PICKWICKIAN SYNDROME, 20 YEARS LATER DOUGLAS CARROLL M.D.
"A remarkable phenomenon associated with excessive fat in young persons is an uncontrollable tendency to sleep-like the fat boy in PickwNick". William Osler In 1955), Auchincloss' reported the first well studicd paticnt wNith obesity, heart failure and respiratory acidosis. The patient wAas alert and bad no unusual breathing pattern. In 1956, Burwell2 reported a patient, also obese, in heart failure aind respiratory acidosis, but in addition, extr( mely slcepy, with periodic breathing and conspicuous twitching. Because of many features similar to the fat boy in "Pickwick Papers" by Charles Dickens, these authors (as had Sir Williamn Osler3) called this clinical situation "a I'ickwickiani Syndrome". The termwnas enthusiastically accepted and a hundred cases have been reported up to 1970. Initially, the reports were made by pulmonary physiologists, fascinated by the relationship between work of breathing and sensitivity of the respiratory center. It wN-as not until 19656 that an understanding of the hypersomnia and periodic breathing began to develop.4 Since then, it has become clear that there are tw o distinct syndromes which have been called the Pickwickian Syndrome. The first (Auchineloss' Syndrome) is eharacterized by respiratory acidosis and cor pulmonale without periodic breathing or hypersomnia.' The second (Gastaut's Syndrome) is characterized principally by sleep apnea associated wNith tongue swallowNing with resulting loss of normal sleep and by severe hypersomnia caused by sleep loss. Itespiratory acidosis anid cor pulmonale are usually present.5 Both of these syndromes occur in obese patients; both may result in respiratory acidosis and cor pulmonale, but only in the second is there sleep apnea and hypersomnia. Both may result in increased work of breathing; the first because of the massive abdomen and thick chest wall; the second, because of upper airway obstruction.6 Both improve with weight loss. Tracheostomy in Gastaut's syndrome results in disappearance of sleep apnea and a miraculous loss of hypersomnia, supporting the idea that upper airwaN- ohbstruction is the fundamen-tal cause of Gastaut's sy ndromve.7 From the Department, of Mledieine, John,s Hopkins School of Medicine, Baltimore City hlospitals, Baltinmore, Mld., 21224.
112
PICKWICKIAN SYNDROMIE, 20 YEARS LATER
113
FIG. 1A: V.I. in about 1950, prior to onset of cor pulmonale with weight over 300
pounds. 1B: V.I. in 1957, weight 184.
THE AuCHINCLOSS SYND1ROMIE V.I. (BCH # 33 47 27) was reported in the literature in 1936 as a "Peculiar type of cardiopulmonary failure associated with obesity".8 He was seen initially at the age of 34, grossly obese (376 pounds), in marked right ventricular failure and with moderate respiratory acidosis. There was no somnolence at any time during his course. He lost nearlY 200 pounds over the first few years (Fig. 1). No evidence of cardiac enlargement or heart failure developed after initial treatmeint. The patient remained on no medication. His weight varied over the y-ears and gradually rose again to around 300 pounds. When it reached 300 on several occasions, the Paco2 was slightly elevated. A study performed on 3/'26/70 shoNwed a normal vital capacity and FEVY before and after Isuprel. The steady state CO diffusing capacity was 13.2 ml. of CO per mm. Hg. per nminute with a predicted value of 9.4. All blood gases were normal and the patient wveighed 260 pounds. The response to 3 % C02 was normal. The minute ventilation in response to 10 % CO2 Nas only 29.73 liters per minute Nhich wEas judged to be a subnornmal response. The patient. complained of Ino shortness of breath. The p)atient, is now 72 years of age, in fine health except for moderate obesity (247 pounds). If onie comlpares his weight, over the years with Pao2,
114
DOUGLAS CARROLL VJ.
IOC
P°OC2
(BCH* 197362)
90
-
*A VITAL CAPACITYa @
9c
0
laS
A
A _
6S
.
0
A
0
zE
Z
A A
70
X
A
"5
0
A
A
0 0
40 z 0 0
603-PZx
A&
.
X 60 0
0
z 4
0
U
11
A
O 50
'&AA
*.
0
U.m 40
0~
U
40
330a
_j
U a
0
a .
U
ILEUI80
A
IU
I
200
220
240
260
WEIGHT
FIG. 2. Blood 1974 in V.I.
gases
280
IN
300
320
340
36a
380
POUNDS
and FVC plotted against weight changes between 1955 and
Paco0 and FVC (Fig. 2), it is clear that the Paco, is significantly higher at increased weights whereas the FVC and the Pa0, are lower. COMMENT The patient's physiological abnormalities were explained initially (Fig. 3) as a result of increased work of breathing resulting in decompensation of the normal control of ventilation, alveolar hypoventilation, hypercapnea, anoxemia, polycythemia and right heart failure. Riley9 had originally suggested that ventilatory response to stress might be limited by the work needed to drive the respiratory muscles. Later observers demonstrated that ventilatory response could be depressed in normals by increasing the work of breathing artificially. Alternately, ventilatory response returned to normal in patients when increased work of breathing could be relieved.", 11 Thus, the basic pathophysiologic cause of Auchincloss' Syndrome is increased work of breathing secondary to obesity. THE GASTAUT SYNDROME J.B. (BCH # 46 82 74) a 26 year old black female was admitted for her final admission July 20, 1967 and died July 31. In 1962 the weight was 140 pounds. In May of 1966 increasing dyspnea and ankle edema for 6 months
PICKWICKIAN SYNDROME, 20 YEARS LATER
115
OBESITY FIXATION OF CHEST WALL
ABDOMINAL BREATHING INCREASED WORK OF BREATHING
It
ALVEOLAR HYPOVENTILATION
*I
HIGH ALVEOLAR CARBON DIOXIDE
PRESSUREE At
HYPERCAPNEA
LOW ALVEOLAR OXYGEN PRESSURE
ARTERIAL BLOOD OXYHEMOGLOBIN K CYANOSIS UNSATURATION
SOMNOLENCE* At PULMONARY HYPERTENSION
POLYCYTHEMIA
x CORONARY ANOXIA
INCREASED BLOOD VOLUME
HEART FAILURE
FIG. 3. Postulated mechanism of the respiratory acidosis, polycythemia and cor pulmonale in obese patients. Somnolence was not present in our first case, but other auithors suggested that the somnolence seen in some cases, was associated with elevated carbon dioxide tension.
brought her to the hospital. She weighed 214 pounds and was somnolent. The blood pressure was 118/84. There was right sided heart failure. A diagnosis of Pickwickian Syndrome was made on the basis of obesity, somnolence, alveolar hypoventilation, polycythemia and right sided heart failure (Fig. 4). Under treatment for heart failure, her symptoms cleared rapidly. It was noted that there were wide fluctuations in respirations, from long periods of apnea to hyperventilation. During exercise at 2 miles per hour with a 160 grade, her Pao, was 75, her Pco2 rose to 57, the pH was 7.18. The patient was given 3 percent, 4 percent, 6 percent carbon dioxide to breathe. There was an irregular breathing pattern. "The pattern is not that of Cheyne-Stokes respiration nor is it characteristic of Biot's breathing, although it more closely resembled the latter". The patient was placed on an obesity diet with low salt and cardiac regimen and in September of 1966 weighed 191 pounds. Thereafter, however, she went off her low salt diet. A re-admission in January of 1967 and again in April of 1967 showed severe respiratory acidosis. She improved each time w-ith treatment of heart failure. Her final admission on 7/20/67 revealed an obese, lethargic, uncooperative patient complaining that she didn't feel well. Her temperature was
DOUGLAS CARROLL
116
1st Admission J.B. 46 82 74
Wt (pounds)
FVC (liters)
2nd Adm. 3rd Adm.
4th Adm.
Predicted
3.05
6/3/66
6/10/66
9/21/66
1/27/67
4/3/67
7/25/67
242
215
191
225
235
222
1.40
1.03
70
88
115
117
27
29
Pao2 (mm. Hg.)
90
68
75
60
40
54
41
Paco2 (mm. Hg.)
40
65
48
55
58
65
53
FEV1 sec (percent) MBC (liters)
pH Hct.
7.40 42
7.26 46
7.28
7.33 58
7.30 60
7.31
7.32
40
FIG. 4. Weight and pulmonary function tests in J.B. Hypersomnia was a major complaint which persisted unchanged even when Paco2 was nearly normal (6/10/66).
101.2, pulse 96, respirations were 40 and shallow, blood pressure 120/80, weight 222 pounds. There was marked cyanosis and papilledema. Except for massive pitting edema of the legs and lowser abdomen, the examination was normal. The hematocrit was 52, white blood couInt 10,500. The roentgenogram of the chest showed an enlarged heart with congestive heart failure. She remained lethargic and tremulous. A lumbar puncture was normal except for a pressure of 540 mm. of saline. Despite aggressive treatment for cardiac failure and use of oxygen and antibiotics, the patient suffered unexpected respiratory and cardiac arrest on the tenth hospital day and could not be resuscitated. Electrocardiogram showed severe right heart strain with a vertical axis and P pulmonale. Post mortem examination showed multiple pulmonary emboli of recent and ancient vintage. The right atrium and adrenal and pelvic veins contained organizing thrombi, but the most likely source of emboli was considered to be the lower extremities. There was severe cor pulmonale with chronic passive congestion of the liver and viscera. The patient had complained of calf pain 4 years prior to admission and had recurrent calf pain over the subsequent course although she never had enough clear-cut symptoms to make a diagnosis of thrombophlebitis or pulmonary embolism. The cause of death was severe cor pulmonale secondary to recurrent pulmonary emboli.
PICKWICKIAN SYNDROMIE, 20 YEARS LATER
117
COM\AlENT This patient differed in several features fromii the first patient. The degree of sominolenece w-as completely out of proportioni to the mild hypereapnea (lF'ig. 4). The peculiar breathing pattern had not beeni seen previously and Nvas niot understood. It did not fit either Cheyne-Stokes nor Biot breathing. Other features of this patient's illness agreed \ith preconceived ideas of pathogenesis (Fig. 3). The Pac02 rose during exercise suggesting a subnormal ventilatory response. There was mild polycythemia, slight anoxemia and very severe right ventricular failure. Loss of weight and treatment of heart failure seemed to improve the patient's somnolence. At post mortem examination, the right ventricular failure proved to be at least partially secondary to multiple pulmonary emboli, a common complication of obesity.i2 13 The pulmonary emboli, however, did not explain the hypersomnia. The Gastaut Syndrome (F ig. .5) has a different genesis from the Auchin(loss' Syndrome. The basic pathophysiologic cause of the Gastaut Syndrome is upper airway obstruction. Simultaneous recording of the diaphragiiatic and respiratory muscle electromyograms, arterial blood gases and ventilation4' 5, 6 during sleep demonstrates that upper airway obstruction is the cause of the sleep apnea in these patients. MIost probably the tongue falls back into the pharynx and causes the obstruction. The M% hole syndrome disappears with Neight loss and Nith tracheostomy. Studies during sleep demonstrate that these patients, because of frequent awakenings, do not experience sufficient normal sleep at night.5' Consequently, they are sleepy during the day. OBESITY
NOCTURNAL SLEEP IDIOPATHIC INTERMITTENT TONGUE SWALLOWING INTERMITTENT UPPER AIRWAY OBSTRUCTION (SLEEP APNEA: RESEMBLES CHEYNE-STOKES RESPIRATION)
INADEQUATE NOCTURNAL SLEEP DIURNAL HYPERSOMNIA
INCREASED WORK OF BREATHING DECREASED VENTILATORY RESPONSE TO CO2
ALVEOLAR HYPOVENTILATION
FIG. 5. Postulated mechanism of the hypersomnia which occurs in obese patients. Somnolence is caused by inadequate nocturnial sleep.
118
DOUGLAS CARROLL
PICKWICKIAN SYNDROMES, CASE REPORTS TO 1971 In an attempt to see how frequently hypersomnia occurred in patients thought to have l'ickwickian Syndrome, we reviewed the literature in English up to 1971. We found 74 adult case reports" 2, 4, 8, 13-40, 53 and added eight new cases which fulfilled our minimal requirements for inclusion in the Pickwickian Syndrome: 1. a recorded weight of over 200 pounds (adults), 2. laboratory evidence of alveolar hypoventilation and 3. elimination of associated diseases which might cause alveolar hypoventilation. There were 82 cases over 16 years of age (Table 1). Males predominated slightly. Shortness of breath was by far the most common presenting symptom. Somnolence was second, followed by a large number of much less common complaints. Most of the patients had been obese for a prolonged period prior to developing any symptoms. Our impression is that the weight gain seen in the last few months prior to presenting to a physician is generally edema fluid gain secondary to right ventricular failure. The mean initial weight was 317 pounds, but the range was from 205 pounds to 588. Initial pulmonary function studies showed a reduction in vital capacity, normal FEV, sec., slightly raised hematocrit, low Pao2, low normal pH, elevated Paco, and slightly elevated RA/TLC. Some patients with initial normal studies later developed abnormalities wchich are not recorded in the table. One criteria of selection of these patients was that there be evidence of alveolar hypoventilation. In 42 patients where an electrocardiogram was reported, there was right axis deviation in 27, left axis in 6 and normal in 9. P -waves were peaked in 7 of 42 cases. Siginificant weight loss over a prolonged period was distinctly unusual in case reports. The time of follow-up varied and some may have lost weight subsequent to the report. Our own experience with repeated admissions of patients as they regained weight is discouraging since this is a curable disease if the patient will cooperate. All patients lost some weight, generally fluid associated with right ventricular failure. Only 4 out of 45 patients lost more than 40 % of their initial weight. Nearly all patients improved, suggesting that the control of heart failure results in improvement even with no loss of body fat. Table 2 gives similar data on eleven children.41-" 1\Iales predominate as does shortness of breath. A number of these children were mentally defective, a finding not present in adults. DIscUSSION The first definitive laboratory studies performed on obese patients with right sided heart failure and respiratory acidosis were reported in 1955.1 At
119
PICKWICKIAN SYNDROMIE 20 YEARS LATER
TABLE 1 82 Cases of Adult Pickwickian Syntdrome, Where Weight was Recorded at More 200 Poiunds Total Cases
Age (yrs. 4: S.D.)
82
46 i 13
Than
Sex
Male 52
Female 30
Presenting Complaintts
Shortness of Breath Somnolence Cyanosis Non-Pickwick complaint Semi-comatose Swelling of ankles Substernal pain Headache Cough High Blood Pressure
Initial Wt. (lbs.)
Duration of Obesity (yrs.)
Cases 77
Total Cases Mean SD
40
9 7 6 4 3 3 2 2
IRange
34 27 17 1-61
Total Cases 82 Mean 317 SD 74 Range 205-588
1 Initial Stutdies Total
Forced Vital Capacity Forced Expiratory Volume Hematocrit Pao2 pH Paco2 RA/TLC
Cases
28 31 61 35 30 46 17
EX,KG Axis: Total Cases-42 P Waves: Total Cases-42 Weight (initial & follow-up): Loss:
*
Mean*
SD*
57 77 55 45 mm 7.36 62 mm 40
22 9 9 14 0.07 14 13
Rt-27 Lt 6 Peaked-7 Total cases-45 Less 20% loss-25 20-40% loss-16 40-60% loss- 3 60+% loss- 1
Range*
17-128
60-98 40-76 7.10-7.54 32-101 19-62 Normal-9
Per cent of predicted value.
approximately the same time, a group of patients Nx ith somewhat different symptoms2 consisting of conspicuous hypersomnia and hat appeared to be
periodic breathing began to be reported and ickian Syndrome. lt
was
X
ere
designated
as
the Pick-
not appreciated until 1966 that the hypersomnia
120
DOUGLAS CARROLL
TABLE 2 11 Patientts Less Than 16 Years of Age with Pickwickiant Sytndrome Total Cases
Age (yrs. i: S.D.)
11
8.5 4 3.2
Sex
Female4
Male7
Presentinig Complainits Cases 10
Shortness of Breath Somnolence Cyanosis
5 4
1
Initial Wt. (lbs.)
Duration of Obesity (yrs.)
11 Total Cases 4 Mean 3 SD 4 mo-ll yrs. Range
11 Total Cases 145 Mean 69 SD 88-346 Range
Intitial Studies Total Cases
Forced Vital Capacity Forced Expiratory Volume Hematocrit Pao pH
6 5
PacM2 RA/TLC
6 3
8
2 5
Total Cases 4 EKG Axis: Total Cases-4 P Waves: Weight (initial & follow-up):
Mean*
67 77
45 39 mm 7.29 67 mm 41
SD*
24 20 39 25
0. 06) 24
17.00
Range*
47-104 45-95 41-54 14-65 7.17-7.34 43-112 18-58
IRt-3 Normal-1 Peaked-3 Decreased-1 Total Cases-11 Less 20% loss-8 21-40% loss 1 41-60% loss 2
* Per cent of predicted value.
and periodic breathing had a different etiology from the right sided heart failure and respiratory acidosis. In order to distinguish these varieties of the l'ickwickian Syndrome, N-e have applied the term Auchincloss Sy?idr6rne to the first described. The essential pathogenic feature of this syndrome is the development of increased work of breathing because of obesity, resulting in inability of the patient to ventilate sufficiently to remove accumulating carbon dioxide. An important problem still remains unanswered. Some patients xx ith severe obesity never develop this syndrome xN hereas others Nx ith only moderate obesity do develop it. It is known that some patients of normal NAeight also develop alveolar hypoventilation presumably caused by some central disorder of
PICKWICKIAN SYNDROME, 20 YEARS LATER
121
ventilatory regulation rather than from increased work of breathing. The possibility therefore exists that the Auchincloss Syndrome develops only in )atients xxho in addition to having increased work of breathing secondary to obesity, also have some disorder of ventilatory regulation. We have seen this syndrome in a fath( r and a son and familial Pickwickian Syndrome has been described in the literature.35' 51 If obcse patients X ho develop respiratory acidosis did indeed have a congenital abnormality of ventilatory control, their ventilatory response to carbon dioxide should continue to be abnormal after recovery from respiratory acidosis. There are only three studies in xx hich ventilatory response to CO2 has been tested after recovery. Burn ell's case2 show ed improvement in response. Pedersen's case29 had serial studies w hich shoN ed improvemnent. One of MAacGregor's cases13 regained sensitivity. Our own case I had decreased sensitivity 14 years after he last recovered from respiratory acidosis. Thus, from the reports of Pickw ickian Syndrome in families and the demonstration of depressed ventilatory response after recovery from respiratory acidosis, there is some support for the theory that these patients have a congenital or possibly an inherited insensitivity of ventilatory control. The second syndrome which we have called the Gastaut Syndrome is associated with hypersomnia and periodic breathing and has a different etiology from the Auchiuicloss Syndrome. The essential feature is upper airway obstruction. This has been clearly demonstrated, but why the tongue obstructs the airway of obese patients with sleep apnea is by no means clear. Two other clinical situations are possible but have not been clearly defined. The first is the obese patient in respiratory acidosis and possibly cor pulmonale w ho is somnolent but does not have sleep apnea. His somnolence, in fact, may be related to elevation of the carbon dioxide tension. These were among the earliest patients described and might be referred to as Sieker's Syndrome."8' 52, 53 A final syndrome resembles the Pickw ickian Syndrome in that there is obesity and somnolence but the patients have no hyperearbia, respiratory acidosis or sleep apnea. This syndrome might be given the name of Alexauider, who first drew attention to it.24, 52
SUAI MARY The l'ickwickian Syndrome stimulated new' pathophysiological concepts in regard to control of ventilation. With the advent of sleep laboratories, the peculiar sleep apnea occurring in some of these patients has been explained on the basis of intermittent upper airway obstruction. Tw o patients with different manifestations of the Pickwickian Syndrome
122
DOUGLAS CARROLL
are presented. The suggestion is made that these two subsyndromes should have unique designations. The Auchincloss Syndrome is manifested by right heart failure and respiratory acidosis in obese patients who are alert and have no major abnormality of breathing pattern. The fundamental cause of this abnormality is the increased work of breathing caused by the obesity. The cost of breathing is so high that the ventilatory regulation is compromised and respiratory acidosis results. The Gastaut Syndronme is characterized principally by hypersomnia and sleep apnea. The fundamental defect is upper airway obstruction during sleep, resulting in increased work of breathing, which together with the increased work caused by obesity leads to respiratory acidosis and right ventricular failure. Hypersomnia, rather than heart failure or respiratory acidosis, is the major manifestation of this syndrome, and is the result of sleep loss. There is a widespread interest in the sleep disorders of obese patients, which should result in the discovery of important new concepts of ventilatory regulation.54-64 REFERENCES 1. AuCHINCLOSS, JR., J. H., COOK, E. AND RENZETTI, A. D.: Clinical and physiological aspects of a case of obesity, polycythemia and hypoventilation. J. Clin. Inivest. 34: 1537, 1955. 2. BURWELL, C. S., ROBIN, E. 1)., WHALEY, R. D. AND BICKELMAN, A. G.: Extreme
3. 4. 5. 6.
7. 8.
9. 10. 11.
obesity associated with alveolar hypoventilation-A Pickwickian Syndrome. Am. J. Med. 21: 811, 1965. OSLER, W.: The principle and practice of medicine. Eighth Edition, 1918. GASTAUT, H., TASSINARI, C. A. AND DURON, B.: Polygraphic study of the episodic diurnal and nocturnal manifestations of the Pickwick syndrome. Brain Res. 2: 167, 1966. Symposium: hypersomnia with periodic breathing. Bull. de Physiopathol. Respir. 8: 965-1292, 1972. WALSH, R. E., MICHAELSON, E. D., HARKLEROAD, L. E., ZIGHELBOIM, A. AND SACKNIER, M. A.: Upper airway obstruction in obese patients with sleep disturbance and somnolence. Ann. Intern. Med. 76: 185, 1972. LUGARESE, E., COCCAGNA, G., MANTOVANI, M. AND BRIGNANI, F.: Effects of tracheostomy in two cases of hypersomnia with periodic breathing. J. Nenlrol. Nerosurg. Psychiatry 36: 15, 1973. CARROLL, D.: Peculiar type of cardiopulmonary failure associated with obesity. Am. J. Med. 21: 819, 1956. RILEY, R. L.: The work of breathing and its relation to respiration acidosis. Anal. It. Med. 41: 172, 1954. CHERNIACK, R. M. AND SNIDAL, D. P.: The effect of obstruction to breathing on the ventilatory response to C02. J. Clini. Invest. 35: 1286, 1956. BRODOVSKY, D., MACDONELL, J. A. AND CHERNIACK, It. M.: The respiration response to carbon dioxide in health and in emphysema. J. Clin. Invest. 724, 1960.
PICKWICKIAN SYNDROME, 20 YEARS LATER
123
12. GODREY, S.: Pulmonary embolism and the Pickwick syndrome. Br. J. Dis. Chest 66: 155, 1972. 13. MACGREGOR, M. I., BLOCK, A. J. AND BALL, W. C., JR.: Serious complications and sudden death in the Pickwickian syndrome. Johns Hopkins Med. J. 126: 279, 1970. 14. RICHTER, T., WEST, J. R. AND FISHMAN, A. P.: The syndrome of alveolar hypoventilation and diminished sensitivity of the respiratory center. N. Eng. J. Med. 256: 1165, 1957. 15. WEIL, M. H. AND PRAS AS, A. S.: Polycythemia of obesity-further studies of its mechanism and a report of two additional cases. Ann. Intern. Med. 46: 60, 1957. 16. SARIANO, A. Q. AND DURHAM, J. R., JR.: Pickwickian syndrome. Del. M. J. 29: 153, 1957. 17. LILLINGTON, G. A., ANDERSON, M. W. AND BRANDENBURG, R. O.: The cardiorespiratory syndrome of obesity. Chest 32: 1, 1957. 18. ESTES, E. H., JR., SIEKER, H. O., MCINTOSH, H. D. AND KELSER, G. A.: Reversible cardiopulmonary syndrome with extreme obesity. Circulation 16: 179, 1957. 19. HERALD, A. A., JR.: The Pickwickian syndrome: a case report. J. La. State Med. Soc. 110: 305, 1958. 20. CO.ATES, F. O., JR., BRINKMAN, G. L. AND NOL, F. E.: Hypoventilation syndrome physiologic studies in selected cases. Anti. Intern. Med. 48: 50, 1958. 21. CHERNIACK, R. M.: Respiratory effects of obesity. Can. Med. Assoc. J. 80: 613, 1958. 22. GOTZSCHE, H. AND PETERSEN, V. P.: Obesity associated with cardiopulmonary failure-the Pickwickian syndrome. Acta Med. Scand. 161: 383, 1958. 23. BERLYN, G. M. AND MANC, M. B.: Cardiorespiratory syndrome of extreme obesity. Lancet (2) (7053) 939, 1958. 24. COLE, V. W. AND ALEXANDER, J. K.: Clinical effects of extreme obesity on cardiopulmonary function. South Med. J. 52: 435, 1959. 25. SMITH, G. M.: Obesity with polycythemia-report of a case. Ann. Itntern. Med. 50: 1530, 1959. 26. GRIPTA, K. K.: Cardiorespiratory syndrome of extreme obesity. J. Indian Med. Assoc. 33: 477, 1959. 27. BORGE, E. AND BASTRUP, M. P.: Secondary erythraemia in extreme obesity the Pickwickian syndrome. Acta Haematol 21: 224, 1959. 28. SCALETTAR, R., MILLER, F. L., SODES, D. B. AND BARRY, K.: Alveolar hypoventilation and cardiopulmonary failure in obesity. U.S. Armed Forces Med. J. 11: 774, 1960. 29. PEDERSEN, J. AND THORP-PEDERSEN, E.: Ventilatory insufficiency in extreme obesity. Acta Med. Scand. 167: 343, 1960. 30. FROHLICK, E. D.: The Pickwickian syndrome. G.P. 24: 83, 1961. 31. MYER, J. S., GOTHAM, J., TAZAKI, Y. AND GATOH, F.: Cardiorespiratory syndrome of extreme obesity with papilledema-report of a fatal case with electroencephalographic, metabolic and necropsy studies. Neurology 11: 950, 1961. 32. GILL.ALM, P. M. S. AND MYMIN, 1).: Hypoventilation and heart disease. Lancet, October 14: 853, 1961. 33. FADE,, F. J., RICHMAN, A. D., WARD, W. W. AND HENDON, J. R.: Fatty infiltration of respiratory muscles in the Pickwickian syndrome. N. Eng. J. Med. 266: 861, 1962. 34. DRACIIMAN, D. B. AND GUMNET. R. J.: Periodic alteration of consciousness in the Pickwickian syndrome. Arch. ANelnrol. 6: 471, 1962.
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DOUGLAS CARROLL
35. FALSETTI, H. L., HANSON, J. S. AND TABAKIN, B. S.: Obesity-hypoventilation syndrome in siblings. Am. Rev. Respir. Dis. 90: 105, 1964. 36. VOGEL, J. H. K. AND BLOUNT, S. G., JR.: The role of hydrogen ion concentration in the regulation of pulmonary arterial pressure: observations in a patient with hypoventilation and obesity. Circulation 32: 788, 1965. 37. ABRAHAMSEN, A. M. AND NITTER-HAUGE, S.: Extreme obesity with respiratory failure, necessitating artificial ventilation. Acta Med. Scauld. 180: 113, 1966. 38. ADDINGTON, W. W., PFEFFER, S. H. AND GAFNSLER, E. A.: Obesity and alveolar
hypoventilation. Respiration 26: 214, 1969. 39. SWANN, B. M.: Alveolar hypoventilation and benign increased intra-cranial pressure. Del. Med. J. 42: 261, 1970. 40. MATHUR, A. S., SETHI, J. P. AND MATHUR, 1). P.: Pickwickian syndrome: a case report. J. Postgrad. Med. 16: 48, 1970. 41. JENAB, M., LODE, R. I., CHIGA, M. AND 1)IEHL, A. M.: Cardiorespiratory syndrome of obesity in a child. Case report and necropsy findings. Pediatrics 24: 23, 1959. 42. SPIER, N. AND KARELITZ, S.: The Pickwickian syndrome: case in a child. Am. J. Dis. Child 99: 822, 1960. 43. ELLISON, L. T., TALLEY, R. E., MIMS, L. 1). AND ELLISON, 11. (J.: The cardiorespiratory syndrome of obesity in a child. A case report with clinical and physiological considerations. Chest 40: 419, 1961. 44. CAYLER, G. G., MAYS, J. AND RILEY, H. D., JR.: Cardiorespiratory syndrome of obesity in children. Pediatrics 27: 237, 1961. 45. WARD, W. A., JR. AND KELSEY, W. M.: The Pickwickian syndrome: a review of the literature and report of a case. J. Pediatr. 61: 745, 1962. 46. FINKELSTEIN, J. W. AND AVERY, M. E.: The Pickwickian syndrome studies oln ventilation and carbohydrate metabolism. Case report of a child who recovered. Am. J. Dis. Child 106: 251, 1963. 47. WALLREN, G., BORJI, B. AND OKMIAN, L.: Ventilatory insufficiency in an obese girl. A case report with pathogenetic considerations. Acta Paediatr. Scald. 54: 288, 1965. 48. NIZAN, M., SPITZER, S. AND ELIAN, E.: Obesity-hypoventilation (Pickwickian) syndrome in a child. Isr. J. Med. Sci. 4: 264, 1968. 49. METZL, K., KEITGES, P., KANTOR, J. AND BORDY, M.: The Pickwickian syndrome in a child. An extreme example of psychoneurotic obesity. Clini. Pediatr. 8: 49, 1969. 50. HIROAKA, M., INABA, Y. AND OHNO, T.: The Pickwickian syndrome in a child. Tohoku J. Exp. Med. 98: 363, 1969. 51. SCARLATO, G.: Familial Pickwickian syndrome (3 cases). Osp. Psichiatr. 38: 188, 1970. 52. CARROLL, D.: Nosology of "Pickwickian Syndrome". Bull. Physiopathol. Respir. 8: 1241, 1972. 53. SIEKER, H. O., ESTES, E. H. JR., KELSER, G. A. AND MCINTOSH, H. D.: A cardiopulmonary syndrome with extreme obesity. J. Clini. Invest. 34: 916, 1955. 54. GUILLEMINAULT, C., ELDRIDGE, F. L. AND 1)1':MENT, W. C.: Insomnia with sleep apnea: a new syndrome. Science 181: 856, 1973. 55. VOGEL, J. H. K., HARTLEY, L. H., JAMIESON, G. AND GROVER, 1. F.: Impairment of ventilatory response to hypoxia in individuals with obesity and hypoventilation: a concept of the Pickwickian Syndrome. Circ. Suppl. II, 35 and 36: 258, (n-
1fnl7
PICKWICKLAN SYNDROME, 20 YEARS LATER
125
56. KRIiGER, A. J. AND RosOMOFF, H. L.: Sleep-induced apnea: II Respiratory failure after anterior spinal surgery. J. Neiiroszirg. 40: 181, 1974. 57. SAFARt, P., ESCARRAGA, L. A. AND CHANG, F.: Upper airway obstruction in the unconscious patient. J. Appl. Physiol. 14: 760, 1959. 58. MORIK NAN, S., SAF.XR, P. AND I)ECARLO, J.: Influence of head-jaw position upon upper airway patency. Anesthesiology 22: 265, 1961. 59. INGRAM, R. H. AND BISHOP, J. B.: Ventilatory response to CO2 after removal of chronic upper airway obstruction. Am. Rev. Resp. Dis. 102: 645, 1970. 60. MILLER, A.: Airway obstruction and somnolence. Annt. Intern. Med. 81: 133, 1974. 61. WPI:TZMAN, E. D. (editor): Advances in sleep research, vol 1. Spectrum Publications, Inc. Flushing, N.Y. 1974. 62. ROCHESTER, 1). F. AND EENSON, Y.: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am. J. Med. 57: 402, 1974. 63. BUTLER, J.: Clinical problems of disordered respiratory control. Am. Rev. Resp. Dis. 110: 695, 1974. 64. SACKNER, M., LAND;, J., FORREST, T. AND GTREEFNFiLTrCH, D. Periodic sleep apnea: chronic sleep deprivation related to intermittent upper airway obstruction and central nervous system disturbance. Chest 67: 164, 1975.
DISCUSSION I)it. J. EDWIN WOOD, III (Philadelphia): I know many of you who will remember D)octor Sidney Burwell as one of our great members. I remember a presentation of his some 20 years in which he presented his first Pickwickian patient. He took great delight in pointing out the patient's chief complaint. The man was a professional poker player, who complained that he had drawn to an inside straight but fallen asleep before his turn came to bet. DR. HARRY W. FRITTS, JR. (Stoneybrook): 1)oug, I know you have been very careful about attributing the diminished response to carbon dioxide to any one part of respiratory apparatus. Yet in the first patient you talked about a diminished sensitivity to 10% C02. You showed us that as the weight went up, the Pco2 went up, and in your summary you've I think mentioned that there might be a relative insensitivity in the respiratory center to CO2. Now the question is what evidence do you have for this? As I view the respiratory center, it responds to stimuli on the part of the cerebral spinal fluid, hydrogen ion, oxygen, carbon dioxide. The output of that center's impulses travel along nerves, muscles contract, the muscles perform work through the chest wall, the lung follows and ventilation results. But these elements interpose between ventilation (the thing you are measuring) and the impulses leaving the respiratory center. It makes the problem almost insoluble at the moment. I don't know what the respiratory centers are doing, and I have never been able to really convince myself that it is doing anything other than what it normally should. What evidence do you have to make you believe that it is relatively insensitive or incapable of responding to 10% carbon dioxide in a normal way? DR. CARROLL: Very good question, and I was fairly careful in what I said. I agree with you. The system is extremely complex. Lambertson, you may recall, studied response to CO2 in normals about ten or fifteen years ago and showed an extremely wide difference in the response of normals. Now this work was not extended, and this is just the CO2 response. Response to CO2 may not be the test that we want. At the American Thoracic Society's last meeting, you will remember there was a symposium on the respiratory center, and there is a tremendous amount of interest in this now, partially because of the development of simplified methods of measuring response to
126
DOUGLAS CARIROLL
CO2. However I muist. say I am Inot store that the response to CO2, as we do it by julst increasing the anmouint of inspired carbon dioxide, is really the test which is going to tell us what we want to know. DR. THOMAS A. WARTHIN (Boston): We've followed a group of so-called Pickwickans for a number of years, including an unfortunate young man who was a very obese lobsterman who had a line tied to his body because he would fall asleep while hauling in his pots. He would fall asleep and topple into the water. After several episodes he sought medical assistance. In a follow-up of over ten years, of a group of about twelve Pickwickians, three have turned out to have myotonia dystrophica and two variants of Parkinsonism which seemed to contribute to their tendency to severe somnolence. Do you believe there may be a significant association of neurologic disease in the true somnolent Pickwickian? DR. CARIROLL: Yes, I think this is a good point. We've known for many years that there are a number of neurological diseases which are associated with respiratory acidosis. It is probable that many of them are not pickedup early and only are identified with long follow-up. The other point here is that there are also some central nervotus system diseases which may effect again these respiratory centers andmay modify the central response of the patient to CO2 inhalation. DR. JOHN H. KNOWLES (New York): I am absolutely fascinated with this new term 'idiopathic intermittent tongue swallowing'. It is something I never heard before, and I wondered several things. First of all did Gastaut actually see some of these patients swallow their tongue and go into apnea during sleep? DR. CARROLL: He didn't see them swallow their tongue, but he had them hooked up with a mouth piece, nose piece, so he could measure ventilation. He had an eleetromyography to see if their chest wall muscles and diaphragm were moving. He was able to show that during these episodes of apnea, no air was passing. Now the second piece of evidence is that if a tracheostomy is performed, these patients are cured immediately. No more sleep apnea, no more somnolence, no obstruction. So although the tongue hasnot actually been seen swallowed, this seems to be the localization of the obstruction. I)R. JOHN T. SESSIONS, JR. (Chapel Hill): I am also fascinated by the tongue swallowing explanation. I have been interested in this because the people doing ilio by-pass procedures report trivial amounts of weight loss reverse the Pickwickian syndrome. That it is one of the first symptom to go away. This is disturbing because of having subscribed to the central nervous system explanation. I noticed your man lost a great deal of weight about his neck and you're suggesting a simple mechanical correction by tracheostomy prevents this. Has anyone measured where weight goes away from first? Could 25 pounds come off the neck, and in that way explain this mechanical problem that you describe? D)R. CARROLL: I don't think anybody studied that, but there is a tremendous amount of interest in the nature of this obstruction right now. There are five or six Sleep Laboratories studying this,6' and the only thing that I know about this obstruction is Safar's work57' which was done fifteen or twenty years ago where he noted changes in the size of the larynx with different head positions. Then you will remember in mouth-to-mouth breathing he recommended that the head be put way back because the patient tended to swallow his tongue. DR. THOMAS H. HUNTER (Charlottesville): To return to the somnolence, I wonder if you have any evidence on whether there is an effect here of what John Pappenheimer has been studying up at Harvard for a good many years. In studying the spinal fluid of goats, he has found a small molecular weight substance, that is correlated with 58
PICKWICKIAN SYNDROMIE, 20 YEARS LATER
127
sleep deprivation and causes sleepiness. I think it is not limited to goats; there is evidence that it appears in other species as well. D)o we know anything about the mechanism of sleepiness in Pickwickians in relation to this work? 1)D. CAR1ROLL: The only thing I can say there is that measurement of sleep levels shows that these patients get less Stage 3, 4 and ItEM sleep than normal people. If normal people are prevented from getting Stage 3, 4 and REM sleep in experiments, these people are sleepy all day too.
"A remarkable phenomenon associated with excessive fat in young persons is an uncontrollable tendency to sleep-like the fat boy in PickwNick". William Osler In 1955), Auchincloss' reported the first well studicd paticnt wNith obesity, heart failure and respiratory acidosis. The patient wAas alert and bad no unusual breathing pattern. In 1956, Burwell2 reported a patient, also obese, in heart failure aind respiratory acidosis, but in addition, extr( mely slcepy, with periodic breathing and conspicuous twitching. Because of many features similar to the fat boy in "Pickwick Papers" by Charles Dickens, these authors (as had Sir Williamn Osler3) called this clinical situation "a I'ickwickiani Syndrome". The termwnas enthusiastically accepted and a hundred cases have been reported up to 1970. Initially, the reports were made by pulmonary physiologists, fascinated by the relationship between work of breathing and sensitivity of the respiratory center. It wN-as not until 19656 that an understanding of the hypersomnia and periodic breathing began to develop.4 Since then, it has become clear that there are tw o distinct syndromes which have been called the Pickwickian Syndrome. The first (Auchineloss' Syndrome) is eharacterized by respiratory acidosis and cor pulmonale without periodic breathing or hypersomnia.' The second (Gastaut's Syndrome) is characterized principally by sleep apnea associated wNith tongue swallowNing with resulting loss of normal sleep and by severe hypersomnia caused by sleep loss. Itespiratory acidosis anid cor pulmonale are usually present.5 Both of these syndromes occur in obese patients; both may result in respiratory acidosis and cor pulmonale, but only in the second is there sleep apnea and hypersomnia. Both may result in increased work of breathing; the first because of the massive abdomen and thick chest wall; the second, because of upper airway obstruction.6 Both improve with weight loss. Tracheostomy in Gastaut's syndrome results in disappearance of sleep apnea and a miraculous loss of hypersomnia, supporting the idea that upper airwaN- ohbstruction is the fundamen-tal cause of Gastaut's sy ndromve.7 From the Department, of Mledieine, John,s Hopkins School of Medicine, Baltimore City hlospitals, Baltinmore, Mld., 21224.
112
PICKWICKIAN SYNDROMIE, 20 YEARS LATER
113
FIG. 1A: V.I. in about 1950, prior to onset of cor pulmonale with weight over 300
pounds. 1B: V.I. in 1957, weight 184.
THE AuCHINCLOSS SYND1ROMIE V.I. (BCH # 33 47 27) was reported in the literature in 1936 as a "Peculiar type of cardiopulmonary failure associated with obesity".8 He was seen initially at the age of 34, grossly obese (376 pounds), in marked right ventricular failure and with moderate respiratory acidosis. There was no somnolence at any time during his course. He lost nearlY 200 pounds over the first few years (Fig. 1). No evidence of cardiac enlargement or heart failure developed after initial treatmeint. The patient remained on no medication. His weight varied over the y-ears and gradually rose again to around 300 pounds. When it reached 300 on several occasions, the Paco2 was slightly elevated. A study performed on 3/'26/70 shoNwed a normal vital capacity and FEVY before and after Isuprel. The steady state CO diffusing capacity was 13.2 ml. of CO per mm. Hg. per nminute with a predicted value of 9.4. All blood gases were normal and the patient wveighed 260 pounds. The response to 3 % C02 was normal. The minute ventilation in response to 10 % CO2 Nas only 29.73 liters per minute Nhich wEas judged to be a subnornmal response. The patient. complained of Ino shortness of breath. The p)atient, is now 72 years of age, in fine health except for moderate obesity (247 pounds). If onie comlpares his weight, over the years with Pao2,
114
DOUGLAS CARROLL VJ.
IOC
P°OC2
(BCH* 197362)
90
-
*A VITAL CAPACITYa @
9c
0
laS
A
A _
6S
.
0
A
0
zE
Z
A A
70
X
A
"5
0
A
A
0 0
40 z 0 0
603-PZx
A&
.
X 60 0
0
z 4
0
U
11
A
O 50
'&AA
*.
0
U.m 40
0~
U
40
330a
_j
U a
0
a .
U
ILEUI80
A
IU
I
200
220
240
260
WEIGHT
FIG. 2. Blood 1974 in V.I.
gases
280
IN
300
320
340
36a
380
POUNDS
and FVC plotted against weight changes between 1955 and
Paco0 and FVC (Fig. 2), it is clear that the Paco, is significantly higher at increased weights whereas the FVC and the Pa0, are lower. COMMENT The patient's physiological abnormalities were explained initially (Fig. 3) as a result of increased work of breathing resulting in decompensation of the normal control of ventilation, alveolar hypoventilation, hypercapnea, anoxemia, polycythemia and right heart failure. Riley9 had originally suggested that ventilatory response to stress might be limited by the work needed to drive the respiratory muscles. Later observers demonstrated that ventilatory response could be depressed in normals by increasing the work of breathing artificially. Alternately, ventilatory response returned to normal in patients when increased work of breathing could be relieved.", 11 Thus, the basic pathophysiologic cause of Auchincloss' Syndrome is increased work of breathing secondary to obesity. THE GASTAUT SYNDROME J.B. (BCH # 46 82 74) a 26 year old black female was admitted for her final admission July 20, 1967 and died July 31. In 1962 the weight was 140 pounds. In May of 1966 increasing dyspnea and ankle edema for 6 months
PICKWICKIAN SYNDROME, 20 YEARS LATER
115
OBESITY FIXATION OF CHEST WALL
ABDOMINAL BREATHING INCREASED WORK OF BREATHING
It
ALVEOLAR HYPOVENTILATION
*I
HIGH ALVEOLAR CARBON DIOXIDE
PRESSUREE At
HYPERCAPNEA
LOW ALVEOLAR OXYGEN PRESSURE
ARTERIAL BLOOD OXYHEMOGLOBIN K CYANOSIS UNSATURATION
SOMNOLENCE* At PULMONARY HYPERTENSION
POLYCYTHEMIA
x CORONARY ANOXIA
INCREASED BLOOD VOLUME
HEART FAILURE
FIG. 3. Postulated mechanism of the respiratory acidosis, polycythemia and cor pulmonale in obese patients. Somnolence was not present in our first case, but other auithors suggested that the somnolence seen in some cases, was associated with elevated carbon dioxide tension.
brought her to the hospital. She weighed 214 pounds and was somnolent. The blood pressure was 118/84. There was right sided heart failure. A diagnosis of Pickwickian Syndrome was made on the basis of obesity, somnolence, alveolar hypoventilation, polycythemia and right sided heart failure (Fig. 4). Under treatment for heart failure, her symptoms cleared rapidly. It was noted that there were wide fluctuations in respirations, from long periods of apnea to hyperventilation. During exercise at 2 miles per hour with a 160 grade, her Pao, was 75, her Pco2 rose to 57, the pH was 7.18. The patient was given 3 percent, 4 percent, 6 percent carbon dioxide to breathe. There was an irregular breathing pattern. "The pattern is not that of Cheyne-Stokes respiration nor is it characteristic of Biot's breathing, although it more closely resembled the latter". The patient was placed on an obesity diet with low salt and cardiac regimen and in September of 1966 weighed 191 pounds. Thereafter, however, she went off her low salt diet. A re-admission in January of 1967 and again in April of 1967 showed severe respiratory acidosis. She improved each time w-ith treatment of heart failure. Her final admission on 7/20/67 revealed an obese, lethargic, uncooperative patient complaining that she didn't feel well. Her temperature was
DOUGLAS CARROLL
116
1st Admission J.B. 46 82 74
Wt (pounds)
FVC (liters)
2nd Adm. 3rd Adm.
4th Adm.
Predicted
3.05
6/3/66
6/10/66
9/21/66
1/27/67
4/3/67
7/25/67
242
215
191
225
235
222
1.40
1.03
70
88
115
117
27
29
Pao2 (mm. Hg.)
90
68
75
60
40
54
41
Paco2 (mm. Hg.)
40
65
48
55
58
65
53
FEV1 sec (percent) MBC (liters)
pH Hct.
7.40 42
7.26 46
7.28
7.33 58
7.30 60
7.31
7.32
40
FIG. 4. Weight and pulmonary function tests in J.B. Hypersomnia was a major complaint which persisted unchanged even when Paco2 was nearly normal (6/10/66).
101.2, pulse 96, respirations were 40 and shallow, blood pressure 120/80, weight 222 pounds. There was marked cyanosis and papilledema. Except for massive pitting edema of the legs and lowser abdomen, the examination was normal. The hematocrit was 52, white blood couInt 10,500. The roentgenogram of the chest showed an enlarged heart with congestive heart failure. She remained lethargic and tremulous. A lumbar puncture was normal except for a pressure of 540 mm. of saline. Despite aggressive treatment for cardiac failure and use of oxygen and antibiotics, the patient suffered unexpected respiratory and cardiac arrest on the tenth hospital day and could not be resuscitated. Electrocardiogram showed severe right heart strain with a vertical axis and P pulmonale. Post mortem examination showed multiple pulmonary emboli of recent and ancient vintage. The right atrium and adrenal and pelvic veins contained organizing thrombi, but the most likely source of emboli was considered to be the lower extremities. There was severe cor pulmonale with chronic passive congestion of the liver and viscera. The patient had complained of calf pain 4 years prior to admission and had recurrent calf pain over the subsequent course although she never had enough clear-cut symptoms to make a diagnosis of thrombophlebitis or pulmonary embolism. The cause of death was severe cor pulmonale secondary to recurrent pulmonary emboli.
PICKWICKIAN SYNDROMIE, 20 YEARS LATER
117
COM\AlENT This patient differed in several features fromii the first patient. The degree of sominolenece w-as completely out of proportioni to the mild hypereapnea (lF'ig. 4). The peculiar breathing pattern had not beeni seen previously and Nvas niot understood. It did not fit either Cheyne-Stokes nor Biot breathing. Other features of this patient's illness agreed \ith preconceived ideas of pathogenesis (Fig. 3). The Pac02 rose during exercise suggesting a subnormal ventilatory response. There was mild polycythemia, slight anoxemia and very severe right ventricular failure. Loss of weight and treatment of heart failure seemed to improve the patient's somnolence. At post mortem examination, the right ventricular failure proved to be at least partially secondary to multiple pulmonary emboli, a common complication of obesity.i2 13 The pulmonary emboli, however, did not explain the hypersomnia. The Gastaut Syndrome (F ig. .5) has a different genesis from the Auchin(loss' Syndrome. The basic pathophysiologic cause of the Gastaut Syndrome is upper airway obstruction. Simultaneous recording of the diaphragiiatic and respiratory muscle electromyograms, arterial blood gases and ventilation4' 5, 6 during sleep demonstrates that upper airway obstruction is the cause of the sleep apnea in these patients. MIost probably the tongue falls back into the pharynx and causes the obstruction. The M% hole syndrome disappears with Neight loss and Nith tracheostomy. Studies during sleep demonstrate that these patients, because of frequent awakenings, do not experience sufficient normal sleep at night.5' Consequently, they are sleepy during the day. OBESITY
NOCTURNAL SLEEP IDIOPATHIC INTERMITTENT TONGUE SWALLOWING INTERMITTENT UPPER AIRWAY OBSTRUCTION (SLEEP APNEA: RESEMBLES CHEYNE-STOKES RESPIRATION)
INADEQUATE NOCTURNAL SLEEP DIURNAL HYPERSOMNIA
INCREASED WORK OF BREATHING DECREASED VENTILATORY RESPONSE TO CO2
ALVEOLAR HYPOVENTILATION
FIG. 5. Postulated mechanism of the hypersomnia which occurs in obese patients. Somnolence is caused by inadequate nocturnial sleep.
118
DOUGLAS CARROLL
PICKWICKIAN SYNDROMES, CASE REPORTS TO 1971 In an attempt to see how frequently hypersomnia occurred in patients thought to have l'ickwickian Syndrome, we reviewed the literature in English up to 1971. We found 74 adult case reports" 2, 4, 8, 13-40, 53 and added eight new cases which fulfilled our minimal requirements for inclusion in the Pickwickian Syndrome: 1. a recorded weight of over 200 pounds (adults), 2. laboratory evidence of alveolar hypoventilation and 3. elimination of associated diseases which might cause alveolar hypoventilation. There were 82 cases over 16 years of age (Table 1). Males predominated slightly. Shortness of breath was by far the most common presenting symptom. Somnolence was second, followed by a large number of much less common complaints. Most of the patients had been obese for a prolonged period prior to developing any symptoms. Our impression is that the weight gain seen in the last few months prior to presenting to a physician is generally edema fluid gain secondary to right ventricular failure. The mean initial weight was 317 pounds, but the range was from 205 pounds to 588. Initial pulmonary function studies showed a reduction in vital capacity, normal FEV, sec., slightly raised hematocrit, low Pao2, low normal pH, elevated Paco, and slightly elevated RA/TLC. Some patients with initial normal studies later developed abnormalities wchich are not recorded in the table. One criteria of selection of these patients was that there be evidence of alveolar hypoventilation. In 42 patients where an electrocardiogram was reported, there was right axis deviation in 27, left axis in 6 and normal in 9. P -waves were peaked in 7 of 42 cases. Siginificant weight loss over a prolonged period was distinctly unusual in case reports. The time of follow-up varied and some may have lost weight subsequent to the report. Our own experience with repeated admissions of patients as they regained weight is discouraging since this is a curable disease if the patient will cooperate. All patients lost some weight, generally fluid associated with right ventricular failure. Only 4 out of 45 patients lost more than 40 % of their initial weight. Nearly all patients improved, suggesting that the control of heart failure results in improvement even with no loss of body fat. Table 2 gives similar data on eleven children.41-" 1\Iales predominate as does shortness of breath. A number of these children were mentally defective, a finding not present in adults. DIscUSSION The first definitive laboratory studies performed on obese patients with right sided heart failure and respiratory acidosis were reported in 1955.1 At
119
PICKWICKIAN SYNDROMIE 20 YEARS LATER
TABLE 1 82 Cases of Adult Pickwickian Syntdrome, Where Weight was Recorded at More 200 Poiunds Total Cases
Age (yrs. 4: S.D.)
82
46 i 13
Than
Sex
Male 52
Female 30
Presenting Complaintts
Shortness of Breath Somnolence Cyanosis Non-Pickwick complaint Semi-comatose Swelling of ankles Substernal pain Headache Cough High Blood Pressure
Initial Wt. (lbs.)
Duration of Obesity (yrs.)
Cases 77
Total Cases Mean SD
40
9 7 6 4 3 3 2 2
IRange
34 27 17 1-61
Total Cases 82 Mean 317 SD 74 Range 205-588
1 Initial Stutdies Total
Forced Vital Capacity Forced Expiratory Volume Hematocrit Pao2 pH Paco2 RA/TLC
Cases
28 31 61 35 30 46 17
EX,KG Axis: Total Cases-42 P Waves: Total Cases-42 Weight (initial & follow-up): Loss:
*
Mean*
SD*
57 77 55 45 mm 7.36 62 mm 40
22 9 9 14 0.07 14 13
Rt-27 Lt 6 Peaked-7 Total cases-45 Less 20% loss-25 20-40% loss-16 40-60% loss- 3 60+% loss- 1
Range*
17-128
60-98 40-76 7.10-7.54 32-101 19-62 Normal-9
Per cent of predicted value.
approximately the same time, a group of patients Nx ith somewhat different symptoms2 consisting of conspicuous hypersomnia and hat appeared to be
periodic breathing began to be reported and ickian Syndrome. lt
was
X
ere
designated
as
the Pick-
not appreciated until 1966 that the hypersomnia
120
DOUGLAS CARROLL
TABLE 2 11 Patientts Less Than 16 Years of Age with Pickwickiant Sytndrome Total Cases
Age (yrs. i: S.D.)
11
8.5 4 3.2
Sex
Female4
Male7
Presentinig Complainits Cases 10
Shortness of Breath Somnolence Cyanosis
5 4
1
Initial Wt. (lbs.)
Duration of Obesity (yrs.)
11 Total Cases 4 Mean 3 SD 4 mo-ll yrs. Range
11 Total Cases 145 Mean 69 SD 88-346 Range
Intitial Studies Total Cases
Forced Vital Capacity Forced Expiratory Volume Hematocrit Pao pH
6 5
PacM2 RA/TLC
6 3
8
2 5
Total Cases 4 EKG Axis: Total Cases-4 P Waves: Weight (initial & follow-up):
Mean*
67 77
45 39 mm 7.29 67 mm 41
SD*
24 20 39 25
0. 06) 24
17.00
Range*
47-104 45-95 41-54 14-65 7.17-7.34 43-112 18-58
IRt-3 Normal-1 Peaked-3 Decreased-1 Total Cases-11 Less 20% loss-8 21-40% loss 1 41-60% loss 2
* Per cent of predicted value.
and periodic breathing had a different etiology from the right sided heart failure and respiratory acidosis. In order to distinguish these varieties of the l'ickwickian Syndrome, N-e have applied the term Auchincloss Sy?idr6rne to the first described. The essential pathogenic feature of this syndrome is the development of increased work of breathing because of obesity, resulting in inability of the patient to ventilate sufficiently to remove accumulating carbon dioxide. An important problem still remains unanswered. Some patients xx ith severe obesity never develop this syndrome xN hereas others Nx ith only moderate obesity do develop it. It is known that some patients of normal NAeight also develop alveolar hypoventilation presumably caused by some central disorder of
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ventilatory regulation rather than from increased work of breathing. The possibility therefore exists that the Auchincloss Syndrome develops only in )atients xxho in addition to having increased work of breathing secondary to obesity, also have some disorder of ventilatory regulation. We have seen this syndrome in a fath( r and a son and familial Pickwickian Syndrome has been described in the literature.35' 51 If obcse patients X ho develop respiratory acidosis did indeed have a congenital abnormality of ventilatory control, their ventilatory response to carbon dioxide should continue to be abnormal after recovery from respiratory acidosis. There are only three studies in xx hich ventilatory response to CO2 has been tested after recovery. Burn ell's case2 show ed improvement in response. Pedersen's case29 had serial studies w hich shoN ed improvemnent. One of MAacGregor's cases13 regained sensitivity. Our own case I had decreased sensitivity 14 years after he last recovered from respiratory acidosis. Thus, from the reports of Pickw ickian Syndrome in families and the demonstration of depressed ventilatory response after recovery from respiratory acidosis, there is some support for the theory that these patients have a congenital or possibly an inherited insensitivity of ventilatory control. The second syndrome which we have called the Gastaut Syndrome is associated with hypersomnia and periodic breathing and has a different etiology from the Auchiuicloss Syndrome. The essential feature is upper airway obstruction. This has been clearly demonstrated, but why the tongue obstructs the airway of obese patients with sleep apnea is by no means clear. Two other clinical situations are possible but have not been clearly defined. The first is the obese patient in respiratory acidosis and possibly cor pulmonale w ho is somnolent but does not have sleep apnea. His somnolence, in fact, may be related to elevation of the carbon dioxide tension. These were among the earliest patients described and might be referred to as Sieker's Syndrome."8' 52, 53 A final syndrome resembles the Pickw ickian Syndrome in that there is obesity and somnolence but the patients have no hyperearbia, respiratory acidosis or sleep apnea. This syndrome might be given the name of Alexauider, who first drew attention to it.24, 52
SUAI MARY The l'ickwickian Syndrome stimulated new' pathophysiological concepts in regard to control of ventilation. With the advent of sleep laboratories, the peculiar sleep apnea occurring in some of these patients has been explained on the basis of intermittent upper airway obstruction. Tw o patients with different manifestations of the Pickwickian Syndrome
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are presented. The suggestion is made that these two subsyndromes should have unique designations. The Auchincloss Syndrome is manifested by right heart failure and respiratory acidosis in obese patients who are alert and have no major abnormality of breathing pattern. The fundamental cause of this abnormality is the increased work of breathing caused by the obesity. The cost of breathing is so high that the ventilatory regulation is compromised and respiratory acidosis results. The Gastaut Syndronme is characterized principally by hypersomnia and sleep apnea. The fundamental defect is upper airway obstruction during sleep, resulting in increased work of breathing, which together with the increased work caused by obesity leads to respiratory acidosis and right ventricular failure. Hypersomnia, rather than heart failure or respiratory acidosis, is the major manifestation of this syndrome, and is the result of sleep loss. There is a widespread interest in the sleep disorders of obese patients, which should result in the discovery of important new concepts of ventilatory regulation.54-64 REFERENCES 1. AuCHINCLOSS, JR., J. H., COOK, E. AND RENZETTI, A. D.: Clinical and physiological aspects of a case of obesity, polycythemia and hypoventilation. J. Clin. Inivest. 34: 1537, 1955. 2. BURWELL, C. S., ROBIN, E. 1)., WHALEY, R. D. AND BICKELMAN, A. G.: Extreme
3. 4. 5. 6.
7. 8.
9. 10. 11.
obesity associated with alveolar hypoventilation-A Pickwickian Syndrome. Am. J. Med. 21: 811, 1965. OSLER, W.: The principle and practice of medicine. Eighth Edition, 1918. GASTAUT, H., TASSINARI, C. A. AND DURON, B.: Polygraphic study of the episodic diurnal and nocturnal manifestations of the Pickwick syndrome. Brain Res. 2: 167, 1966. Symposium: hypersomnia with periodic breathing. Bull. de Physiopathol. Respir. 8: 965-1292, 1972. WALSH, R. E., MICHAELSON, E. D., HARKLEROAD, L. E., ZIGHELBOIM, A. AND SACKNIER, M. A.: Upper airway obstruction in obese patients with sleep disturbance and somnolence. Ann. Intern. Med. 76: 185, 1972. LUGARESE, E., COCCAGNA, G., MANTOVANI, M. AND BRIGNANI, F.: Effects of tracheostomy in two cases of hypersomnia with periodic breathing. J. Nenlrol. Nerosurg. Psychiatry 36: 15, 1973. CARROLL, D.: Peculiar type of cardiopulmonary failure associated with obesity. Am. J. Med. 21: 819, 1956. RILEY, R. L.: The work of breathing and its relation to respiration acidosis. Anal. It. Med. 41: 172, 1954. CHERNIACK, R. M. AND SNIDAL, D. P.: The effect of obstruction to breathing on the ventilatory response to C02. J. Clini. Invest. 35: 1286, 1956. BRODOVSKY, D., MACDONELL, J. A. AND CHERNIACK, It. M.: The respiration response to carbon dioxide in health and in emphysema. J. Clin. Invest. 724, 1960.
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12. GODREY, S.: Pulmonary embolism and the Pickwick syndrome. Br. J. Dis. Chest 66: 155, 1972. 13. MACGREGOR, M. I., BLOCK, A. J. AND BALL, W. C., JR.: Serious complications and sudden death in the Pickwickian syndrome. Johns Hopkins Med. J. 126: 279, 1970. 14. RICHTER, T., WEST, J. R. AND FISHMAN, A. P.: The syndrome of alveolar hypoventilation and diminished sensitivity of the respiratory center. N. Eng. J. Med. 256: 1165, 1957. 15. WEIL, M. H. AND PRAS AS, A. S.: Polycythemia of obesity-further studies of its mechanism and a report of two additional cases. Ann. Intern. Med. 46: 60, 1957. 16. SARIANO, A. Q. AND DURHAM, J. R., JR.: Pickwickian syndrome. Del. M. J. 29: 153, 1957. 17. LILLINGTON, G. A., ANDERSON, M. W. AND BRANDENBURG, R. O.: The cardiorespiratory syndrome of obesity. Chest 32: 1, 1957. 18. ESTES, E. H., JR., SIEKER, H. O., MCINTOSH, H. D. AND KELSER, G. A.: Reversible cardiopulmonary syndrome with extreme obesity. Circulation 16: 179, 1957. 19. HERALD, A. A., JR.: The Pickwickian syndrome: a case report. J. La. State Med. Soc. 110: 305, 1958. 20. CO.ATES, F. O., JR., BRINKMAN, G. L. AND NOL, F. E.: Hypoventilation syndrome physiologic studies in selected cases. Anti. Intern. Med. 48: 50, 1958. 21. CHERNIACK, R. M.: Respiratory effects of obesity. Can. Med. Assoc. J. 80: 613, 1958. 22. GOTZSCHE, H. AND PETERSEN, V. P.: Obesity associated with cardiopulmonary failure-the Pickwickian syndrome. Acta Med. Scand. 161: 383, 1958. 23. BERLYN, G. M. AND MANC, M. B.: Cardiorespiratory syndrome of extreme obesity. Lancet (2) (7053) 939, 1958. 24. COLE, V. W. AND ALEXANDER, J. K.: Clinical effects of extreme obesity on cardiopulmonary function. South Med. J. 52: 435, 1959. 25. SMITH, G. M.: Obesity with polycythemia-report of a case. Ann. Itntern. Med. 50: 1530, 1959. 26. GRIPTA, K. K.: Cardiorespiratory syndrome of extreme obesity. J. Indian Med. Assoc. 33: 477, 1959. 27. BORGE, E. AND BASTRUP, M. P.: Secondary erythraemia in extreme obesity the Pickwickian syndrome. Acta Haematol 21: 224, 1959. 28. SCALETTAR, R., MILLER, F. L., SODES, D. B. AND BARRY, K.: Alveolar hypoventilation and cardiopulmonary failure in obesity. U.S. Armed Forces Med. J. 11: 774, 1960. 29. PEDERSEN, J. AND THORP-PEDERSEN, E.: Ventilatory insufficiency in extreme obesity. Acta Med. Scand. 167: 343, 1960. 30. FROHLICK, E. D.: The Pickwickian syndrome. G.P. 24: 83, 1961. 31. MYER, J. S., GOTHAM, J., TAZAKI, Y. AND GATOH, F.: Cardiorespiratory syndrome of extreme obesity with papilledema-report of a fatal case with electroencephalographic, metabolic and necropsy studies. Neurology 11: 950, 1961. 32. GILL.ALM, P. M. S. AND MYMIN, 1).: Hypoventilation and heart disease. Lancet, October 14: 853, 1961. 33. FADE,, F. J., RICHMAN, A. D., WARD, W. W. AND HENDON, J. R.: Fatty infiltration of respiratory muscles in the Pickwickian syndrome. N. Eng. J. Med. 266: 861, 1962. 34. DRACIIMAN, D. B. AND GUMNET. R. J.: Periodic alteration of consciousness in the Pickwickian syndrome. Arch. ANelnrol. 6: 471, 1962.
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35. FALSETTI, H. L., HANSON, J. S. AND TABAKIN, B. S.: Obesity-hypoventilation syndrome in siblings. Am. Rev. Respir. Dis. 90: 105, 1964. 36. VOGEL, J. H. K. AND BLOUNT, S. G., JR.: The role of hydrogen ion concentration in the regulation of pulmonary arterial pressure: observations in a patient with hypoventilation and obesity. Circulation 32: 788, 1965. 37. ABRAHAMSEN, A. M. AND NITTER-HAUGE, S.: Extreme obesity with respiratory failure, necessitating artificial ventilation. Acta Med. Scauld. 180: 113, 1966. 38. ADDINGTON, W. W., PFEFFER, S. H. AND GAFNSLER, E. A.: Obesity and alveolar
hypoventilation. Respiration 26: 214, 1969. 39. SWANN, B. M.: Alveolar hypoventilation and benign increased intra-cranial pressure. Del. Med. J. 42: 261, 1970. 40. MATHUR, A. S., SETHI, J. P. AND MATHUR, 1). P.: Pickwickian syndrome: a case report. J. Postgrad. Med. 16: 48, 1970. 41. JENAB, M., LODE, R. I., CHIGA, M. AND 1)IEHL, A. M.: Cardiorespiratory syndrome of obesity in a child. Case report and necropsy findings. Pediatrics 24: 23, 1959. 42. SPIER, N. AND KARELITZ, S.: The Pickwickian syndrome: case in a child. Am. J. Dis. Child 99: 822, 1960. 43. ELLISON, L. T., TALLEY, R. E., MIMS, L. 1). AND ELLISON, 11. (J.: The cardiorespiratory syndrome of obesity in a child. A case report with clinical and physiological considerations. Chest 40: 419, 1961. 44. CAYLER, G. G., MAYS, J. AND RILEY, H. D., JR.: Cardiorespiratory syndrome of obesity in children. Pediatrics 27: 237, 1961. 45. WARD, W. A., JR. AND KELSEY, W. M.: The Pickwickian syndrome: a review of the literature and report of a case. J. Pediatr. 61: 745, 1962. 46. FINKELSTEIN, J. W. AND AVERY, M. E.: The Pickwickian syndrome studies oln ventilation and carbohydrate metabolism. Case report of a child who recovered. Am. J. Dis. Child 106: 251, 1963. 47. WALLREN, G., BORJI, B. AND OKMIAN, L.: Ventilatory insufficiency in an obese girl. A case report with pathogenetic considerations. Acta Paediatr. Scald. 54: 288, 1965. 48. NIZAN, M., SPITZER, S. AND ELIAN, E.: Obesity-hypoventilation (Pickwickian) syndrome in a child. Isr. J. Med. Sci. 4: 264, 1968. 49. METZL, K., KEITGES, P., KANTOR, J. AND BORDY, M.: The Pickwickian syndrome in a child. An extreme example of psychoneurotic obesity. Clini. Pediatr. 8: 49, 1969. 50. HIROAKA, M., INABA, Y. AND OHNO, T.: The Pickwickian syndrome in a child. Tohoku J. Exp. Med. 98: 363, 1969. 51. SCARLATO, G.: Familial Pickwickian syndrome (3 cases). Osp. Psichiatr. 38: 188, 1970. 52. CARROLL, D.: Nosology of "Pickwickian Syndrome". Bull. Physiopathol. Respir. 8: 1241, 1972. 53. SIEKER, H. O., ESTES, E. H. JR., KELSER, G. A. AND MCINTOSH, H. D.: A cardiopulmonary syndrome with extreme obesity. J. Clini. Invest. 34: 916, 1955. 54. GUILLEMINAULT, C., ELDRIDGE, F. L. AND 1)1':MENT, W. C.: Insomnia with sleep apnea: a new syndrome. Science 181: 856, 1973. 55. VOGEL, J. H. K., HARTLEY, L. H., JAMIESON, G. AND GROVER, 1. F.: Impairment of ventilatory response to hypoxia in individuals with obesity and hypoventilation: a concept of the Pickwickian Syndrome. Circ. Suppl. II, 35 and 36: 258, (n-
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56. KRIiGER, A. J. AND RosOMOFF, H. L.: Sleep-induced apnea: II Respiratory failure after anterior spinal surgery. J. Neiiroszirg. 40: 181, 1974. 57. SAFARt, P., ESCARRAGA, L. A. AND CHANG, F.: Upper airway obstruction in the unconscious patient. J. Appl. Physiol. 14: 760, 1959. 58. MORIK NAN, S., SAF.XR, P. AND I)ECARLO, J.: Influence of head-jaw position upon upper airway patency. Anesthesiology 22: 265, 1961. 59. INGRAM, R. H. AND BISHOP, J. B.: Ventilatory response to CO2 after removal of chronic upper airway obstruction. Am. Rev. Resp. Dis. 102: 645, 1970. 60. MILLER, A.: Airway obstruction and somnolence. Annt. Intern. Med. 81: 133, 1974. 61. WPI:TZMAN, E. D. (editor): Advances in sleep research, vol 1. Spectrum Publications, Inc. Flushing, N.Y. 1974. 62. ROCHESTER, 1). F. AND EENSON, Y.: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Am. J. Med. 57: 402, 1974. 63. BUTLER, J.: Clinical problems of disordered respiratory control. Am. Rev. Resp. Dis. 110: 695, 1974. 64. SACKNER, M., LAND;, J., FORREST, T. AND GTREEFNFiLTrCH, D. Periodic sleep apnea: chronic sleep deprivation related to intermittent upper airway obstruction and central nervous system disturbance. Chest 67: 164, 1975.
DISCUSSION I)it. J. EDWIN WOOD, III (Philadelphia): I know many of you who will remember D)octor Sidney Burwell as one of our great members. I remember a presentation of his some 20 years in which he presented his first Pickwickian patient. He took great delight in pointing out the patient's chief complaint. The man was a professional poker player, who complained that he had drawn to an inside straight but fallen asleep before his turn came to bet. DR. HARRY W. FRITTS, JR. (Stoneybrook): 1)oug, I know you have been very careful about attributing the diminished response to carbon dioxide to any one part of respiratory apparatus. Yet in the first patient you talked about a diminished sensitivity to 10% C02. You showed us that as the weight went up, the Pco2 went up, and in your summary you've I think mentioned that there might be a relative insensitivity in the respiratory center to CO2. Now the question is what evidence do you have for this? As I view the respiratory center, it responds to stimuli on the part of the cerebral spinal fluid, hydrogen ion, oxygen, carbon dioxide. The output of that center's impulses travel along nerves, muscles contract, the muscles perform work through the chest wall, the lung follows and ventilation results. But these elements interpose between ventilation (the thing you are measuring) and the impulses leaving the respiratory center. It makes the problem almost insoluble at the moment. I don't know what the respiratory centers are doing, and I have never been able to really convince myself that it is doing anything other than what it normally should. What evidence do you have to make you believe that it is relatively insensitive or incapable of responding to 10% carbon dioxide in a normal way? DR. CARROLL: Very good question, and I was fairly careful in what I said. I agree with you. The system is extremely complex. Lambertson, you may recall, studied response to CO2 in normals about ten or fifteen years ago and showed an extremely wide difference in the response of normals. Now this work was not extended, and this is just the CO2 response. Response to CO2 may not be the test that we want. At the American Thoracic Society's last meeting, you will remember there was a symposium on the respiratory center, and there is a tremendous amount of interest in this now, partially because of the development of simplified methods of measuring response to
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CO2. However I muist. say I am Inot store that the response to CO2, as we do it by julst increasing the anmouint of inspired carbon dioxide, is really the test which is going to tell us what we want to know. DR. THOMAS A. WARTHIN (Boston): We've followed a group of so-called Pickwickans for a number of years, including an unfortunate young man who was a very obese lobsterman who had a line tied to his body because he would fall asleep while hauling in his pots. He would fall asleep and topple into the water. After several episodes he sought medical assistance. In a follow-up of over ten years, of a group of about twelve Pickwickians, three have turned out to have myotonia dystrophica and two variants of Parkinsonism which seemed to contribute to their tendency to severe somnolence. Do you believe there may be a significant association of neurologic disease in the true somnolent Pickwickian? DR. CARIROLL: Yes, I think this is a good point. We've known for many years that there are a number of neurological diseases which are associated with respiratory acidosis. It is probable that many of them are not pickedup early and only are identified with long follow-up. The other point here is that there are also some central nervotus system diseases which may effect again these respiratory centers andmay modify the central response of the patient to CO2 inhalation. DR. JOHN H. KNOWLES (New York): I am absolutely fascinated with this new term 'idiopathic intermittent tongue swallowing'. It is something I never heard before, and I wondered several things. First of all did Gastaut actually see some of these patients swallow their tongue and go into apnea during sleep? DR. CARROLL: He didn't see them swallow their tongue, but he had them hooked up with a mouth piece, nose piece, so he could measure ventilation. He had an eleetromyography to see if their chest wall muscles and diaphragm were moving. He was able to show that during these episodes of apnea, no air was passing. Now the second piece of evidence is that if a tracheostomy is performed, these patients are cured immediately. No more sleep apnea, no more somnolence, no obstruction. So although the tongue hasnot actually been seen swallowed, this seems to be the localization of the obstruction. I)R. JOHN T. SESSIONS, JR. (Chapel Hill): I am also fascinated by the tongue swallowing explanation. I have been interested in this because the people doing ilio by-pass procedures report trivial amounts of weight loss reverse the Pickwickian syndrome. That it is one of the first symptom to go away. This is disturbing because of having subscribed to the central nervous system explanation. I noticed your man lost a great deal of weight about his neck and you're suggesting a simple mechanical correction by tracheostomy prevents this. Has anyone measured where weight goes away from first? Could 25 pounds come off the neck, and in that way explain this mechanical problem that you describe? D)R. CARROLL: I don't think anybody studied that, but there is a tremendous amount of interest in the nature of this obstruction right now. There are five or six Sleep Laboratories studying this,6' and the only thing that I know about this obstruction is Safar's work57' which was done fifteen or twenty years ago where he noted changes in the size of the larynx with different head positions. Then you will remember in mouth-to-mouth breathing he recommended that the head be put way back because the patient tended to swallow his tongue. DR. THOMAS H. HUNTER (Charlottesville): To return to the somnolence, I wonder if you have any evidence on whether there is an effect here of what John Pappenheimer has been studying up at Harvard for a good many years. In studying the spinal fluid of goats, he has found a small molecular weight substance, that is correlated with 58
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sleep deprivation and causes sleepiness. I think it is not limited to goats; there is evidence that it appears in other species as well. D)o we know anything about the mechanism of sleepiness in Pickwickians in relation to this work? 1)D. CAR1ROLL: The only thing I can say there is that measurement of sleep levels shows that these patients get less Stage 3, 4 and ItEM sleep than normal people. If normal people are prevented from getting Stage 3, 4 and REM sleep in experiments, these people are sleepy all day too.
