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Medical Staff Conference

Refer to: The pickwickian syndrome-Medical Staff Conference, University of California, San Francisco. West J Med 127:24-31, Jul 1977

The Pickwickian Syndrome

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and H. David Watts, Assistant Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.

DR. SMITH: * At Medical Grand Rounds this morning we are going to have an interesting and important topic related to respiratory difficulties, the pickwickian syndrome. The case presentation will be given by Dr. Homer Boushey, who will also lead the discussion. DR. BOUSHEY:t The major problem of today's patient is one of daytime somnolence. The patient is a 35-year-old unemployed cab driver who presented with a two-year history of repeatedly falling asleep throughout the day. The somnolence occurred at any time-while watching television, conversing with another person or playing with his children. He had twice fallen asleep while driving his car and had once driven his car into a ditch. On one occasion he alarmed a passenger by driving his cab several blocks on a downtown street, acting as if he were "in a trance." One consequence of these events was the suspension of his driver's license, depriving him of his means of support. During the same two years, the patient had difficulties with sleeping at night. He slept with great difficulty, often waking with a gagging sensation, feeling as though "a valve had
ment of Medicine.

*Lloyd H. Smith, Jr., MD, Professor

and Chairman, Depart-

tHomer Boushey, MD, Assistant Professor of Medicine.

been turned" in his throat so that he rose from the bed fighting for air. His wife reported that he snored loudly and thrashed about in bed, twice striking her in his sleep. She had taken to retiring on the couch in self-defense. The patient said that there had been no hallucinations, cataplexy, sleep walking or urinary incontinence. One year before referral here he was admitted to hospital for massive edema of both legs, extending from the ankles to the thighs. Findings on a radiograph of the chest, electrocardiogram, electroencephalogram, and CT brain scan showed no abnormalities. He was treated with hydrochlorothiazide and methylphenidate hydrochloride usp (Ritalin), in doses from 10 to 40 mg three times a day. The leg edema cleared, but somnolence did not improve and the patient was referred here for further evaluation. Additional history was obtained, some of it from his mother. The patient's birth weight was 12 pounds. He was the biggest of eight siblings. His mother recalled that he had heavy breathing as a child, and that she twice asked a physician about its significance. She was reassured that it was unimportant. She specifically did not recall episodes in which she was alarmed that her baby


JULY 1977 * 127 * 1


had stopped breathing. The patient's development was slow. He did not walk until the age of three, and pubescent changes appeared later than in his brothers. At the age of 16 he weighed 265 pounds and played defensive tackle on the high school football team. Three years before admission his weight was 300 pounds; two years before admission, at the onset of his difficulties with sleep and with somnolence, his weight was 385 pounds. At the time of referral it was 418 pounds. The patient's social history is remarkable for a long history of difficulty with authority. He ran away from home at the age of 12 and reports that he has since had 157 felony arrests and has spent nine years in penal institutions. He is the only one of his siblings to have been arrested or incarcerated. He married three years ago and has three stepchildren. He has had no further difficulty with the police, and has been gainfully employed until the recent loss of his driver's license. On physical examination he presented as a massive, well-muscled man who fell asleep twice during the examination, but who conversed lucidly while awake. Vital signs included a blood pressure of 140/80 mm of mercury, pulse 78, respiratory rate 18 and regular. He was afebrile. He had no papilledema; the tonsils were absent. No abnormal tissue was noted in the posterior pharyngeal wall. Indirect laryngoscopy showed no abnormalities. He had a short, thick neck; the thyroid was not enlarged or nodular. The findings on examination of the chest were remarkable only for the presence of distant breath sounds. There was no distention of the jugular venous pulse. The point of maximal cardiac impulse was not palpable. Heart tones were distant. The abdomen

was remarkable only for immense girth. Extremities showed 1 to 2+ ankle edema. General neurological examination was within normal limits. Laboratory data showed normal values for hemoglobin, hematocrit and leukocyte count. Results of blood studies were remarkable only for a bicarbonate value of 33 mEq per liter. No abnormalities were noted on an electrocardiogram, an x-ray study of the chest and thyroid studies. An echocardiogram was difficult to interpret because of the thickness of the chest wall, but was thought consistent with slight right ventricular hypertrophy. Pulmonary function tests (Table 1) were done with difficulty. The patient fell asleep in the body plethysmograph, while breathing on the spirometer and at other times. The studies showed reduced lung volumes and vital capacity. Measurements of maximal expiratory flow were normal. There was very slight maldistribution of inspired air and airway resistance was normal. Despite this normal appearance of awake pulmonary function, arterial blood gases were abnormal: oxygen pressure (Po,) equaled 45, carbon dioxide pressure (Pco2) equaled 50, pH equaled 7.38. In summary, this patient with a lifelong history of obesity presented with daytime somnolence, difficulty with sleep at night, and laboratory studies showing hypoxemia and hypercapnea despite normal values for screening pulmonary function studies while awake. The association of obesity, somnolence and polycythemia has been described in the medical literature for 150 years, but the association was not given the name of pickwickian syndrome until 1956 by Burwell, Robin and co-workers.' They defined the major features of the syndrome

TABLE 1.-Findings on Screening Pulmonary Function Studies

............. Vital Capacity (liters): ....... Expiratory Reserve Volume (liters): .... .... ............ Residual Volume (liters): ...... ......... Total Lung Capacity (liters): ..... Residual Volume/Total Lung Capacity



Percent Predicted

5.5 1.8 2.2 7.7

4.0 0.3 2.0 6.0 34.0 39.6 2.8 83.0 2.2


72 115 9)I 777

28.0 (percent):. . ...................... Pulmonary Diffusing Capacity: (ml/minute per mm of mercury) .... .... 34.4 Forced Expired Volume, 1 second (liters): ... 4.4 ......... 80.0 Percent expired in 1 second: ..... Single Breath Distribution (percent): ...... 2.0 Airway Resistance (cm of water/liters per second) ........ 1.0 - 2.8


Arterial Blood Gases: Po2 45 mm, Pco2 50 mm, Ph 7.38; Base excess +3.2 mEq/L Clinical Diagnosis: Narcolepsy vs. Pickwickian Syndrome Sex: M, Age: 32, Ht: 185 cm., Wt: 189 kg., Hb: 13.6 gm/dl



TABLE 2.-Clinical Features of the Pickwickian Syndrome* 1. 2. 3. 4. 5. 6. 7. 8.

Obesity, pronounced Somnolence Twitching Cyanosis Periodic respiration Polycythemia, secondary Right ventricular hypertrophy Right ventricular failure

*From Burwell CS, Robin ED, Whaley RD, et al: Am J Med 21:811, Nov 19561

(Table 2). They suggested that this association be named the pickwickian syndrome because they resembled the description of Joe, the fat boy, in Charles Dickens' book The Posthumous Papers of the Pickwick Club, commonly called the "Pickwick Papers." Dr. Comroe objects to this designation on both literary and scientific grounds.2 First, he points out that Joe was neither a member of Mr. Charles Pickwick's family nor a member of his club; he was simply not a Pickwickian. If the features of the pickwickian syndrome did describe the members of the club, we should imagine their meetings much like those of the ad hoc subcommittee on the teaching of nutrition on the undergraduate curriculum, a collection of well-fed people sleeping quietly after a delicious lunch at the faculty club. Dr. Comroe's scientific objections are that Joe, the fat boy, is never described to be cyanotic, apneic or suffering from alveolar hypoventilation. Dr. Comroe goes on to note that the syndrome is simply misleading, as it was in this case. Fat people can suffer from somnolence and from life-threatening disturbances in respiratory function and yet not meet the criteria described. Today's patient, for example, was not polycythemic. At times in this hospital stay, his arterial Pco2 was normal, showing that he did not hypoventilate at all times. If he had been tested at only one point when awake and stimulated, the diagnosis could easily have been overlooked. In the remainder of my discussion, I hope to review several aspects of this engrossing subject. How does obesity affect the mechanics of breathing? Why do some but not all obese patients hypoventilate? Why are some but not all patients somnolent? I would like to raise further questions about the causes of the syndrome and to share some speculations about the problems faced by this patient in particular. The most obvious fact about obese people may be the most important: they have an immense additional amount of tissue
JULY 1977 * 127 * 1

to move. In inspiration, the respiratory musculature not only faces the weight of the additional tissue on the chest wall but must also displace the abdominal wall outwards to permit the downward movement of the diaphragm. In obesity the compliance of the chest wall, by which one really means the chest and abdominal wall, is reduced. Two very important effects result from this decrease in chest wall compliance. The first is that the work of breathing is greater. It simply requires more work to move the chest in and out. The second effect is to reduce the volume of lungs at the end of inspiration (functional residual capacity), the rest point at which the patient is making no inspiratory or expiratory effort (Figures IA and iB). The reduction in functional residual capacity is the most consistent abnormality found in pulmonary function tests of obese patients. A second way of looking at this, as shown in Figure 2, is by examining the flow volume curve, a familiar test of pulmonary function. At lower lung volumes, where obese patients normally breathe, the cross-sectional diameter of the airways is smaller than at high lung volumes, due to the lower values for lung recoil pressure. In the patient under discussion, the functional residual capacity was virtually superimposed on the residual volume. This has two important consequences. The first is that he breathes at a point where the airways are not so distended-their diameter is smaller. Therefore, not only must he do an increased amount of work to move the chest wall, he must also do more work to overcome the resistance to air flow in these narrowed airways, further increasing the already great work of breathing. The second point is that at residual volume the air inspired is distributed predominately to the middle and upper lung zones. Perfusion is distributed primarily to the lower and middle lung zones. Normally, when one breathes at a higher lung volume, as a nonobese person does, ventilation is distributed to the same areas where perfusion goes. As a result of obesity then, a person breathes at a lower lung volume and ventilation goes to areas which are poorly perfused, the well-perfused bases receive less air. Arterial hypoxemia results. In summary, the mechanics of breathing are largely affected by the decrease in chest wall compliance. The work of breathing is increased and the functional residual capacity is decreased. Gas exchange shows hypoxemia due to mismatching of ventilation and perfusion of the lung bases.








90 H80

0 10



<60( c





0 130/---RESIDUAL 20 0-RSDA 10



-10 0 10 20 PRESSURE (cm. H20)


0 10 20 PRESSURE (cm. H20)

Figure 1.-A, Determinants of function residual capacity. The volume of the lung when the subject makes no inspiratory or expiratory effort (pressure = 0) is set by the opposing effects of the chest wall and the lung, B shows the reduction in functional residual capacity (FRC) resulting from a decrease in chest wall compliance. (Figure 1A is from Rahn H, Otis AB, et al: The pressure-volume diagram of the thorax and lung. Am J Physiol 146:161, 1946)

There are several theories as to why some obese patients are hypercapneic. One theory is that patients are hypercapneic because the work of breathing is so great. Another theory is that they have relative weakness of the respiratory muscles. A third theory is that the mechanisms controlling ventilation are altered, so their sensitivity to carbon dioxide and to oxygen is abnormal. The great increase in the work of breathing is shown by the rise in oxygen consumption produced by voluntary hyperventilation. Normally, one can achieve a seven-fold increase in minute ventilation with a small increase in oxygen consumption. Patients who have congestive heart failure, emphysema or obesity can achieve an increase in minute ventilation only at the price of a great increase in oxygen consumption because the work of breathing is so great.3 To avoid the high energy cost of such work, the central "thermostat" which sets the arterial Pco., may be readjusted to a higher level. This theory argues that one has alveolar hypo-ventilation to avoid the high work of breathing. The problem with the theory

D Z 07 W _




is that it does not explain why some people who

are fat hypoventilate and others, equally fat, do not. not. Rochester and Enson4 speculate that hypoventilation results not simply from the increase in the work of breathing but from a combined increase in the work of breathing and weakness of

Figure 2.-The flow-volume curve. and The expiratory outer envelope flow shows the maximal inspiratory

rates (vertical axis, expiration upward) plotted against

TLC=total lung capacity.

lung volume (horizontal axis). Tidal breathing is seen to occur at low lung volumes, so that functional residual capacity is superimposed on residual volume (RV).



the respiratory muscles. They support this contention with few data, but it does suggest that patients who are obese and hypoventilate can generate smaller maximal inspiratory pressures than normal, and can achieve less than normal maximal voluntary ventilation. We investigated this latter possibility in the patient under discussion first by taking a careful history. While last incarcerated in prison he occupied his recreational time practicing weight lifting. At one time he could clean-snatch 475 pounds. This is 50 pounds short of the world's record, but probably puts him in at least the normal range for muscle strength. His measured maximal inspiratory pressure was 93 cm of water, in the middle of the normal range for his age. We did not test how this relates to the massive impedance imposed by the chest wall. So his muscle strength was normal, but it is true that his work of breathing was greatly increased. Another theory to explain why obese patients hypoventilate is that some have a diminished sensitivity to low oxygen or to elevated carbon dioxide tensions. In the normal population the response to carbon dioxide varies greatly. Some people of normal habitus and without lung disease are relatively insensitive to carbon dioxide. They increase minute ventilation very little with an increase in arterial carbon dioxide (CO2). The theory is that if these people acquire a disease which increases their work of breathing-either obstructive lung disease or obesity-alveolar hypoventilation is apt to develop. There are some problems with this theory. Some patients with the obesity-hypoventilation syndrome have been reported to have normal CO2 sensitivity. Furthermore, patients with the syndrome who are insensitive to CO., are found to have a normal response to CO2 after they have lost weight. We have no way of directly measuring the neural output from the respiratory center. Ventilation is a function of the efficiency of the entire respiratory system in response to a given neural output. Other investigators have argued that the hypoventilation is not due to insensitivity to carbon dioxide, but to an insensitivity to low oxygen levels.5 Dr Severinghaus' laboratory carried out tests of the response to hypoxemia and hypercapnea in our patient. Our patient's response to carbon dioxide was about 48 percent of normal, a modest diminution in CO2 sensitivity. The increase in ventilation on reducing the Po, from 150 to 40 is in the normal range. We believe that the patient
JULY 1977 * 127 * 1

may have a slight insensitivity to carbon dioxide but has a normal response to hypoxemia. The causes of hypercapnea are somewhat unclear, but more satisfying explanations can be offered for the daytime somnolence of these patients. The somnolence is not a function of arterial Pco2; patients with obstructive lung disease who have equally high arterial Pco2 are not somnolent. The secret of the somnolence was discovered by Gastaut, who showed that patients with this syndrome fail to breathe normally at night.6 Their sleep is frequently interrupted by apneic periods of at least two types. The first is central, in which the patient makes no effort to breathe, and the second is obstructive, in which the inspiratory effort moves no air because of an obstruction in the upper airway. In this latter case, what has probably happened is that the tongue falls against the posterior pharyngeal wall. Apnea occurs up to 300 or 400 times per night, and explains a great deal about the syndrome. The patient is awakened repeatedly throughout the night by the fall in Po2 and rise in Pco2 produced by the apneic periods. Throughout the day the patient is somnolent, trying to recover what has been denied to him throughout the night. Another consequence of recurrent apnea is failure of the right side of heart. The rise in Pco2 and fall in Po2 stimulate pulmonary vasoconstriction. As this occurs hundreds of times throughout the night, the mean load imposed on the right side of the heart is increased, and right heart failure may develop. Our patient proved a very good example of the syndrome. The patient was observed in the intensive care unit overnight with an arterial catheter and esophageal balloon in place. A CO2 probe was placed at the nose (Figures 3A and 3B). Shortly after falling asleep, the pattern of breathing was slightly irregular, but not remarkably so. Gas exchange was normal. Some hours later the pattern of breathing became remarkable. Periods of apnea of 14 seconds appeared, during which he made no attempt to breathe. Subsequent inspiratory efforts were of progressively greater magnitude, as he tried to move air against an obstructed airway. Finally, with a snore and with movement of the arms and legs, the patient resumed breathing, tobk two or three breaths and reentered an apneic period. This pattern went on throughout the night. Gas exchange became abnormal; hypoxia, hypercapnea and respiratory acidosis developed. During the apneic period, his pulse fell to as low as 44 beats per minute. When


ETf C2

-dSS 2d '!:1 ;'S'S iN

*R esophC

SS l
pH 7.39

9:10 PM

p02 70 pC02 41

ET C02

P02 40

PC02 61



11:30 PM

pH 7.31

Figure 3.-Pattern of breathing during sleep. End-tidal carbon dioxide (C02) is measured by a probe placed at the nose, esophageal pressure by an esophageal balloon. A shows slight irregularities in the pattern of breathing, but gas exchange is normal. B shows periods in which neither end-tidal C02 nor esophageal pressure (P esoph.) changes, indicating that the patient has made no effort to breathe (central apnea; shown on far left of the tracing) and periods in which end-tidal C02 does not change despite increasingly great changes in esophageal pressure, indicating the presence of obstruction of the upper airway (obstructive apnea, shown in center and far right of


he resumed breathing the pulse rose and the blood pressure increased to 220/130 mm of mercury. A second sleep study was done on the following night when an electroencephalogram was also recorded during sleep. Again the patient's sleep was interrupted by recurrent apnea. He breathed for 10 seconds, was apneic for 30, breathed for 10, and so on. These studies supported a diagnosis of obesity, alveolar hypoventilation and sleep apnea. The therapeutic options at this point were to induce weight loss, to try hormonal therapy, or to gain control of the upper airway. The patient stated that many attempts at dieting had been so unsuccessful that he was reluctant to try dieting again. An intestinal bypass operation, which has been done here in five similar patients with

good response, was therefore considered. Another approach to therapy would be to treat the patient with progesterone. Progesterone has been shown to diminish alveolar hypoventilation and to diminish the daytime somnolence suffered by these patients,7 but it has not been shown to abolish sleep apnea. The third possibility considered was to carry out a tracheostomy, bypassing the obstructed airway and immediately reversing the abnormal loss of sleep. The importance of prompt, effective therapy is shown by the high in-hospital mortality of the pickwickian syndrome, due to ventilatory failure, to arrhythmias associated with the change in blood gases in the apneic period and to pulmonary emboli.8 We discussed the options with the patient. He was very eager to go home for the weekend to



consider them, and we permitted him to do so. We reasoned that as he had his symptoms for two years it would be safe to let him go home for a brief period. While at home, however, apneic periods began to develop even while he was awake. Because he knew that the apneas were associated with sleep, he resolved to stay awake, taking up to 100 mg of Ritalin at a time in an attempt not to sleep, fearing that he would not wake up if he did so. He returned an exhausted, frightened and desperate man. An attempt to have him sleep with an endotracheal tube in place to bypass the upper airway obstruction was unsuccessful. On the following day, a tracheostomy was done. The change in the patient after the tracheostomy was striking. Somnolence disappeared within two days. He has been alert, personable and responsive. He also reported that he had resumed dreaming, something he could not recall doing since his early childhood. A repeat study of ventilation and electroencephalogram during sleep showed his respiration to be regular and uninterrupted. Analysis of an electroencephalogram showed sleep spindles, indicating deeper and possibly more restful sleep (Figure 4). These occurred only infrequently in the study done before tracheostomy. Blood gases

were much better throughout the night, with Po2, 56 mm; Pco2, 52 mm, and pH, 7.40. One might speculate that this patient's problem with sleep may have been a primary event, explaining both his obesity and his difficulties with authority throughout his lifetime. Dement reported that dream deprivation for one week caused many normal subjects to act paranoid, hostile or uncooperative.9 In several subjects hyperphagia also developed, with gains in weight of from 3 to 5 pounds in one week of dream deprivation. This suggests that sleep deprivation may alter the satiety center, leading to hyperphagia and weight gain, and might also cause changes in personality, accounting for our patient's difficulty with legal authorities. There are obviously a myriad of determinants of personality, so this speculation is tendered with hesitation. The nursing staff on the ward, however, have been struck with the change in the patient after the tracheostomy was done, as he has suddenly developed a sense of humor and a greater tolerance of hospital routines. Even if the speculation that this patient's personality was altered by sleep deprivation is too bold, it is clear that his somnolence and difficulty with sleep were related to abnormal breathing at







pH 7.41


Figure 4.-Sleep study done after tracheostomy. From the top downward: upper three tracings show electroencephalographic activity (eea); EKG indicates the electrocardiogram; EOG indicates electromyogram of the extraocular muscles; the nasal thermistor indicates the temperature of air at the nose (inspiration with cooling of air, is downward; expiration upward); pleural pressure was measured from an esophageal balloon. Note the regular pattern of breathing and the presence of high frequency "sleep spindles" on the electroencephalographic tracings.


JULY 1977 * 127 * 1


night. His case illustrates the limitations of examining a patient when awake: the cardinal abnormality was observed when he was asleep. As we have all learned so often, the practice of medicine does not end at sundown.
REFERENCES 1. Burwell CS, Robin ED, Whaley RD, et al: Extreme obesity associated with alveolar hypoventilation-Pickwickian syndrome. Am J Med 21:811-818, Nov 1956 2. Comroe JH: Frankenstein, Pickwick, and Ondine. Am Rev Resp Dis 111:689-692, Apr 1975 3. Cherniack RM, Cherniack L, Naimark A: Respiration in Health and Disease. Philadelphia, WB Saunders, 1972, pp 496

4. Rochester DF. Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am J Med 57: 402-420, Sep 1974 5. Zwillich CW, Sutton FD, Pierson DJ, et al: Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 59:343-348, Sep 1975 6. Gastaut H, Tassinari CA, Duron B: Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res 1:167-186, Feb 1967 7. Lyons HA, Haung CT: Therapeutic use of progesterone in alveolar hypoventilation associated with obesity. Am J Med 44: 881-888, Jun 1968 8. Miller A, Granada M: In-hospital mortality in the pickwickian syndrome. Am J Med 56:144-150, Feb 1974 9. Dement W: The effect of dream deprivation. Science 131: 1705-1707, Jun 1960

Estrogens and Endometrial Cancer

DR. KiSTNER: ". . . estrogens per se do not cause endometrial cancer in women. They may be related, but I don't think they cause it. There is no evidence that I know of that indicates estrogens are cell transformers. Estrogens do play a role in endometrial priming, which is really a permissive relationship. However, misuse of estrogenic substances may produce varying degrees of endometrial hyperplasia, which in certain unknown predisposed persons may lead to carcinoma of the endometrium, if continued stimulation by the estrogen is permitted. "Now, if a physician elects to use estrogen for the correction of symptoms or signs of estrogen insufficiency, there are two therapeutic regimens available for the prevention of hyperplasia. The more popular and generally adopted method is the cyclic administration of the lowest effective dose for the shortest possible time with appropriate monitoring for endometrial cancer. The selection of the patient for estrogen therapy is most important. Obesity, hypertension, diabetes and infertility associated with oligoovulation are predisposing factors in the development of endometrial cancer and, therefore, in patients having this background endometrial biopsy or uterine aspiration should be done before the institution of therapy. Furthermore, annual endometrial sampling is recommended as long as estrogen is given.... Stated simply, then, the amount of estrogen given should ameliorate the signs and symptoms of estrogen insufficiency without producing bleeding or endometrial hyperplasia. "The second regimen of estrogen administration takes advantage of the antiestrogenic effect of progestins. In this sequence, which I have not adopted, the estrogen is given constantly and the inevitable hyperplasia is averted by the intermittent use of potent progestins. However, the progestin must be given in adequate amounts, and monthly, in order to prevent the hyperplastic process from developing. This results in a withdrawal flow each month, an event that is undesirable to many postmenopausal women."
-ROBERT W. KISTNER, MD, Boston Extracted from Audio-Digest Obstetrics and Gynecology, Vol. 23, No. 13, in the Audio-Digest Foundation's subscription series of tape recorded programs. For subscription information: 1577 East Chevy Chase Drive, Glendale, CA 91206.