Refer to: Morgan EJ, Zwillich CW: The obesity-hypoventilation syndrome (Medical Progress). West J Med 129:387-393, Nov 1978
Medical Progress
The Obesity-Hypoventilation Syndrome EDWARD J. MORGAN, MD, PhD, and CLIFFORD W. ZWILLICH, MD, Denver
The triad of obesity, hypoventilation and inordinate hypersomnolence characterizes the obesity-hypoventilation syndrome. The reasons for daytime hypoventilation appear related to decreased chemical drives to breathe combined with the added physical impediment of extreme obesity. When the physiology of sleep was investigated in patients with this syndrome, intermittent nocturnal obstructive apneas were documented that produced blood gas abnormalities, arrhythmias and serious elevations of both pulmonary and systemic pressures. The obstructive apneas are due to intermittent loss of muscle tone of the tongue resulting in its prolapse against the posterior pharynx. The special importance of the obesity-hypoventilation syndrome lies in its being an example of a disorder of sleep and breathing that can appear in widely different clinical settings. Therapeutic measures include weight loss, progestational agents or permanent tracheostomy. THE OBESITY-HYPOVENTILATION SYNDROME (OHS) is an uncommon illness characterized by obesity,
hypoventilation and often irresistible hypersomnolence. It might have remained only a grotesque curiosity were it not for interest in its fascinating pathophysiology, involving disorders of both sleep and the control of breathing. When investigators examined the physiology of sleep in OHS, an unexpected series of life-threatening events was documented. Even such dissimilar examples as sleep at high altitude' and respiratory control in some patients with chronic obstructive lung disease2 share a mechanism with OHS. Therefore, the reader should realize that the pathophysiology of the OHS is similar to that found in more common medical disorders. This From the Cardiovascular Pulmonary Research Laboratory and Division of Pulmonary Sciences, Department of Medicine, University of Colorado Medical Center, Denver. Dr. Zwillich is a recipient of NIH Research Career Development Award (HL 00225). Reprint requests to: Clifford W. Zwillich, MD, CVP Research Laboratory, B-133, University of Colorado Medical Center, 4200 E. Ninth Avenue, Denver, CO 80262.
review describes in detail the physiology of OHS, discusses its interrelationships with other disorders and provides a basis for therapy.
Background The OHS has been recognized for over a hundred years. Early investigators knew that a coffelation existed between obesity and cardiopulmonary problems. In the past it has been called obesity heart disease3 and the postural syndrome related to obesity and cardiorespiratory failure.4 In 1956 Burwell, Robin and colleagues coined the term Pickwickian syndrome.5 We prefer the name obesity-hypoventilation syndrome (OHS), which emphasizes the abnormal ventilation found in these patients.
Pathophysiology Hypoventilation with an elevated arterial partial pressure of carbon dioxide (Pco,) is the central pathophysiologic disturbance in patients THE WESTERN JOURNAL OF MEDICINE
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with OHS. The subsequent hypercapnia, acidemia and hypoxemia cause a rise in the mean pulmonary artery pressure with resultant right heart failure. Hypoventilation is most severe during sleep, and may result in severe transient systemic hypertension which places a significant burden on left ventricular ejection. Left ventricular failure then ensues which further compromises the patient's condition.6 Erythrocytosis commonly occurs with a hematocrit over 60 percent.7 Mechanical Factors Early investigators attempted to blame obesity alone as the major cause of hypoventilation.8'0 Several lines of evidence show that this is not the case. First, only a minority of obese patients have significant hypoventilation8-'2 and there is no correlation between body weight and arterial carbon dioxide pressure (Pco,) in obese patients.'3 Second, in patients with OHS, arterial blood gas values easily return to normal with voluntary hyperventilation, indicating that mechanical factors are not critically limiting the patients' ability to ventilate normally.14" 5 Third, one need not be massively obese to hypoventilate, which suggests that other factors are also at work."1"16-18 Last, elastic loading of respiration in normal persons (used to simulate obesity) is not associated with hypoventilation.'9 Although patients with OHS have restrictive abnormalities of lung function that are more severe than those of patients with simple obesity,20 this alone appears insufficient as a cause of hypoventilation. Moderate weight reduction in patients with OHS leads to marked improvement in vital capacity, lung compliance, arterial blood gas values, and clinical symptoms.20 This suggests that either the absolute weight or the distribution of obesity which is usually truncal in patients with OHS may be important factors in the pathogenesis. Weight loss may result in a critical decrease in the work of breathing.21 Although the role of excess weight in patients with OHS is only a cofactor, it undoubtedly plays a synergistic role. There is no doubt, however, that weight reduction is effective in treating patients with OHS.5'8"18'20'22 The hypoxemia associated with OHS is frequently more severe than what would be expected on the basis of the degree of hypoventilation.'5 This may be explained by ventilation/perfusion mismatch with decreased basilar ventilation.23 388
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Factors That Control Respiration Mechanical factors alone do not provide an explanation for hypoventilation, as was emphasized by Bedell, Wilson and Seebohm in 1958 when they showed that most obese persons do not hypoventilate unless an insult such as pneumonia or myxedema is added.8 Because obesity alone does not explain the hypoventilation of patients with OHS, studies have been done to evaluate the homeostatic mechanisms controlling arterial Pco2 and oxygen pressure (Po2) in this syndrome. Arterial Pco2 is closely controlled in healthy persons within a narrow range. Increases of Pco2 are met with a steep linear ventilatory response averaging at least a three-fold increase in minute ventilation per rise in Pco2 of 10 mm of mercury.24 The normal increase in ventilation stimulated by inhalation of carbon dioxide (co2) is blunted in patients with OHS and not in patients with comparable simple obesity.25'26 Decreased responses to co2 have also been shown in nonobese patients who hypoventilate,'7 and in patients with idiopathic hypoventilation (Ondine's curse) .16,27 In patients with OHS, weight loss usually improves the hypercapnic ventilatory response, suggesting that the decreased response may be the result of mechanical consequences of obesity and not the primary cause of hypoventilation.5'28 Whether a blunted hypercapnic response is a primary pathogenetic mechanism of the syndrome or is only a secondary finding is unresolved. Similarly, a blunted hypoxic ventilatory response is a common finding in these patients25'29 and is reduced to approximately 20 percent of normal values.25 The carotid body is the major detector of decreased levels of arterial oxygen tension,30 and minute ventilation rises exponentially when Po2 falls below 50 to 60 mm of mercury.3' Chronic hypoxemia can blunt the hypoxic ventilatory response, as seen in residents of high altitude32 and in patients with cyanotic congenital heart disease.33 Since weight loss may not improve the ventilatory response to hypoxia,34 a blunted hypoxic response may be a primary rather than a secondary feature of the syndrome. Blunting of the response due to chronic hypoxemia is an unlikely possibility, because it takes over 25 years of hypoxemia before a reduced hypoxic drive is seen in persons living at high altitude.32 Hence, the reason for this blunted hypoxic re-
OBESITY-HYPOVENTILATION SYNDROME
sponse in OHS iS unknown. There is evidence to suggest that a decreased hypoxic response may be genetically mediated. Studies in endurance athletes,35 in patients with chronic obstructive lung disease with hypoventilation,2 and in twins36 all suggest that there is a significant familial predisposition for the hypoxic ventilatory response. It may be that in obese patients who are genetically preselected for abnormalities in ventilatory drive, OHS develops. An enticing theory about obesity and decreased chemical drives to breathe is alluded to in a report of an obese child with hypoventilation and evidence of hypothalamic injury. The patient was found to have a voracious appetite, diabetes insipidus, lethargy and cyanosis.37 However, this possible central nervous system abnormality has not proved to be universal in patients with OHS, as post-mortem studies on these patients typically failed to show any consistent central nervous system abnormalities.
Sleep Studies Hypersomnolence is a severe and striking part of the OHS. Joe in Dickens' The Posthumous Papers of the Pickwick Club fell asleep while knocking on a door.38 Burwell's patient realized that he needed medical help when he fell asleep holding a full house during a poker game.5 Patients have B.Mass. 13yrs
also been known to fall asleep while driving a car. The reasons for this hypersomnolence have only recently been understood. Because acute elevations of arterial Pco2 values produce disorientation, lethargy, and coma, it was thought that somnolence was related to carbon dioxide narcosis. However, somnolence does not correlate with an elevated Pco2.3940 Indeed, somnolence usually precedes any rise in Pco2 in patients who are awake. Patients with an acutely elevated Pco2 become disoriented, obtunded and finally comatose and unarousable. Patients with OHS display a different pattern, with irresistible somnolence yielding to a deep sleep from which the patient can be aroused." Critical studies which ultimately led to the understanding of the mechanism of sleep-wakefulness disturbances in OHS were those of Gastaut, Tassinari and Duron, who documented dramatic cyclic breathing pauses or apneas in certain patients with OHS.39 During such pauses airflow ceased but respiratory effort, measured as intrathoracic pressure swings, continued. These are termed obstructive, or peripheral apneas. This intermittent upper airway obstruction was accompanied by significant hypercapnia and hypoxemia.39 No apneas were detected during wakefulness. This observation has been extended to
Sleep St 3
Awake
R.Front-Temp R Cent-Occ _~~~~~~~~
E M G~-
M 604
0"._
-
A.M0 N
--
EKGG Heart Rate
(Beats/mr.) 2Cse:
Arter Press -, i (mm Hg)
Pulm Art Press (mm Hg)
Thor Resp
Oral Resp
mm
Figure 1.-Nocturnal sleep record of a patient with OHS and obstructive sleep apnea. Oral respiration has stopped although thoracic excursions of increasing effort continue. Pulmonary and systemic hypertension are illustrated along with the cyclic bradycardia often found in OHS. (From Coccagna et al6). THE WESTERN JOURNAL OF MEDICINE
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large numbers of patients with OHS.6""22"9- The collected evidence shows that soon after the onset of sleep, apnea caused by upper airways obstruction ensues, accompanied by continued but ineffective diaphragmatic attempts at ventilation. Within thirty seconds to two minutes, the arterial Po2 falls to values often as low as 20 to 30 mm of mercury and the arterial Pco2 rises to a range of 60 mm of mercury. During this time both pulmonary and systemic hypertension41'42 occur, probably caused by the combined effects of hypoxia, hypercapnia and reflex sympathetic discharge. Both right and left ventricular failure may ensue. A sleep recording in a patient with OHS in which some of these findings are documented is shown in Figure 1. The cause and site of the obstructive apnea are -debatable. Cinefluoroscopy and fiberoptic observation have shown that during sleep the tongue may fall backwards into the posterior pharynx. The obstruction appears to be in the posterior pharynx at the base of the tongue. A clue to the cause of the obstruction came from electromyographic (EMG) studies of several muscles whose function is to insure a patent airway. These muscles have a tonic discharge while an individual is upright that normally intensifies while supine in order to insure airway patency. For example, the genioglossus is a large muscle located at the base of the tongue, and active contraction of this muscle appears to be required to maintain a patent airway. Recent electromyographic studies of this muscle in patients with OHS have shown that suboptimal EMG activity may occur, thus allowing the base of the tongue to remain prolapsed against the posterior pharynx.45 7UPRIGHT
u
SUPINE
EU
AIRWAY OPEN
Genioglossal EMG:
INSPIRATORY BURSTS
TENDENCY OF TONGU E TO RELAPSE AIRWAY OPEN
Gonloglossal EMG: TONIC ACTIVITY + INSPIRATORY BURSTS
The possible site of obstruction is shown in Figure 2. Bypassing the intermittent obstruction with a nasopharyngeal tube has reversed the symptoms of OHS.22 In obese patients with a florid nocturnal obstructive sleep apnea syndrome tracheostomy has returned arterial blood gas values to normal and has dramatically reversed subjective symptoms, hypoxemia-induced erythrocytosis, pulmonary hypertension and heart failure.40'4' Symptoms return and signs of right ventricular failure and erythrocytosis recur up to a year later if the tracheostomy tube is occluded.22 Moderate weight loss has a beneficial but incomplete effect on obstructive apnea, supporting the view that the distribution of fat may be important.18 At the end of the apnea the electroencephalogram shows that the sleep stage lightens, frequently to full awakening, and ventilation resumes with a snorting gasp as the obstruction is broken.43 The Po2 and Pco2 values return toward normal, only to enter a new cycle a few minutes later. Such patients may sleep less than 30 seconds at a time,29 may actually be awakened over 30 times an hour and may spend less than two hours in effective sleep per night.39 Each period of apnea lasts from 15 to 60 seconds.4' In the morning the patient awakes disoriented, groggy and usually with no knowledge of the recent struggle. Only the patient's spouse may have noted the snoring, twitching, periodic breathing and spells of cyanosis.
The -sleep deprivation sustained by these patients can be subtle, and often only psychiatric disturbances are evident. Personality disorders including paranoia, agitated depression and hosSUP NE
TONGUE RELAPSED AGAINST POSTERIOR PHARYNGEAL WALL AIRWAY OBSTRUCTION
Genioglossal EMG: GREATLY DIMINISHED OR ABSENT ACTIVITY HARPER
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X
SAUE*LANC.
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Figure 2.-Median sections through the region of the pharynx showing the probable site of obstruction. Normally, EMG activity increases in the supine position in an attempt to insure a patent airway. Obstruction appears to occur when supine EMG activity is greatly diminished. (Reproduced by permission from Harper RM, Sauerland EK: The role of the tongue in sleep apnea, In Guilleminault C, Dement WC (Eds): Sleep Apnea Syndromes. New York, Alan R. Liss Inc, 1978, p 225). EMG= electromyogram.
OBESITY-HYPOVENTILATION SYNDROME
tility have been shown to occur frequently and can be abolished with treatment." Life-threatening accidents, job loss, and familial alienation may all be related to hypersomnolence. Life-threatening arrhythmias occurring during obstructive apneas have been noted in these patients during sleep.6 Although tachyarrhythmias, including ventricular tachycardia, occur, severe cyclic bradyarrhythmias appear to be more common (Figure 1). It is likely that this cyclic bradycardia is vagally mediated because it responds to atropine. Cyclic bradycardia is suggestive of OHS, and affords a convenient means to confirm the diagnosis by use of a Holter monitor. The occurrence of sudden death in these patients may be related to such arrhythmias."
Clinical Presentation and Diagnosis The gross obesity and hypersomnolence of the patient with classic OHS provide an unforgettable and unfortunate picture (Figure 3). However, the diagnosis in mild variants of the syndrome is more difficult. In fact such patients are frequently mislabeled and treated for pure erythrocytosis in a hematology clinic, depression or paranoia in a psychiatric unit, idiopathic congestive heart fail-
ure in a cardiology clinic, or atypical chronic obstructive pulmonary disease with cor pulmonale in a general medical clinic. It has been found at the Stanford University sleep clinic that over 15 percent of patients presenting with insomnia have sleep apnea and physiologic disturbances similar to those of OHS.47 Studies of patients with OHS show a five-year mortality rate of over 50 percent due to causes including pulmonary emboli, respiratory failure and sudden death.46'48 Suspicion followed by clinical observation play a major role in diagnosing OHS. Disturbed sleep, morning headache, idiopathic heart failure or erythrocytosis are clues. Because of an almost amnesic state sometimes produced by sleep deprivation, subjective complaints may be absent. Frequently, as mentioned earlier, only the patient's spouse will recall the snoring, spells of apnea or episodes of cyanosis. Observing the patient during sleep will often provide convincing proof. Cessation of airflow at the mouth and nose while vigorous abortive attempts at breathing continue, is diagnostic. Reliance on arterial blood gas samples taken during wakefulness to detect hypoventilation is fraught with error. Often these patients hypoventilate only while supine or asleep and when obstruction occurs. Patients in whom the classic features of OHS are seen should not be hard to diagnose (see Table 1). However, in more subtle cases, nocturnal monitoring is very helpful. The fiberoptic ear oximeter may be used to document nocturnal oxygen desaturation.49 If desaturation occurs during an episode of obstructive apnea that is corrected by a nasopharyngeal tube, the desaturation is probably due to an obstructive apnea. If, however, saturation falls without obvious diaphragmatic excursions, the apneas may be centrally mediated and not obTABLE 1-Features of the Obesity-Hypoventilation
Syndrome
Figure 3.-A woman patient in whom the classic obesity hypoventilation syndrome is seen. Irresistible hypersomnolence, cor pulmonale and polycythemia were present. Hypoventilation was severe (arterial carbon dioxide tension [PaCO2]=68 mm of mercury) but was normal (PaCO2=37 mm of mercury) after two minutes of voluntary hyperventilation.
Primary Obesity Hypoventilation Hypersomnolence
Secondary Polycythemia Cyanosis Periodic respiration Psychiatric disturbances Snoring Tlwitching Right ventricular failure Morning headache
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structive. This is an important point regarding the choice of therapy. Cardiac monitoring is also a helpful way to evaluate such patients. The cyclic episodes of bradycardia often seen in these patients may be the first clue that obstruction is occurring, and reviewing, a 24 hour Holter recording may document arrhythmias suggestive of apneas occurring at night. Documenting nocturnal obstructive apneas and, if possible, showing improvement after several nights sleep with a nasopharyngeal tube in place should be required before any invasive form of therapy such as tracheostomy is attempted. Because some patients may require life-long tracheostomy, questionable cases should be referred to an experienced sleep laboratory for specific diagnosis.
Treatment It may be that obstructive apneas and other events during sleep represent the most pressing indications for treatment. Life-threatening forms of obstructive OHS, particularly those associated with serious bradyarrhythmias and tachyarrhythmias, and profound oxygen desaturation, require immediate endotracheal intubation followed by elective tracheostomy. In less serious cases, weight reduction and low flow oxygen breathing benefit many patients. Weight reduction is clearly the first mode of therapy to be attempted and ventilation can be expected to improve with as little as a 5 to 10 percent loss of body weight. After such a weight loss, obstructive apneas, hypercapnia, pulmonary hypertension and somnolence often lessen.18'43 Unfortunately, weight reduction is often not possible in this group of patients, and long-term success is unlikely. When the attempt at losing weight fails and the degree of hypoxemia is severe, low flow oxygen breathing should be administered at night. Increasing nocturnal arterial blood oxygen saturation to about 90 percent should not produce severe co2 retention and will often result in substantial reversal of cor pulmonale and erythrocytosis, although the obstructive sleep apneas may continue. Another approach to therapy is the use of progestational agents. Progesterone is known to be responsible for hyperventilation in pregnancy and the luteal phase of the menstrual cycle.50'l5 It stimulates alveolar ventilation with a reduction 392
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TABLE 2.-Factors Known to Exacerbate Hypoventilation and Hypoxemia Intrinsic lung diseases Altitude
Thyroid insufficiency Neuromuscular disease Mechanical restriction Sedative-hypnotic drugs Respiratory tract infections Reactive airways diseases Congestive heart failure Neurological diseases Pulmonary emboli
in Pco2 values and increases the ventilatory response to hypercarbia and hypoxia in normal persons.52 In patients with OHS, medroxyprogesterone acetate improves ventilation and reduces heart failure and erythrocytosis,'4'53 although obstructive apneas may continue. Patients with the obstructive form of OHS have dramatically responded to tracheostomy. Within days, florid heart failure, hypersomnolence and paranoid ideations have disappeared. Occlusion of the tracheostomy tube at any time thereafter has caused the syndrome to reoccur.22'40'4' Indications for tracheostomy include severe asphyxia, sleep deprivation due to nocturnal arousals and major arrhythmias. Alternatively, a nasopharyngeal tube has been used to establish an airway each night, but patient acceptance of this has not been good. Every effort must be made to exclude or minimize other causes of hypoventilation or hypoxemia (see Table 2). These causes must be evaluated and corrected before the patient can be assumed to have the syndrome. In many cases, the patient will improve after elimination of a secondary cause. REFERENCES 1. Weil JV, Kryger MH, Scoggin CH: Sleep and breathing at high altitude, In Guilleminault C, Dement WC (Eds): Sleep Apnea Syndromes. New York, Alan R. Liss, 1978 (In Press) 2. Mountain R, Zwillich CW, Weil JV: Hypoventilation in obstructive lung disease: The role of familial factors. N Engl J Med 298:521-525, 1978 3. Sieker HO, Estes EH Jr, Kelser GA, et al: A cardiorespiratory syndrome associated with extreme obesity. J Clin Invest 34: 916-917, 1953 4. Kerr WJ, Lagen JB: The postural syndrome related to obesity leading to postural emphysema and cardiorespiratory failure. Ann Intern Med 10:569-595, 1936 5. Burwell CS, Robin ED, Whaley RD, et al: Extreme obesity associated with alveolar hypoventilation-A pickwickian syndrome. Am J Med 21:811-818, 1956 6. Coccagna G, Mantovani G, Brignani F, et al: Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physio-Path 8:1159-1172, 1972 7. Weil MH, Prasad AS: Polycythemia of obesity-Further studies of its mechanism and a report of two additional cases. An Intern Med 46:60-67, 1957 8. Bedell GN, Wilson WR, Seebohm PM: Pulmonary function in obese persons. J Clin Invest 37:1049-1060, 1958 9. Kaufman BJ, Ferguson MH, Cherniack RM: Hypoventilation in obesity. J Clin Invest 38: 500-507, 1959 10. Gilbert R, Sipple JH, Auchincloss JH: Respiratory control and work of breathing in obese subjects. J Appl Physiol 16:21-26, 1961 11. Addington WW, Pfeiffer SH, Gaensler EA: Obesity and alveolar hypoventilation. Respiration 26:214-225, 1969
OBESITY-HYPOVENTILATION SYNDROME 12. Alexander JK, Amad KH, Cole VW: Observations on some clinical features of extreme obesity, with particular reference to cardiorespiratory effects. Am J Med 32:512-524, 1962 13. Cullen JH, Formel PF: The respiratory defects in extreme obesity. Am J Med 32:525-531, 1962 14. Sutton FD, Zwillich CW, Creagh CE, et al: Progesterone for outpatient treatment of pickwickian syndrome. Ann Intern Med 83:476-479, 1975 15. Said SJ: Abnormalities of pulmonary gas exchange in obesity. Ann Intern Med 53:1121-1129, 1960 16. Mellins RB, Balfour HH, Turino GM, et al: Failure of automatic control of ventilation (Ondine's curse). Medicine 49: 487-504, 1970 17. Richter T, West JR, Fishman AP: The syndrome of alveolar hypoventilation and diminished sensitivity of the respiratory center. N Engl J Med 256:1165-1170, 1957 18. Hishikawa Y, Furuya E, Wakamatsu H, et al: A polygraphic study of hypersomnia with periodic-breathing and primary alveolar hypoventilation. Bull Physio-Path Resp 8:1139-1151, 1970 19. Mcllroy MB, Eldridge FL, Thomas JP, et al: The effect of added elastic and non-elastic resistances on the pattern of breathing in normal subjects. Clin Sci 15:336-344, 1956 20. Rochester DF, Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am J Med 57: 402-420, 1974 21. Sharp JT, Henry JP, Sweany SK, et al: The total work of breathing in normal and obese men. J Clin Invest 43:728-739, 1964 22. Walsh RE, Michaelson ED, Harkleroad LE, et al: Upper airway obstruction in obese patients with sleep disturbance and somnolence. Ann Intern Med 76:185-192, 1972 23. Holley HS, Milic-Emili J, Becklake MR, et al: Regional distribution of pulmonary ventilation and perfusion in obesity. J Clin Invest 46:475-481, 1967 24. Read DJC: A clinical method for assessing the ventilatory response to C02. Aust Ann Med 16:20-32, 1966 25. Zwillich CW, Sutton FD, Pierson DJ: Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 59:343-348, 1975 26. Kronenberg RS, Gabel RA, Severinghaus JW: Normal chemoreceptor function in obesity before and after ileal bypass surgery to force weight reduction. Am J Med 59:349-356, 1975 27. Rodman T, Resnick ME, Berkowitz RD, et al: Alveolar hypoventilation due to involvement of the respiratory center by obscure disease of the central nervous system. Am J Med 32: 208-217, 1962 28. Pedersen J, Torp-Pedersen E: Ventilatory insufficiency in extreme obesity. Acta Med Scand 167:343-352, 1960 29. Kronenberg RS, Drage CW, Stevenson JE: Acute respiratory failure and obesity with normal vent'ilatory response to carbon dioxide and absent hypoxic ventilatory drive. Am J Med 62:772776, 1977 30. Comroe JH: The peripheral chemoreceptor, In Fenn WO, Rahn H (Eds); Handbook of -Physiology. American Physiological Society, Section 3, 1:557-583, 1964 31. Weil JV, Byrne-Quinn E, Sodal IE, et al: Hypoxic ventilatory drive in man. J Clin Invest 49:1061-1072, 1970 32. Weil JV, Byrne-Quinn E, Sodal IE, et al: Acquired attenuation of chemoreceptor function in chronically hypoxic man at altitude. J Clin Invest 50:186-195, 1971 33. Sorensen SC, Severinghaus JW: Respiratory insensitivity to
acute hypoxia persisting after correction of Tetralogy of Fallot. J Appl Physiol 25:221-223, 1968 34. Vogel JH, Hartley LH, Jamieson G, et al: Impairment of ventilatory response to hypoxia in individuals with obesity and hypoventilation-A concept of the pickwickian syndrome. Circulation 36:1I1-258, 1967 35. Scoggin CH, Zwillich CW, Doeckel RC, et al: Familial aspects of decreased hypoxic ventilatory response in endurance runners. J AppI Physiol 44:464-468, 1978 36. Collins D, Scoggin C, Zwillich CW, et al: Hereditary aspects of decreased hypoxic response. J Clin Invest 62:105-110, 1978 37. Fishman LS, Samson JH, Sperling DR: Primary alveolar hypoventilation syndrome (Ondine's curse)-Association with manifestations of hypothalamic disease. Am J Dis Child 110: 155-161, 1965 38. Dickens C: The Posthumous Papers of the Pickwick Club. 39. Gastaut H, Tassinari LA, Duron B: Polygraphic study of the episodic diurnal manifestations of the Pickwick syndrome. Brain Research 2:167-186, 1966 40. Coccagna G, Mantovani M, Brignani F, et al: Tracheostomy in hypersomnia with periodic breathing. Bull Physio-Path Resp 8:1217-1227, 1972 41. Kuhlo W, Doll E: Pulmonary hypertension and the effect of tracheotomy in a case of pickwickian syndrome. Bull PhysioPath Resp 8:1205-1216, 1972 42. Lonsdorfer J, Meviner-Caris J, Lampert-Benignus E, et al: Haemodynamic and respiratory aspects of the pickwickian syndrome. Bull Physio-Path Resp 8:1181-1192, 1972 43. Lugaresi E, Coccagna G, Mantovani M, et al: Hypersomnia with periodic breathing-Periodic apneas and alveolar hypoventilation during sleep. Bull Physio Path Resp 8:1103-1113, 1972 44. Sackner MA, Landa J, Forrest T, et al: Periodic sleep apnea-Chronic sleep deprivation related to intermittent upper airway obstruction and central nervous system disturbance. Chest 67:164-171, 1975 45. Sauerland EK, Harper RM: The human tongue during sleep-Electromyographic activity of the genioglossus muscle. Exp Neurol 51:160-170, 1976 46. MacGregor MI, Block AJ, Ball WC Jr: Serious complications and sudden death in the pickwickian syndrome. J Hopkins Mdd J 126:279-295, 1970 47. Guilleminault C, Tilkian A, Dement WC: The sleep apnea syndromes. Ann Rev Med 27:465-484, 1976 48. Miller A, Granada M: In-hospital mortality in the pickwickian syndrome. Am J Med 56:144-150, 1974 49. Scoggin C, Nett L, Petty TL: Clinical evaluation of a new ear oximeter. Heart and Lung 6:121-126, 1977 50. Goodland RL, Reynolds JG, Pommerenke WT: Alveolar carbon dioxide tension levels during pregnancy and early puerperium. J Clin Endocr 14:522-530, 1954 51. Doring GH, Ioeschcke HH: Atmung und Saure-Basengleichogewicht in der Schwangerschaft. Pfluegers Arch Gesamte PhysiolMenschen Tiere 249:437-451, 1947 52. Zwillich CW, Natalino MR, Sutton F, et al: Effects of progesterone on ventilation in normal man. J Clin Lab Med (in
Press)
53. Lyons H, Huang CT: Therapeutic fse of progesterone in alveolar hypoventilation associated with obesity. Am J Med 44: 881-888, 1968
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Medical Progress
The Obesity-Hypoventilation Syndrome EDWARD J. MORGAN, MD, PhD, and CLIFFORD W. ZWILLICH, MD, Denver
The triad of obesity, hypoventilation and inordinate hypersomnolence characterizes the obesity-hypoventilation syndrome. The reasons for daytime hypoventilation appear related to decreased chemical drives to breathe combined with the added physical impediment of extreme obesity. When the physiology of sleep was investigated in patients with this syndrome, intermittent nocturnal obstructive apneas were documented that produced blood gas abnormalities, arrhythmias and serious elevations of both pulmonary and systemic pressures. The obstructive apneas are due to intermittent loss of muscle tone of the tongue resulting in its prolapse against the posterior pharynx. The special importance of the obesity-hypoventilation syndrome lies in its being an example of a disorder of sleep and breathing that can appear in widely different clinical settings. Therapeutic measures include weight loss, progestational agents or permanent tracheostomy. THE OBESITY-HYPOVENTILATION SYNDROME (OHS) is an uncommon illness characterized by obesity,
hypoventilation and often irresistible hypersomnolence. It might have remained only a grotesque curiosity were it not for interest in its fascinating pathophysiology, involving disorders of both sleep and the control of breathing. When investigators examined the physiology of sleep in OHS, an unexpected series of life-threatening events was documented. Even such dissimilar examples as sleep at high altitude' and respiratory control in some patients with chronic obstructive lung disease2 share a mechanism with OHS. Therefore, the reader should realize that the pathophysiology of the OHS is similar to that found in more common medical disorders. This From the Cardiovascular Pulmonary Research Laboratory and Division of Pulmonary Sciences, Department of Medicine, University of Colorado Medical Center, Denver. Dr. Zwillich is a recipient of NIH Research Career Development Award (HL 00225). Reprint requests to: Clifford W. Zwillich, MD, CVP Research Laboratory, B-133, University of Colorado Medical Center, 4200 E. Ninth Avenue, Denver, CO 80262.
review describes in detail the physiology of OHS, discusses its interrelationships with other disorders and provides a basis for therapy.
Background The OHS has been recognized for over a hundred years. Early investigators knew that a coffelation existed between obesity and cardiopulmonary problems. In the past it has been called obesity heart disease3 and the postural syndrome related to obesity and cardiorespiratory failure.4 In 1956 Burwell, Robin and colleagues coined the term Pickwickian syndrome.5 We prefer the name obesity-hypoventilation syndrome (OHS), which emphasizes the abnormal ventilation found in these patients.
Pathophysiology Hypoventilation with an elevated arterial partial pressure of carbon dioxide (Pco,) is the central pathophysiologic disturbance in patients THE WESTERN JOURNAL OF MEDICINE
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with OHS. The subsequent hypercapnia, acidemia and hypoxemia cause a rise in the mean pulmonary artery pressure with resultant right heart failure. Hypoventilation is most severe during sleep, and may result in severe transient systemic hypertension which places a significant burden on left ventricular ejection. Left ventricular failure then ensues which further compromises the patient's condition.6 Erythrocytosis commonly occurs with a hematocrit over 60 percent.7 Mechanical Factors Early investigators attempted to blame obesity alone as the major cause of hypoventilation.8'0 Several lines of evidence show that this is not the case. First, only a minority of obese patients have significant hypoventilation8-'2 and there is no correlation between body weight and arterial carbon dioxide pressure (Pco,) in obese patients.'3 Second, in patients with OHS, arterial blood gas values easily return to normal with voluntary hyperventilation, indicating that mechanical factors are not critically limiting the patients' ability to ventilate normally.14" 5 Third, one need not be massively obese to hypoventilate, which suggests that other factors are also at work."1"16-18 Last, elastic loading of respiration in normal persons (used to simulate obesity) is not associated with hypoventilation.'9 Although patients with OHS have restrictive abnormalities of lung function that are more severe than those of patients with simple obesity,20 this alone appears insufficient as a cause of hypoventilation. Moderate weight reduction in patients with OHS leads to marked improvement in vital capacity, lung compliance, arterial blood gas values, and clinical symptoms.20 This suggests that either the absolute weight or the distribution of obesity which is usually truncal in patients with OHS may be important factors in the pathogenesis. Weight loss may result in a critical decrease in the work of breathing.21 Although the role of excess weight in patients with OHS is only a cofactor, it undoubtedly plays a synergistic role. There is no doubt, however, that weight reduction is effective in treating patients with OHS.5'8"18'20'22 The hypoxemia associated with OHS is frequently more severe than what would be expected on the basis of the degree of hypoventilation.'5 This may be explained by ventilation/perfusion mismatch with decreased basilar ventilation.23 388
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Factors That Control Respiration Mechanical factors alone do not provide an explanation for hypoventilation, as was emphasized by Bedell, Wilson and Seebohm in 1958 when they showed that most obese persons do not hypoventilate unless an insult such as pneumonia or myxedema is added.8 Because obesity alone does not explain the hypoventilation of patients with OHS, studies have been done to evaluate the homeostatic mechanisms controlling arterial Pco2 and oxygen pressure (Po2) in this syndrome. Arterial Pco2 is closely controlled in healthy persons within a narrow range. Increases of Pco2 are met with a steep linear ventilatory response averaging at least a three-fold increase in minute ventilation per rise in Pco2 of 10 mm of mercury.24 The normal increase in ventilation stimulated by inhalation of carbon dioxide (co2) is blunted in patients with OHS and not in patients with comparable simple obesity.25'26 Decreased responses to co2 have also been shown in nonobese patients who hypoventilate,'7 and in patients with idiopathic hypoventilation (Ondine's curse) .16,27 In patients with OHS, weight loss usually improves the hypercapnic ventilatory response, suggesting that the decreased response may be the result of mechanical consequences of obesity and not the primary cause of hypoventilation.5'28 Whether a blunted hypercapnic response is a primary pathogenetic mechanism of the syndrome or is only a secondary finding is unresolved. Similarly, a blunted hypoxic ventilatory response is a common finding in these patients25'29 and is reduced to approximately 20 percent of normal values.25 The carotid body is the major detector of decreased levels of arterial oxygen tension,30 and minute ventilation rises exponentially when Po2 falls below 50 to 60 mm of mercury.3' Chronic hypoxemia can blunt the hypoxic ventilatory response, as seen in residents of high altitude32 and in patients with cyanotic congenital heart disease.33 Since weight loss may not improve the ventilatory response to hypoxia,34 a blunted hypoxic response may be a primary rather than a secondary feature of the syndrome. Blunting of the response due to chronic hypoxemia is an unlikely possibility, because it takes over 25 years of hypoxemia before a reduced hypoxic drive is seen in persons living at high altitude.32 Hence, the reason for this blunted hypoxic re-
OBESITY-HYPOVENTILATION SYNDROME
sponse in OHS iS unknown. There is evidence to suggest that a decreased hypoxic response may be genetically mediated. Studies in endurance athletes,35 in patients with chronic obstructive lung disease with hypoventilation,2 and in twins36 all suggest that there is a significant familial predisposition for the hypoxic ventilatory response. It may be that in obese patients who are genetically preselected for abnormalities in ventilatory drive, OHS develops. An enticing theory about obesity and decreased chemical drives to breathe is alluded to in a report of an obese child with hypoventilation and evidence of hypothalamic injury. The patient was found to have a voracious appetite, diabetes insipidus, lethargy and cyanosis.37 However, this possible central nervous system abnormality has not proved to be universal in patients with OHS, as post-mortem studies on these patients typically failed to show any consistent central nervous system abnormalities.
Sleep Studies Hypersomnolence is a severe and striking part of the OHS. Joe in Dickens' The Posthumous Papers of the Pickwick Club fell asleep while knocking on a door.38 Burwell's patient realized that he needed medical help when he fell asleep holding a full house during a poker game.5 Patients have B.Mass. 13yrs
also been known to fall asleep while driving a car. The reasons for this hypersomnolence have only recently been understood. Because acute elevations of arterial Pco2 values produce disorientation, lethargy, and coma, it was thought that somnolence was related to carbon dioxide narcosis. However, somnolence does not correlate with an elevated Pco2.3940 Indeed, somnolence usually precedes any rise in Pco2 in patients who are awake. Patients with an acutely elevated Pco2 become disoriented, obtunded and finally comatose and unarousable. Patients with OHS display a different pattern, with irresistible somnolence yielding to a deep sleep from which the patient can be aroused." Critical studies which ultimately led to the understanding of the mechanism of sleep-wakefulness disturbances in OHS were those of Gastaut, Tassinari and Duron, who documented dramatic cyclic breathing pauses or apneas in certain patients with OHS.39 During such pauses airflow ceased but respiratory effort, measured as intrathoracic pressure swings, continued. These are termed obstructive, or peripheral apneas. This intermittent upper airway obstruction was accompanied by significant hypercapnia and hypoxemia.39 No apneas were detected during wakefulness. This observation has been extended to
Sleep St 3
Awake
R.Front-Temp R Cent-Occ _~~~~~~~~
E M G~-
M 604
0"._
-
A.M0 N
--
EKGG Heart Rate
(Beats/mr.) 2Cse:
Arter Press -, i (mm Hg)
Pulm Art Press (mm Hg)
Thor Resp
Oral Resp
mm
Figure 1.-Nocturnal sleep record of a patient with OHS and obstructive sleep apnea. Oral respiration has stopped although thoracic excursions of increasing effort continue. Pulmonary and systemic hypertension are illustrated along with the cyclic bradycardia often found in OHS. (From Coccagna et al6). THE WESTERN JOURNAL OF MEDICINE
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large numbers of patients with OHS.6""22"9- The collected evidence shows that soon after the onset of sleep, apnea caused by upper airways obstruction ensues, accompanied by continued but ineffective diaphragmatic attempts at ventilation. Within thirty seconds to two minutes, the arterial Po2 falls to values often as low as 20 to 30 mm of mercury and the arterial Pco2 rises to a range of 60 mm of mercury. During this time both pulmonary and systemic hypertension41'42 occur, probably caused by the combined effects of hypoxia, hypercapnia and reflex sympathetic discharge. Both right and left ventricular failure may ensue. A sleep recording in a patient with OHS in which some of these findings are documented is shown in Figure 1. The cause and site of the obstructive apnea are -debatable. Cinefluoroscopy and fiberoptic observation have shown that during sleep the tongue may fall backwards into the posterior pharynx. The obstruction appears to be in the posterior pharynx at the base of the tongue. A clue to the cause of the obstruction came from electromyographic (EMG) studies of several muscles whose function is to insure a patent airway. These muscles have a tonic discharge while an individual is upright that normally intensifies while supine in order to insure airway patency. For example, the genioglossus is a large muscle located at the base of the tongue, and active contraction of this muscle appears to be required to maintain a patent airway. Recent electromyographic studies of this muscle in patients with OHS have shown that suboptimal EMG activity may occur, thus allowing the base of the tongue to remain prolapsed against the posterior pharynx.45 7UPRIGHT
u
SUPINE
EU
AIRWAY OPEN
Genioglossal EMG:
INSPIRATORY BURSTS
TENDENCY OF TONGU E TO RELAPSE AIRWAY OPEN
Gonloglossal EMG: TONIC ACTIVITY + INSPIRATORY BURSTS
The possible site of obstruction is shown in Figure 2. Bypassing the intermittent obstruction with a nasopharyngeal tube has reversed the symptoms of OHS.22 In obese patients with a florid nocturnal obstructive sleep apnea syndrome tracheostomy has returned arterial blood gas values to normal and has dramatically reversed subjective symptoms, hypoxemia-induced erythrocytosis, pulmonary hypertension and heart failure.40'4' Symptoms return and signs of right ventricular failure and erythrocytosis recur up to a year later if the tracheostomy tube is occluded.22 Moderate weight loss has a beneficial but incomplete effect on obstructive apnea, supporting the view that the distribution of fat may be important.18 At the end of the apnea the electroencephalogram shows that the sleep stage lightens, frequently to full awakening, and ventilation resumes with a snorting gasp as the obstruction is broken.43 The Po2 and Pco2 values return toward normal, only to enter a new cycle a few minutes later. Such patients may sleep less than 30 seconds at a time,29 may actually be awakened over 30 times an hour and may spend less than two hours in effective sleep per night.39 Each period of apnea lasts from 15 to 60 seconds.4' In the morning the patient awakes disoriented, groggy and usually with no knowledge of the recent struggle. Only the patient's spouse may have noted the snoring, twitching, periodic breathing and spells of cyanosis.
The -sleep deprivation sustained by these patients can be subtle, and often only psychiatric disturbances are evident. Personality disorders including paranoia, agitated depression and hosSUP NE
TONGUE RELAPSED AGAINST POSTERIOR PHARYNGEAL WALL AIRWAY OBSTRUCTION
Genioglossal EMG: GREATLY DIMINISHED OR ABSENT ACTIVITY HARPER
390
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X
SAUE*LANC.
1976
Figure 2.-Median sections through the region of the pharynx showing the probable site of obstruction. Normally, EMG activity increases in the supine position in an attempt to insure a patent airway. Obstruction appears to occur when supine EMG activity is greatly diminished. (Reproduced by permission from Harper RM, Sauerland EK: The role of the tongue in sleep apnea, In Guilleminault C, Dement WC (Eds): Sleep Apnea Syndromes. New York, Alan R. Liss Inc, 1978, p 225). EMG= electromyogram.
OBESITY-HYPOVENTILATION SYNDROME
tility have been shown to occur frequently and can be abolished with treatment." Life-threatening accidents, job loss, and familial alienation may all be related to hypersomnolence. Life-threatening arrhythmias occurring during obstructive apneas have been noted in these patients during sleep.6 Although tachyarrhythmias, including ventricular tachycardia, occur, severe cyclic bradyarrhythmias appear to be more common (Figure 1). It is likely that this cyclic bradycardia is vagally mediated because it responds to atropine. Cyclic bradycardia is suggestive of OHS, and affords a convenient means to confirm the diagnosis by use of a Holter monitor. The occurrence of sudden death in these patients may be related to such arrhythmias."
Clinical Presentation and Diagnosis The gross obesity and hypersomnolence of the patient with classic OHS provide an unforgettable and unfortunate picture (Figure 3). However, the diagnosis in mild variants of the syndrome is more difficult. In fact such patients are frequently mislabeled and treated for pure erythrocytosis in a hematology clinic, depression or paranoia in a psychiatric unit, idiopathic congestive heart fail-
ure in a cardiology clinic, or atypical chronic obstructive pulmonary disease with cor pulmonale in a general medical clinic. It has been found at the Stanford University sleep clinic that over 15 percent of patients presenting with insomnia have sleep apnea and physiologic disturbances similar to those of OHS.47 Studies of patients with OHS show a five-year mortality rate of over 50 percent due to causes including pulmonary emboli, respiratory failure and sudden death.46'48 Suspicion followed by clinical observation play a major role in diagnosing OHS. Disturbed sleep, morning headache, idiopathic heart failure or erythrocytosis are clues. Because of an almost amnesic state sometimes produced by sleep deprivation, subjective complaints may be absent. Frequently, as mentioned earlier, only the patient's spouse will recall the snoring, spells of apnea or episodes of cyanosis. Observing the patient during sleep will often provide convincing proof. Cessation of airflow at the mouth and nose while vigorous abortive attempts at breathing continue, is diagnostic. Reliance on arterial blood gas samples taken during wakefulness to detect hypoventilation is fraught with error. Often these patients hypoventilate only while supine or asleep and when obstruction occurs. Patients in whom the classic features of OHS are seen should not be hard to diagnose (see Table 1). However, in more subtle cases, nocturnal monitoring is very helpful. The fiberoptic ear oximeter may be used to document nocturnal oxygen desaturation.49 If desaturation occurs during an episode of obstructive apnea that is corrected by a nasopharyngeal tube, the desaturation is probably due to an obstructive apnea. If, however, saturation falls without obvious diaphragmatic excursions, the apneas may be centrally mediated and not obTABLE 1-Features of the Obesity-Hypoventilation
Syndrome
Figure 3.-A woman patient in whom the classic obesity hypoventilation syndrome is seen. Irresistible hypersomnolence, cor pulmonale and polycythemia were present. Hypoventilation was severe (arterial carbon dioxide tension [PaCO2]=68 mm of mercury) but was normal (PaCO2=37 mm of mercury) after two minutes of voluntary hyperventilation.
Primary Obesity Hypoventilation Hypersomnolence
Secondary Polycythemia Cyanosis Periodic respiration Psychiatric disturbances Snoring Tlwitching Right ventricular failure Morning headache
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structive. This is an important point regarding the choice of therapy. Cardiac monitoring is also a helpful way to evaluate such patients. The cyclic episodes of bradycardia often seen in these patients may be the first clue that obstruction is occurring, and reviewing, a 24 hour Holter recording may document arrhythmias suggestive of apneas occurring at night. Documenting nocturnal obstructive apneas and, if possible, showing improvement after several nights sleep with a nasopharyngeal tube in place should be required before any invasive form of therapy such as tracheostomy is attempted. Because some patients may require life-long tracheostomy, questionable cases should be referred to an experienced sleep laboratory for specific diagnosis.
Treatment It may be that obstructive apneas and other events during sleep represent the most pressing indications for treatment. Life-threatening forms of obstructive OHS, particularly those associated with serious bradyarrhythmias and tachyarrhythmias, and profound oxygen desaturation, require immediate endotracheal intubation followed by elective tracheostomy. In less serious cases, weight reduction and low flow oxygen breathing benefit many patients. Weight reduction is clearly the first mode of therapy to be attempted and ventilation can be expected to improve with as little as a 5 to 10 percent loss of body weight. After such a weight loss, obstructive apneas, hypercapnia, pulmonary hypertension and somnolence often lessen.18'43 Unfortunately, weight reduction is often not possible in this group of patients, and long-term success is unlikely. When the attempt at losing weight fails and the degree of hypoxemia is severe, low flow oxygen breathing should be administered at night. Increasing nocturnal arterial blood oxygen saturation to about 90 percent should not produce severe co2 retention and will often result in substantial reversal of cor pulmonale and erythrocytosis, although the obstructive sleep apneas may continue. Another approach to therapy is the use of progestational agents. Progesterone is known to be responsible for hyperventilation in pregnancy and the luteal phase of the menstrual cycle.50'l5 It stimulates alveolar ventilation with a reduction 392
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TABLE 2.-Factors Known to Exacerbate Hypoventilation and Hypoxemia Intrinsic lung diseases Altitude
Thyroid insufficiency Neuromuscular disease Mechanical restriction Sedative-hypnotic drugs Respiratory tract infections Reactive airways diseases Congestive heart failure Neurological diseases Pulmonary emboli
in Pco2 values and increases the ventilatory response to hypercarbia and hypoxia in normal persons.52 In patients with OHS, medroxyprogesterone acetate improves ventilation and reduces heart failure and erythrocytosis,'4'53 although obstructive apneas may continue. Patients with the obstructive form of OHS have dramatically responded to tracheostomy. Within days, florid heart failure, hypersomnolence and paranoid ideations have disappeared. Occlusion of the tracheostomy tube at any time thereafter has caused the syndrome to reoccur.22'40'4' Indications for tracheostomy include severe asphyxia, sleep deprivation due to nocturnal arousals and major arrhythmias. Alternatively, a nasopharyngeal tube has been used to establish an airway each night, but patient acceptance of this has not been good. Every effort must be made to exclude or minimize other causes of hypoventilation or hypoxemia (see Table 2). These causes must be evaluated and corrected before the patient can be assumed to have the syndrome. In many cases, the patient will improve after elimination of a secondary cause. REFERENCES 1. Weil JV, Kryger MH, Scoggin CH: Sleep and breathing at high altitude, In Guilleminault C, Dement WC (Eds): Sleep Apnea Syndromes. New York, Alan R. Liss, 1978 (In Press) 2. Mountain R, Zwillich CW, Weil JV: Hypoventilation in obstructive lung disease: The role of familial factors. N Engl J Med 298:521-525, 1978 3. Sieker HO, Estes EH Jr, Kelser GA, et al: A cardiorespiratory syndrome associated with extreme obesity. J Clin Invest 34: 916-917, 1953 4. Kerr WJ, Lagen JB: The postural syndrome related to obesity leading to postural emphysema and cardiorespiratory failure. Ann Intern Med 10:569-595, 1936 5. Burwell CS, Robin ED, Whaley RD, et al: Extreme obesity associated with alveolar hypoventilation-A pickwickian syndrome. Am J Med 21:811-818, 1956 6. Coccagna G, Mantovani G, Brignani F, et al: Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physio-Path 8:1159-1172, 1972 7. Weil MH, Prasad AS: Polycythemia of obesity-Further studies of its mechanism and a report of two additional cases. An Intern Med 46:60-67, 1957 8. Bedell GN, Wilson WR, Seebohm PM: Pulmonary function in obese persons. J Clin Invest 37:1049-1060, 1958 9. Kaufman BJ, Ferguson MH, Cherniack RM: Hypoventilation in obesity. J Clin Invest 38: 500-507, 1959 10. Gilbert R, Sipple JH, Auchincloss JH: Respiratory control and work of breathing in obese subjects. J Appl Physiol 16:21-26, 1961 11. Addington WW, Pfeiffer SH, Gaensler EA: Obesity and alveolar hypoventilation. Respiration 26:214-225, 1969
OBESITY-HYPOVENTILATION SYNDROME 12. Alexander JK, Amad KH, Cole VW: Observations on some clinical features of extreme obesity, with particular reference to cardiorespiratory effects. Am J Med 32:512-524, 1962 13. Cullen JH, Formel PF: The respiratory defects in extreme obesity. Am J Med 32:525-531, 1962 14. Sutton FD, Zwillich CW, Creagh CE, et al: Progesterone for outpatient treatment of pickwickian syndrome. Ann Intern Med 83:476-479, 1975 15. Said SJ: Abnormalities of pulmonary gas exchange in obesity. Ann Intern Med 53:1121-1129, 1960 16. Mellins RB, Balfour HH, Turino GM, et al: Failure of automatic control of ventilation (Ondine's curse). Medicine 49: 487-504, 1970 17. Richter T, West JR, Fishman AP: The syndrome of alveolar hypoventilation and diminished sensitivity of the respiratory center. N Engl J Med 256:1165-1170, 1957 18. Hishikawa Y, Furuya E, Wakamatsu H, et al: A polygraphic study of hypersomnia with periodic-breathing and primary alveolar hypoventilation. Bull Physio-Path Resp 8:1139-1151, 1970 19. Mcllroy MB, Eldridge FL, Thomas JP, et al: The effect of added elastic and non-elastic resistances on the pattern of breathing in normal subjects. Clin Sci 15:336-344, 1956 20. Rochester DF, Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am J Med 57: 402-420, 1974 21. Sharp JT, Henry JP, Sweany SK, et al: The total work of breathing in normal and obese men. J Clin Invest 43:728-739, 1964 22. Walsh RE, Michaelson ED, Harkleroad LE, et al: Upper airway obstruction in obese patients with sleep disturbance and somnolence. Ann Intern Med 76:185-192, 1972 23. Holley HS, Milic-Emili J, Becklake MR, et al: Regional distribution of pulmonary ventilation and perfusion in obesity. J Clin Invest 46:475-481, 1967 24. Read DJC: A clinical method for assessing the ventilatory response to C02. Aust Ann Med 16:20-32, 1966 25. Zwillich CW, Sutton FD, Pierson DJ: Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 59:343-348, 1975 26. Kronenberg RS, Gabel RA, Severinghaus JW: Normal chemoreceptor function in obesity before and after ileal bypass surgery to force weight reduction. Am J Med 59:349-356, 1975 27. Rodman T, Resnick ME, Berkowitz RD, et al: Alveolar hypoventilation due to involvement of the respiratory center by obscure disease of the central nervous system. Am J Med 32: 208-217, 1962 28. Pedersen J, Torp-Pedersen E: Ventilatory insufficiency in extreme obesity. Acta Med Scand 167:343-352, 1960 29. Kronenberg RS, Drage CW, Stevenson JE: Acute respiratory failure and obesity with normal vent'ilatory response to carbon dioxide and absent hypoxic ventilatory drive. Am J Med 62:772776, 1977 30. Comroe JH: The peripheral chemoreceptor, In Fenn WO, Rahn H (Eds); Handbook of -Physiology. American Physiological Society, Section 3, 1:557-583, 1964 31. Weil JV, Byrne-Quinn E, Sodal IE, et al: Hypoxic ventilatory drive in man. J Clin Invest 49:1061-1072, 1970 32. Weil JV, Byrne-Quinn E, Sodal IE, et al: Acquired attenuation of chemoreceptor function in chronically hypoxic man at altitude. J Clin Invest 50:186-195, 1971 33. Sorensen SC, Severinghaus JW: Respiratory insensitivity to
acute hypoxia persisting after correction of Tetralogy of Fallot. J Appl Physiol 25:221-223, 1968 34. Vogel JH, Hartley LH, Jamieson G, et al: Impairment of ventilatory response to hypoxia in individuals with obesity and hypoventilation-A concept of the pickwickian syndrome. Circulation 36:1I1-258, 1967 35. Scoggin CH, Zwillich CW, Doeckel RC, et al: Familial aspects of decreased hypoxic ventilatory response in endurance runners. J AppI Physiol 44:464-468, 1978 36. Collins D, Scoggin C, Zwillich CW, et al: Hereditary aspects of decreased hypoxic response. J Clin Invest 62:105-110, 1978 37. Fishman LS, Samson JH, Sperling DR: Primary alveolar hypoventilation syndrome (Ondine's curse)-Association with manifestations of hypothalamic disease. Am J Dis Child 110: 155-161, 1965 38. Dickens C: The Posthumous Papers of the Pickwick Club. 39. Gastaut H, Tassinari LA, Duron B: Polygraphic study of the episodic diurnal manifestations of the Pickwick syndrome. Brain Research 2:167-186, 1966 40. Coccagna G, Mantovani M, Brignani F, et al: Tracheostomy in hypersomnia with periodic breathing. Bull Physio-Path Resp 8:1217-1227, 1972 41. Kuhlo W, Doll E: Pulmonary hypertension and the effect of tracheotomy in a case of pickwickian syndrome. Bull PhysioPath Resp 8:1205-1216, 1972 42. Lonsdorfer J, Meviner-Caris J, Lampert-Benignus E, et al: Haemodynamic and respiratory aspects of the pickwickian syndrome. Bull Physio-Path Resp 8:1181-1192, 1972 43. Lugaresi E, Coccagna G, Mantovani M, et al: Hypersomnia with periodic breathing-Periodic apneas and alveolar hypoventilation during sleep. Bull Physio Path Resp 8:1103-1113, 1972 44. Sackner MA, Landa J, Forrest T, et al: Periodic sleep apnea-Chronic sleep deprivation related to intermittent upper airway obstruction and central nervous system disturbance. Chest 67:164-171, 1975 45. Sauerland EK, Harper RM: The human tongue during sleep-Electromyographic activity of the genioglossus muscle. Exp Neurol 51:160-170, 1976 46. MacGregor MI, Block AJ, Ball WC Jr: Serious complications and sudden death in the pickwickian syndrome. J Hopkins Mdd J 126:279-295, 1970 47. Guilleminault C, Tilkian A, Dement WC: The sleep apnea syndromes. Ann Rev Med 27:465-484, 1976 48. Miller A, Granada M: In-hospital mortality in the pickwickian syndrome. Am J Med 56:144-150, 1974 49. Scoggin C, Nett L, Petty TL: Clinical evaluation of a new ear oximeter. Heart and Lung 6:121-126, 1977 50. Goodland RL, Reynolds JG, Pommerenke WT: Alveolar carbon dioxide tension levels during pregnancy and early puerperium. J Clin Endocr 14:522-530, 1954 51. Doring GH, Ioeschcke HH: Atmung und Saure-Basengleichogewicht in der Schwangerschaft. Pfluegers Arch Gesamte PhysiolMenschen Tiere 249:437-451, 1947 52. Zwillich CW, Natalino MR, Sutton F, et al: Effects of progesterone on ventilation in normal man. J Clin Lab Med (in
Press)
53. Lyons H, Huang CT: Therapeutic fse of progesterone in alveolar hypoventilation associated with obesity. Am J Med 44: 881-888, 1968
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