, D. J., Santiago, T.V., and Edelman, N.H.: Complications ofobesity-hypoventilation syndrome in childhood. Am. J. Dis. Child., 130:671--674, 1976. 35. Roberts, C. C., Herbst, J. J., Jolley, S. G., eta!.: Evaluation of tests for gastroesophageal reflux in patients operated on for tracheoesophageal fistula. Pediatr. Res., 14:509, 1980. 36. Sanders, M. G.: Sleep apnea syndromes. Clin. Note on Resp. Dis., Winter, 3--10, 1980. 37. Shannon, D. C., and Kelly, D. H. SIDS and Near-SIDS. N. Engl. J. Med., 306:959965, 1982. 38. Shapiro, G. G., and Christie, D. L.: Gastroesophageal reflux in steroid-dependent asthmatic youths. Pediatrics, 63:207-212, 1979. 39. Smith, T. F., and Hudgel, D. W.: Arterial oxygen desaturation during sleep in children with asthma and its relation to airway obstruction and ventilatory drive. Pediatrics, 66:746-751, 1980. 40. Sondheimer, J. M., and Morris, B. A.: Gastroesophageal reflux among severely retarded children. J. Pediatr., 94:710-714, 1979. 41. Stokes, D. C., McBridge, J. T., Wall, M. A., eta!.: Sleep hypoxemia in young adults with cystic fibrosis. Am. J. Dis. Child., 134:741-743, 1980. 42. Stool, S. E., Eavey, R. D., Stein, N. L., eta!.: The "chubby puffer" syndrome. Clin. Pediatr., 16:43--50, 1977 . 43. Tusiewicz, K., Moldofsky, H., Bryan, A. C., eta!.: Mechanics of the rib cage and diaphragm during sleep. J. Appl. Physiol., 43:600-602, 1977. 44. Westley, C. R., Cotton, E. K., and Brooks, J. G.: Nebulized racemic epinephrine by IPPB for the treatment of croup. Am. J. Dis. Child., 132:484-487, 1978. 45. Wynne, J. W., Block, A. J., Hemenway, J., et a!.: Disordered breathing and oxygen desaturation during sleep in patients with chronic obstructive lung disease (COLD). N . Engl. J. Med., 300:513--517, 1979. 46. Young, P.: Asthma and allergies: An optimistic future, NIH Publication No. 80-388, U.S . Dept. of Health and Human Services, March 1980.
Strong Memorial Hospital 601 Elmwood Avenue, Box 667 Rochester, New York 14642
Sleep-Associated Airway Problems in Children John D. Mark, M.D.,* and]ohn G. Brooks, M.D.t
Airway problems during sleep are often difficult to document and may be overlooked if the child appears normal when awake. The primary and secondary symptoms of these disorders vary widely in children and may range from behavioral changes to hypoxemia with secondary right heart failure (cor pulmonale), pulmonary edema, and even death. 27 Several of the most common and important sleep-associated airway problems are the topic of this review. Other sleep-related respiratory disorders in children, such as obesity hypoventilation syndrome, 34 failure of autonomic ventilation (On dine's curse), 15 apnea of prematurity, 23 apnea of infancy, 3 and sudden infant death syndrome (SIDS), 3 · 37 although important, will not be discussed.
RESPIRATION DURING SLEEP There are several mechanisms that may cause airway problems to appear or to worsen during sleep in children. Some of the adverse pathophysiology is unique to children as a result of their immature or incompletely developed respiratory system, while other sleep problems are common to adults and children. 26 Sleep is not a homogeneous state; it comprises several stages, each with specific electroencephalographic, behavioral, and physiologic characteristics. Sleep begins with a slow wave, or quiet, stage that alternates with rapid-eye movement (REM) sleep at intervals of 60 to 90 minutes. REM sleep is associated with abrupt movements of the eyes and an irregular breathing pattern with frequent, brief (less than 10 seconds) periods of apnea. 33 Ventilatory responses to hypercapnea and arousal responses to hypercapnea, hypoxia, and airway irrita-
*Fellow and Clinical Instructor in Pediatrics, Pulmonary Division; University of Rochester, Rochester, New York t Associate Professor of Pediatrics, Director Pediatric Pulmonary Division; University of Rochester, Rochester, New York
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tion are depressed during REM sleep. There is also a decrease in skeletal muscle tone (diaphragm excluded) during sleep that is most pronounced in the REM stage. The patency of the upper airway, particularly during inspiration, is maintained by the appropriate phasic contraction of the muscles of the tongue (primarily the genioglossus), pharynx, and larynx; this overcomes the collapsing effects of negative intraluminal pressure caused by the inspiratory activity of the primary respiratory muscles, the diaphragm, and the intercostal muscles. Cranial nerves, such as the facial, recurrent laryngeal (vagus), and hypoglossal, and nerves innervating the larynx and pharynx, have sustained tonic and phasic activity cycling with respiration. The control of upper airway muscles may be normal during wakefulness, but abnormal during sleep when negative upper airway pressure due to inspiration can collapse the pharyngeal wall and allow the tongue to fall back into the airway.36 In infants and children, many structural abnormalities of the airway can produce fixed or dynamic airway narrowing or instability (Table 1) and thus predispose the child to obstructive sleep apnea or hypoventilation. Finally, individuals with blunted ventilatory responses to carbon dioxide are at significant risk for respiratory compromise during sleep, particularly when respiratory work requirements are increased as occurs during an upper or lower respiratory tract infection. 31
OBSTRUCTIVE SLEEP APNEA SYNDROME The most common significant airway problem associated with sleep in children is the obstructive sleep apnea syndrome (OSAS). 27 By Guilleminault' s criteria for diagnosing OSAS (Table 2), there must be at least 30 apneic periods (greater than 10 seconds) during a seven-hour sleep period.14 Criteria and definitions, however, vary with different investigators, and the range between normal and abnormal has not been well defined in Table 1.
Causes of Sleep-Related Airway Obstruction in Children
COMMON STRUCTURAL ABNORMALITIES
Enlarged tonsils and adenoids Choana! atresia or stenosis Nasal septal deviation Nasal hematoma or tumor Enlarged tongue Temporomandibular joint dysfunction Generalized facial abnormalities Crouzon' s syndrome Trisomy 21 Pierre-Robin (micrognathia) Larsen's syndrome Cleft palate Velopharyngeal incompetence repair
*May improve with sleep.
LESS COMMON STRUCTURAL ABNORMALITIES
Vocal cord paralysis Glottic web Goiter Subglottic stenosis* Laryngomalacia* Tracheomalacia* Vascular abnormalities* Aberrant arteries Double aortic arch NEUROMUSCULAR WEAKNESS
Hypotonic cerebral palsy Dysautonomias Myotonic dystrophy Congenital myopathy
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Table 2.
Obstructive Sleep Apnea Syndrome: Definitions and Diagnostic Criteria
Respiratory pause--less than 10 seconds Apneic period-greater than 15 seconds Central apnea-no chest wall movement or air flow Obstructive apnea-inspiratory effort without air flow Mixed apnea~ombination of central and obstructive Obstructive Sleep Apnea Syndrome---30 or more apneic periods per 7 hours of sleep
children. Prolonged respiratory pauses may be central, obstructive, or mixed; in children, the majority are obstructive secondary to one of the structural abnormalities listed. 4• 12• 13 Frank et al. 12 reviewed the cases of 32 children studied for OSAS over a three-year period and found 23 of 32 (72 per cent) had hypertrophy of the tonsils and adenoids and that 84 per cent were under eight years of age (range 2 to 14 years). The duration of symptoms prior to the diagnosis was longer than one year in all but one patient and longer than four years in 10 children (31 per cent). These findings are in agreement with other reported pediatric series of patients with OSAS. 4, 25, 2s The signs and symptoms of OSAS in children vary (Table 3), and the delay in diagnosis may be due to lack of physician awareness of the more subtle clinical changes, especially when these are only behavioral. Most typically, the parents complain of loud snoring in the child during nighttime sleep, and may even describe periods of obstruction where the child's snoring is followed by brief periods of silence with persistence of respiratory effort. The silent period is followed by a typical, loud, sonorous "breakthrough" gasp or snort and is associated with a brief arousal. Most children with OSAS sleep restlessly and assume abnormal positions, such as sleeping in a sitting position on their elbows and knees.
DIAGNOSIS A detailed history is the first step in evaluating the child with possible sleep-associated airway obstruction. The child's sleeping habits should be described; the presence of loud snoring with or without respiratory pauses, Table 3.
Signs and Symptoms in Obstructive Sleep Apnea Syndrome COMMON
Excessive daytime sleepiness or napping Loud, noisy snoring Nocturnal insomnia Nocturnal enuresis Abnormal or increased activity during sleep Frequent arousals during sleep Mouthbreathing Behavioral changes Declining school performance Hyperactivity
LESS COMMON
Disorientation on awakening Morning headaches Irritability Systemic hypertension Pectus excavatum Cardiomegaly Polycythemia Right ventricular hypertrophy on ECG
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recent onset of enuresis, abnormal sleep positions, and peculiar behaviors should be noted. A home tape recording during sleep, if possible, is helpful in determining whether "snoring" is a significant problem. Daytime symptoms, such as a decline in school performance, mood changes, "hyperactivity," weight loss, and hypersomnolence may be present. The excessive daytime sleepiness is often difficult to document because of the varied sleep patterns seen in normal children. The child who appears normal when awake provides the most difficult clinical challenge; however, a careful physical examination may help determine the site of obstruction as well as demonstrate signs of recurrent hypoxemia. Special attention should be given to the exam of the nose and throat. The presence of nasal obstruction secondary to nasal septal deviation, nasal polyps, enlarged nasal turbinates, or tumor may be seen by direct visualization. The finding of enlarged tonsils, especially if the tonsils touch each other in the midline, is a likely cause of the problem. Noisy respirations and mouth breathing provide further clues to a nasal or nasopharyngeal obstruction. Physical findings that may occur as a result of recurrent hypoxemia or cor pulmonale include a prominent second heart sound (P 2), cardiac gallop murmur, chest rales, hepatosplenomegaly, and clubbing or edema of the extremities. An ECG, systemic blood pressure measurement, and chest radiograph are routinely done to rule out right ventricular hypertrophy or strain, systemic hypertension, and cardiomegaly respectively. Whenever possible, the child should be examined while asleep or at least in the supine position. Often, if excessive daytime sleepliness is present, the child will fall asleep easily and obstructive apnea may be dramatically demonstrated. Frequently, further evaluation is necessary to locate the site of airway obstruction. In the past, instillation of 2 to 3 ml of radiopaque contrast material in the nasal passage, followed by fluoroscopy, was used in an attempt to demonstrate partial choanal atresia or stenosis (complete choanal atresia presents in the newborn period). Recently, the pediatric flexible fiberoptic nasopharyngoscope has been used with increasing frequency, since the posterior nasopharynx, adenoids, and tonsils can be directly and clearly visualized with the patient awake. Examination with the fiberoptic scope, however, may obscure airway collapse, since its presence will alter dynamic airway function. A lateral nasopharyngeal radiograph may give an indication of airway patency (Fig. 1), but, depending on the phase of respiration when obtained, may again miss airway collapse. Cinefluoroscopy during sleep, though it involves a relatively large amount of radiation exposun:;, allows the physician to directly visualize the dynamics of the upper airway and area of airway obstruction during both inspiration and expiration. This obstruction may involve forward movement of retropharyngeal soft tissue, displacement of enlarged tonsils posteriorly, narrowing between the soft palate and adenoidal tissue, or posterior displacement of the tongue or mandible. Formal sleep studies (polysomnography) are usually done after airway obstruction during sleep has been documented or strongly suspected, to clarify the type, duration, amount (episodes per hour of sleep), and severity (oxygen desaturation and ECG changes) of the apneic episodes. Polysomnography can also be helpful in determining if children with underly-
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Figure 1. A, Adenoidal hypertrophy with upper airway obstruction in a four-year-old girl. Note the narrowed airway between the adenoid shadow (A) and the soft palate (P). B, Enlarged palatine tonsils (T) in a 10-year-old boy resulting in chronic airway obstruction.
ing disorders, such as neuromuscular weakness with disordered control of airway musculature, have a significant central component to their OSAS. The polysomnography may include electroencephalography (EEG), electrocardiography (ECG) or heart rate, electromyography (EMG) of the diaphragm or chin muscles, electro-oculography (EOG) to record eye movement, a measure of nasal air flow (end tidal C0 2 analyzer or nasal thermistor), and a recording of thoracoabdominal movements (chest wall,
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abdominal wall, and the sum by inductance method or magnetometers). Blood oxygen is monitored by an ear oximeter (0 2 saturation), transcutaneous oxygen monitor, or an indwelling arterial catheter.
TREATMENT Successful treatment of OSAS in children requires removal (or bypass) of the airway obstruction. Hospitalization is often necessary to adequately monitor children while sleeping, and, if evidence of cor pulmonale is present, hospitalization is mandatory. Oxygen therapy, if used either before or after surgery, should be given cautiously, since, as in any patient with severe chronic airway obstruction, the patient may rely on hypoxic respiratory drive so that oxygen adminstration may depress ventilation. Brouillette et al. 4 reported 22 children with OSAS, all of whom underwent one or more operations to relieve or bypass the obstruction. Tonsillectomy and adenoidectomy was the most common procedure performed. Eight patients with micrognathia, generalized facial abnormalities, or repaired cleft palate required tracheostomy, as did 3 of 14 tonsillectomy and adenoidectomy patients (prior to T and A) owing to severe cardiopulmonary failure. All of these children, as in other pediatric series, 10. 12, 13, 42 improved after surgery, with less labored breathing, quieter sleep, fewer arousals during sleep, and improved growth and development. The presence of enlarged tonsils and adenoids and a history of mouthbreathing, excessive daytime sleepiness, and loud snoring, with or without respiratory pauses, in the child without other underlying medical problems are indications for tonsillectomy and adenoidectomy. Tonsillectomy and adenoidectomy is effective in relieving OSAS in approximately two thirds of all pediatric patients evaluated, and the majority of children can avoid permanent tracheostomy. A temporary tracheostomy may be necessary, however, when other surgical procedures are required to correct other congenital abnormalities, or when the child has severe cardiopulmonary failure. There are cases reported of children with normal lungs and respiratory muscles who continue to have sleep-related hypercapnea after tracheostomy.4· 20 Respiratory stimulants such as progesterone, theophylline, caffeine, and pemoline, used alone or in combination, have helped some of these children as well as children who are not candidates for surgical correction. 4· 12 Another means of nonsurgical treatment is the placement of nasopharyngeal tubes or "trumpets" during sleep. 25 Unfortunately, the tubes are irritating to the nasopharyngeal mucosa, so this is not satifactory for long-term management. In summary, OSAS has many different presentations and manifestations. Delays in diagnosis can lead to cor pulmonale, failure to thrive, and neurologic dysfunction resulting in developmental delay. Treatment in the majority of pediatric cases involves the removal of the tonsils and adenoids with resolution of obstructive sleep apnea and all secondary signs and symptoms. Increased physician awareness of these signs and symptoms of
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OSAS, especially in the child who appears normal when awake, and careful observation of the sleeping child with suspected OSAS, will expedite diagnosis and will decrease the associated morbidity and mortality. NOCTURNAL ASTHMA Asthma is the most common chronic respiratory disease of childhood, affecting 2 to 5 per cent of school-age children in the United States. 46 Of these eight million children under the age of 17 who experience episodic asthma, there is a subgroup who have acute exacerbations of airway obstruction primarily during the night, usually during sleep. 8 • 9 Various mechanisms have been proposed to explain this nocturnal exacerbation but none have been proven, including allergic exposure in the bedroom, 29, 32 variability of the blood or tissue levels of bronchodilator drugs, 8 position during sleep, 19 circadian decrease in circulating epinephrine levels, 2 and gastroesophageal reflux.lB, 38 Murray et al.32 studied 20 children with asthma using histamine bronchial challenge to measure airway hyperreactivity. Airway reactivity of one group of 10 children whose bedrooms were modified to a "dust-free" state was compared with the airway reactivity of another group of 10 children, matched for age and severity of disease, who did not change their bedrooms. The group with modified bedrooms had significantly less airway hyperreactivity than did the other group. Barnes et al. 2 measured circulating epinephrine, cyclic AMP, and plasma histamine, every four hours over a 24-hour period, in five adults with asthma and five adults with no history of asthma. Peak flow rates were also measured every four hours in the asthma group. A circadian fall in plasma epinephrine and cyclic AMP with a corresponding rise in plasma histamine was found in the asthma group; the lowest level of epinephrine and the highest level of histamine was at 4 A.M. Normal subjects showed a similar circadian variation, but the plasma histamine level was significantly lower than in the adults with asthma. The asthma group also demonstrated a decrease in peak flow rates that correlated with the increase in histamine and decrease in epinephrine. This suggests that nocturnal asthma is due to the loss of circulating epinephrine protection during the night associated with an abnormally high level of circulating histamine, resulting in bronchoconstriction. Shapiro et al. 38 studied 19 steroid-dependent asthmatic youths and found 9 of 19 to have gastroesophageal reflux (GER) by acid reflux test. Nocturnal asthma exacerbations could be secondary to reflux with aspiration or reflex bronchoconstriction from irritation of receptors in the esophagus or upper airway. However, another study, 21 comparing nine children (six with a history of nighttime cough and three with a history of heartburn) with seven children without asthma, found no significant differences in the number of reflux episodes, duration of episodes, or symptoms such as cough, wheezing, or oxygen desaturation. Although the factors involved in nocturnal asthma may be variable and are probably a combination of the proposed mechanisms in the susceptible child, the treatment is similar to that for episodic or chronic asthma. En-
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vironmental control (for example, not allowing pets in the bedroom; closing the windows at night) may improve symptoms dramatically. A very compliant and well-motivated family may attempt to modify the child's bedroom to a dust-free state; this requires vinyl cases for pillows, mattress, and box spring; frequent laundering of curtains and bed linens; removing stuffed toys, upholstered furniture, and carpet; closing hot air ducts; and daily cleaning of the floor with a damp mop. A reasonable compromise would be some combination of environmental control and asthma medication. For the child with episodic (including nocturnal) or chronic asthma, the medication most commonly used in the United States is theophylline. 30 The slow-release theophylline preparation is the treatment of choice in nocturnal asthma, since it can be taken easily (scored tablets or sprinkles) on a twice-daily dosage schedule and achieve relatively stable theophylline blood levels in most patients. It is especially important that the theophylline level be maintained in the therapeutic range (12 to 18 J.Lg/ml) if this can be achieved without significant side effects, such as hyperactivity. A starting dose of 12 to 15 mg/kg/day is used, but there is wide variability in an individual's theophylline metabolism, and, if nighttime wheezing occurs, a blood level should be obtained prior to the morning dose to assess the adequacy of nighttime protection. An alternative medication that may be used alone or in combination with theophylline is a 13 2-adrenergic sympathomimetic agent such as albuterol or metaproterenol. The metereddose inhaler (1 or 2 puffs) or oral preparations (2 to 4 mg of albuterol or 10 to 20 mg of metaproterenol) used prior to bedtime may provide relief of nocturnal exacerbations. Cromolyn (20 mg by inhaler four times a day) is thought to decrease airway hyperreactivity and prevent mast cell mediator release, and therefore may benefit the child with nocturnal asthma. Through simple environmental control and these medications, most cases of nocturnal asthma will be adequately treated. If nighttime wheezing or coughing persists despite therapeutic theophylline levels and use of 132 adrenergic agents, further studies may be necessary to pursue the possibility of gastroesophageal reflux, chronic sinusitis, allergic bronchopulmonary aspergillosis, and other causes of recalcitrant asthma. GASTROESOPHAGEAL REFLUX AND NOCTURNAL ASPIRATION Gastroesophageal reflux (GER) results from dysfunction of the lower esophageal sphincter. Refluxed gastric contents may rise only to the lower portion of the esophagus or may ascend to the pharynx and higher with vomiting. The incidence of GER in infants less than 18 months has been estimated to be 1:500 in Great Britain, 5 but reflux with aspiration causing respiratory symptoms is probably much less frequent. 16 Although most children resolve GER by 18 months of age, 18 there are certain disorders in children where GER and possible aspiration are more common. These groups at increased risk include children with central nervous system abnormalities,22 institutionalized children with mental retardation, 46 and children with tracheoesophageal fistula repair.35 Gastroesophageal reflux with
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aspiration is more likely to occur when the child is supine, particularly during sleep, but can occur in any position, especially if the child is at increased risk for GER. IS The child may present with a history of chronic cough, recurrent pneumonia, recent onset of wheezing, or failure to gain weight with developmental delay.1 1 In addition, older children may give a history of epigastric pain, substernal burning, and a "bad taste" upon awakening.' Infants who are less than six months of age may have only frightening episodes of cyanosis and apnea. 33 A history of cough or choking occurring during or immediately following a feeding is useful in making the diagnosis of GER. The evaluation for GER with aspiration includes a chest radiograph that may reveal patchy infiltrates and chronic appearing perihilar streakiness. An esophagram, noting the swallowing coordination and the presence of reflux, is one of the most helpful tests in establishing nasopharyngeal and gastroesophageal reflux. Studies of esophageal motility and sphincter pressures (manometry), extended (24-hour) esophageal pH monitoring, esophagoscopy, and esophageal biopsy are often used in addition to the esophagram, especially when surgical intervention is considered. Appropriate therapy for infants and children with symptomatic GER with aspiration begins with thickened feedings if the infant is primarily taking liquids, elevation of the head after feedings and during sleep, and taking medications such as bethanechol, which strengthens lower esophageal sphincter tone, and metaclopromide, which accelerates gastric emptying. Caution must be taken when bethanechol is prescribed, since it may produce bronchoconstriction in some children with underlying asthma. Medical management of GER with aspiration is frequently unsuccessful, particularly if there is neurologic impairment, and surgical intervention may be necessary. Since a feeding gastrostomy or jejunostomy will not stop the reflux of gastric secretions, the Nissen or Thal fundoplications have been used; if no other congenital anomalies are present, they are 90 to 95 per cent successful.!, 17
SPASMODIC CROUP Spasmodic croup occurs almost exclusively at night usually in children between the ages of one and three years. The mechanism is unclear, but it is thought to be related to an interaction of laryngotracheal bronchitis of viral etiology with an underlying allergic predisposition. 7 Since its onset is rapid and resolution often spontaneous, the pathophysiology may involve a mild noninflammatory edema within the submucosa of the subglottic area. Often, these children, who previously had been well or who had a mild upper respiratory tract infection, will awake with inspiratory stridor and a croupy, barking cough. The symptoms may disappear over several hours without specific treatment, while in more severe cases cool mist therapy is beneficial. Nebulized racemic epinephrine probably helps, but this has not been proved. If racemic epinephrine is used, it is advisable to hospitalize the child for observation, since acute deterioration one to two hours later may occur. 44 In rare circumstances for children with recurrent
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severe spasmodic croup and when medical facilities are far away, home nebulized racemic epinephrine may be used, but only to ensure improvement while the child is en route to medical care. Corticosteroids are not recommended for children with spasmodic croup.
SLEEP HYPOXEMIA IN CHRONIC LUNG DISEASE Adults with chronic obstructive pulmonary disease (COPD) have arterial oxygen desaturation during sleep, and, although the mechanisms remain uncertain, some episodes are associated with hypopnea and obstructive sleep apnea. 24 • 45 Cattarall et al. 6 studied 20 adults with severe chronic bronchitis and emphysema and found that 29 of 40 hypoxemic episodes occurred during periods of hypoventilation. Similarly, some children with obstructive pulmonary disease, such as cystic fibrosis and asthma, develop sleep hypoxemia. In a study of eight patients with cystic fibrosis, 41 one patient with mild disease showed a single fall in oxygen saturation of 10 per cent after a severe coughing episode, and two other patients had significant falls in oxygen saturation (greater than 10 per cent) during REM sleep lasting 5 to 17 minutes and occurring during more than one sleep cvcle. Similar findings (though not as dramatic) have been shown in childrPn with chronic asthma. Smith et al.39 studied 16 children with wellcorrtrolled asthma and 10 healthy control children during sleep and found botlr a greater oxygen desaturation and number of desaturations per hour of sleep in the asthmatic group. A subgroup of eight asthmatic children were studied after their asthma medications had been reduced, and again these children had further decrease in oxygen saturation, suggesting that poorly controlled or unstable asthma can be associated with significant oxygen desaturation during sleep. As in adults with COPD, the mechanisms involved in this sleep-related oxygen desaturation are unclear. The chronic inflammatory process and increased mucus production in cystic fibrosis and asthma associated with decreased mucociliary clearance during sleep may produce more airflow limitation. Tusiewicz et al. 43 postulated that patients with COPD and an increase in gas trapping will have a flattened, less efficient diaphragm. This less efficient diaphragm and the reduced intercostal muscle tone that occurs during REM sleep could result in reduced ventilation and less even distribution of inspired air with resultant hypoxemia. Nighttime oxygen desaturation and poor control of disease should be suspected in the asthmatic or cystic fibrosis patient who complains of restless sleep, frequent arousals, mornings headaches, or increased respiratory symptoms upon awakening. These children may have many of the same signs and symptoms described in the obstructive sleep apnea syndrome. A chest radiograph and ECG should be obtained to rule out cardiomegaly and right ventricular hypertrophy respectively. Treatment centers around better control in the unstable asthmatic and, although not proved, low flow nighttime oxygen in the cystic fibrosis patient with sleep hypoxemia may delay the development of pulmonary hypertension and cor pulmonale.
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REFERENCES 1. Ashcraft, K. W., Holder, T. M., and Amoury, R. A.: Treatment of gastroesophageal reflux in children by Thai fundoplication. J. Thorac. Cardiovasc. Surg., 82:706-712, 1981. 2. Barnes, P., Fitzgerald, G., Brown, M., et al.: Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N. Engl. J. Med., 303:263-267, 1980. 3. Brooks, J. G.: Apnea of infancy and sudden death syndrome. Am. J. Dis. Child., 136:1012-1023, 1982. 4. Brouillette, R. T., Fernbach, S. K., and Hunt, C. E.: Obstructive sleep apnea in infants and children. J. Pediatr., 100:31-40, 1982. 5. Carre, I. J.: The natural history of the partial thoracic stomach (hiatal hernia) in children. Arch. Dis. Child., 34:344-353, 1959. 6. Catterall, J. R., Douglas, N. J., Claverly, P. M. A., et al.: Transient hypoxemia during sleep in chronic obstructive pulmonary disease is not a sleep apnea syndrome. Am. Rev. Respir. Dis., 128:24-29, 1983. 7. Cherry, J. D.: The treatment of croup: Continued controversy due to failure of recognition of historic, ecologic, etiologic and clinical perspectives. J. Pediatr., 94:352-354, 1979. 8. Clark, T. J. H., and Hetzel, M. R.: Diurnal variation of asthma. Br. J. Dis. Chest., 71:87-92, 1977. 9. Connolly, C. K.: Diurnal rhythms in airway obstruction. Br. J. Dis. Chest, 73:357-366, 1979. 10. Eliaschar, 1., Lavie, P., Halperin, E., et al.: Sleep apneic episodes as indications for adenotonsillectomy. Arch. Otolaryngol., 106:492-496, 1980. 11. Euler, A. R., Byrne, W. J., Ament, M. E., et al.: Recurrent pulmonary disease in children: a complication of gastroesophageal reflux. Pediatrics, 71:737-742, 1983. 12. Frank, Y., Kravath, R. E., Pollak, C. P., et al.: Obstructive sleep apnea and its therapy: Clinical and polysomnographic manifestations. Pediatrics, 71:737-742, 1983. 13. Guilleminault, C., Eldridge, F. L., Simmons, F. B., et al.: Sleep apnea in eight children. Pediatrics, 58:23-31, 1976. 14. Guilleminault, C., Tilkian, A., and Dement, W. C.: The sleep apnea syndromes. Ann. Rev. Med., 27:465-484, 1976. 15. Guilleminault, C., McQuitty, J., Arragno, R. L., et al.: Congenital central hypoventilation syndrome in six infants. Pediatrics, 70:684-694, 1982. 16. Guttman, F. M.: On the incidence of hiatal hernias in infants. Pediatrics, 50:325-328, 1972. 17. Harnsberger, J. K., Corey, J. J., Johnson, D. G., et al.: Long-term follow-up of surgery for gastroesophageal reflux in infants and children. J. Pediatr., 102:505-508, 1983. 18. Herbst, J. J.: Gastroesophageal reflux. J. Pediatr., 98:859--870, 1981. 19. Hetzel, M. R., and Clark, T. J. H.: Does sleep cause nocturnal asthma? Thorax, 34:749754, 1979. 20. Hollinger, P. C., Holi';lger, L. D., Reichert, T. J., et al.: Respiratory obstruction and apnea in infants with bilateral abductor vocal cord paralysis, meningomyelocele, hydrocephalus and Arnold-Chiari malformation. J. Pediatr., 92:368-373, 1979. 21. Hughes, D. M., Spier, S., Rivlin, J., et al.: Gastroesophageal reflux during sleep in asthmatic patients. J. Pediatr., 102:666-672, 1983. 22. Jolley, S. G., Herbst, J. J., Johnson, D. G., et al.: Surgery in children with gastroesophageal reflux and respiratory symptoms. J. Pediatr., 96:194-198, 1980. 23. Kattwinkel, J.: Apnea in the neonatal period. Pediatr. Rev., 2:115-120, 1980. 24. Kline, N. W., DeLancey, D. A., and Giblin, E. C.: Sleep apnea in patients with chronic obstructive pulmonary disease. Am. Rev. Respir. Dis., 117(Suppl.):140, 1978. 25. Kravath, R. E., Pollak, C. P., and Borowiecki, B.: Hypoventilation during sleep in children who have lymphoid airway obstruction treated by nasopharyngeal tube and T and A. Pediatrics, 59:865-871, 1977. 26. Loughlin, G. M., and Taussig, L. M.: Upper airway obstruction. Semin. Respir. Med., 1:131-146, 1979. 27. Mandel, E. M., and Reynolds, C. F.: Sleep disorders associated with upper airway obstruction in children. I'EDIATR. CLIN. NoRTH AM .. 28:897-903. 1981.
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28. Mangat, D., Orr, W. C., and Smith, R. 0.: Sleep apnea, hypersomnolence, and upper airway obstruction secondary to adenotonsillar enlargement. Arch. Otolaryngol., 103:38:h386, 1977. 29. Maunsell, K., Wraith, D. G., and Cunnington, A. M.: Mites and house-dust allergy in bronchial asthma. Lancet, 1:1267-1270, 1968. 30. Mathews, K. P.: Respiratory atopic disease. J.A.M.A., 248:2587-2610, 1982. 31. Moore, G., Zwillich, C. W., Battaglia, J., et a!.: Familial depression of ventilatory response to hypoxia and hypercapnia. N. Engl. J. Med., 295:861--865, 1976. 32. Murray, A. B., and Ferguson, A.: Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: A controlled study. Pediatrics, 71 :418--422, 1983. 33. Phillipson, E. A.: Breathing disorder during sleep. Basics of RD, 7:18-23, 1979. 34. Riley, D. J., Santiago, T.V., and Edelman, N.H.: Complications ofobesity-hypoventilation syndrome in childhood. Am. J. Dis. Child., 130:671--674, 1976. 35. Roberts, C. C., Herbst, J. J., Jolley, S. G., eta!.: Evaluation of tests for gastroesophageal reflux in patients operated on for tracheoesophageal fistula. Pediatr. Res., 14:509, 1980. 36. Sanders, M. G.: Sleep apnea syndromes. Clin. Note on Resp. Dis., Winter, 3--10, 1980. 37. Shannon, D. C., and Kelly, D. H. SIDS and Near-SIDS. N. Engl. J. Med., 306:959965, 1982. 38. Shapiro, G. G., and Christie, D. L.: Gastroesophageal reflux in steroid-dependent asthmatic youths. Pediatrics, 63:207-212, 1979. 39. Smith, T. F., and Hudgel, D. W.: Arterial oxygen desaturation during sleep in children with asthma and its relation to airway obstruction and ventilatory drive. Pediatrics, 66:746-751, 1980. 40. Sondheimer, J. M., and Morris, B. A.: Gastroesophageal reflux among severely retarded children. J. Pediatr., 94:710-714, 1979. 41. Stokes, D. C., McBridge, J. T., Wall, M. A., eta!.: Sleep hypoxemia in young adults with cystic fibrosis. Am. J. Dis. Child., 134:741-743, 1980. 42. Stool, S. E., Eavey, R. D., Stein, N. L., eta!.: The "chubby puffer" syndrome. Clin. Pediatr., 16:43--50, 1977 . 43. Tusiewicz, K., Moldofsky, H., Bryan, A. C., eta!.: Mechanics of the rib cage and diaphragm during sleep. J. Appl. Physiol., 43:600-602, 1977. 44. Westley, C. R., Cotton, E. K., and Brooks, J. G.: Nebulized racemic epinephrine by IPPB for the treatment of croup. Am. J. Dis. Child., 132:484-487, 1978. 45. Wynne, J. W., Block, A. J., Hemenway, J., et a!.: Disordered breathing and oxygen desaturation during sleep in patients with chronic obstructive lung disease (COLD). N . Engl. J. Med., 300:513--517, 1979. 46. Young, P.: Asthma and allergies: An optimistic future, NIH Publication No. 80-388, U.S . Dept. of Health and Human Services, March 1980.
Strong Memorial Hospital 601 Elmwood Avenue, Box 667 Rochester, New York 14642