Erythrocytosis and Hypoxemia without Pulmonary Symptoms

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CLINICAL CONFERENCE IN PULMONARY DISEASE

Erythrocytosis and Hypoxemia without Pulmonary Symptoms* Clinical Conference in Pulmonary Disease from Northwestern University Medical Center. Chicago Co-Chairmen: William B. Buckingham, M.D., F.G.C.P., Assistant Professor of Medicine David W. Gugell, M.D., F.C.C.P., Ernest S. Bazley Professor of Medicine; Chief, Pulmonary Disease Section Louis ]. Kettel, M.D., F.G.G.P.,oo Assistant Professor of Medicine and Chief, Pulmonary Disease Section, Veterans Administration Research Hospital Walter A. Rambach, M.D., Associate Professor of Medicine

Dr. Buckingham: The Pulmonary Disease Section

other than phenylbutazone, 100 mg tablets three times daily, but for five days before admission had taken no medication. He had numerous allergies (hay fever, dust, molds, etc). He appeared to be slightly obese but otherwise healthy looking. The vital signs and balance of the physical examination were normal except for some minor left eighth nerve damage. The chest roentgenogram was normal and his relevant laboratory data is shown in Table 1.

is often consulted whenever the laboratory

finds an unexpected increase in either hemoglobin concentration, red cell mass or both. We have just such a problem to discuss now. Dr. H. Brown: A 26-year-old salesman was hospitalized for evaluation of an elevated hematocrit (60 percent) which had been noted first one year earlier. Two weeks before admission he developed acute gouty arthritis (uric acid 9.0 mg/l00 ml) of the medial portion of the right great toe shortly following an avulsion of a tendon in his right foot. His hematocrit was again 60 percent. He denied having any symptoms except for an occasional nonproductive cough and slight dyspnea upon climbing one flight of stairs. He smoked approximately one package of cigarettes daily and had done so for ten years. At the age of 14 he had a severe bout of pneumonia. His family history was positive for hypertension, diabetes, obesity, and cerebral vascular disease. He took no medication

Dr. Buckingham: We were asked to evaluate this patient's lung function and arterial blood gas composition. The physical examination and roentgenogram of the chest were normal as were the ventilatory tests, although some of these values are borderline low (Table). I think we can quickly conclude that ventilatory impairment is not causing him any difficulty and certainly is not contributing to his polycythemia. The results of the blood gas measurements were a bit different and I have asked Dr. Kettel to say something about them.

·Supported in part by the Ernest S. Bazler Research Fund and U.S. Public Health Service, Nationa Heart Institute, Training Grant No. HE05694. ··Present address: Veterans Administration Hospital, Tucson, Arizona.

Dr. Kettel: The specific question asked was, "Is there a hypoxemic stimulus to red cell formation in this patient?" Several casual blood gas measure-

344

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ERYTHROCYTOSIS AND HYPOXEMIA

ments during the hospitalization taken while the patient was supine gave oxygen tensions of 55 to 62 mm Hg. These values are clearly abnormal. Why? At another time, after discharge from the hospital, the measurements were repeated with the samples obtained with the patient again lying Hat in bed. The p02 was 62 mm Hg, identical to what was previously obtained (Table). The pC0 2 of 35 and the pH are essentially normal but the oxygen saturation is definitely abnormal. Therefore, he definitely has hypoxemia. What might the cause be for his hypoxemia? His ventilatory abnormalities are negligible. The recumbent position could result in compression of some lower portions of his lung, creating areas of atelectasis which were not ventilated but through which blood continued to perfuse. To answer this question we do two things; ( 1) have the patient take deep breaths while lying down and (2) breathe normally while erect. After 15 deep breaths his p02 increased 21 mm Hg to a normal value of 83 Hg. Of course he colew off" carbon dioxide and became alkalotic temporarily. Clearly, he was capable of achieving a normal arterial oxygen saturation. Standing for five minutes and breathing normally also resulted in a p02 considerably higher than the supine value. A true anatomic shunt such as a pulmonary A-V fistula could contribute to the hypoxemia but was excluded by 100 percent oxygen breathing. If peripheral arterial oxyhemoglobin desaturation is due to an anatomic cause for venous blood bypassing the lungs then hypoxemia will remain

despite 100 percent oxygen breathing. After 20 minutes of oxygen breathing this patient's p02 rose to 565 mm Hg. An arterial p02 over 550 mm Hg at sea level virtually excludes any significant anatomic shunt. The relationship between posture and arterial oxygen tension deserves comment. In the supine position the expiratory reserve volume is reduced.! This reduction may be accentuated in obese people, particularly people with very large abdomens. 2 The intra-abdominal pressure rises greatly with recumbency and the balance between the elastic properties of the thorax and the lungs shifts, resulting in elevation of the diaphragm and loss of expiratory reserve volume. s The arterial oxygen tension in resting, supine normal subjects over 60 years of age is less than in similar subjects when sitting. 4 The possibility that the altered diaphragmatic position leads to ventilation-perfusion alterations as the cause for this change in blood oxygen tension seems likely. Erythropoietin output in the supine position is increased in overweight, hypoxic patients with erythrocytosis. 5 This patient was not a great deal overweight but he did have a large amount of abdominal fat. Therapy for such patients is weight reduction and! or oxygen while in the supine position, particularly during sleep. The secondary erythrocytosis then disappears.

Dr. Buckingham: Thank you Dr. Kettel. This man clearly has positional hypoxemia. Dr. Rambach, is his erythrocytosis the consequence thereof?

Table l-LabOf'atory Data Observed 153 5.4 3.8 1.2 6.7 2.9 5.55 55 18.1 8,100 1.73 X 10cs

Max. volunt. ventilation, liter/min. Vital capacity, liter Forced exp vol, 1 ~'ec/L Residual volume, liter Total lung capacity, liter Max. mid-expo flow, liter/sec. Red blood cells, mmS Hematocrit, ml/l00 ml Hemoglobin, gm/loo ml White blood cells, mmS Platelets, mmS Supine ~

pH pC02 , mm Hg Std. bicarb., mMlliter p 0 2,mmHg 02 Sat., percent

---...A

Rest 7.38 35 20 62 91

°KORyet al: Amer.]. Med., 30:243, 1961. oONEEDHAM et al: Thorax, 9:313, 1954.

~

Hypervent. 7.55 22 20

83

97

,

Predicted 192 0 5.6 0 4.5 0 1.7 0 • 7.2 4.7 ± 1.1 00 • 5.4 ± 0.8t 47 ± 7.0t 16 ± 2.0t 5,000-10,OOOt 1.4-3.4 X 10cs t Standing

Rest 7.39 32 19 76 94

Amer. Rev. Tuberc. and Pulm. Dis.,72:783 1955. tClinical Hematology, 5th 00., M.M. Wintrobe: Lea & Febiger, Philadelphia, 1961.

oooLEUALLEN AND FOWLER:

ttAsTRUP et al: Lancet, 1035, May 14, 1960.

tttSEVERINGHAUS: ]. App. Physiol., 21:1108, 1966.

CHEST, VOL. 57, NO.4, APRIL 1970

Predicted

A.

1~02

7.39

32

19 565 100

Rest Rm. Air 7.35-7.42tt 34-45tt 21-25tt

>80 >95+++

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Dr. Rambach: Before exploring mechanisms let us consider definitions for a moment. One looks at polycythemia as either absolute or relative. Under the former category we are concerned with erythrocytosis and erythremia. Erythrocytosis is an elevation of the red cell mass secondary to some known stimulus. Erythremia is an elevation in red cell mass due to unknown causes. The difference between the terms leukocytosis and leukemia offers a useful comparison. What values actually constitute a significant increase in red cell mass? In a young healthy man hematocrit values of 55 percent and hemoglobin concentrations of 18 gm are found. These findings are not representative of erythrocytosis but rather a physiologic variation of normal. When the values exceed 18 gm and 55 percent, erythremia has to be considered. But, in the absence of usually associated symptoms and physical findings it is all unlikely diagnosis and one is probably dealing with an individual with erythrocytosis. Thus this patient had none of the findings commonly observed with erythremia, such as headache, rubor, hepatomegaly or splenomegaly, or itching after bathing. Furthermore, his white blood cell counts and platelet counts were normal. I do not believe one can make a diagnosis of erythremia in the young man until one can demonstrate an increase in more than the erythroid elements because erythremia is a disease of myeloid and megakaryocytic production as well as of erythrOid production. In other words, it is a myeloproliferative disease. Patients with ventilatory impairment and associated hypoxemia demonstrate an increased output of erythropoietin in their urine. Phlebotomy also increases erythropoietin output. This represents the normal physiologic response to a decrease in the oxygen supply. In other states erythropoietin secretion is relatively autonomous and inappropriate. Thus, patients with hepatoma, renal cystic disease, hypernephroma and cerebellar hemangioma may have increased levels of erythropoietin. Interestingly, these patients will not increase their erythropoietin output if stimulated by phlebotomy. They appear to have an autonomous, inappropriate secretion of an erythropoietin-like material which is not under normal physiologic control. In a third category is the autonomous red blood cell production of erythremia. These patients have hepatosplenomegaly, symptoms of polycythemia vera, elevated white blood counts and elevated platelet counts. In these individuals the levels of erythropoietin in the serum and urine are virtually nil. Their red blood cell production is autonomous. Following a phlebo-

BUCKINGHAM ET AL

tomy they increase their erythropoietin production. Thus, their erythropoietin producing mechanism is operating, but is suppressed by the high red cell volume. Although time consuming to do, erythropoietin secretion can be studied in patients when one is confronted with a difficult differential diagnosis. Assay of urine erythropoietin concentrations before and after phlebotomy may distinguish between hypoxic polycythemia, erythrocytosis, inappropriate or autonomous erythropoietin production and autonomous red blood cell production.

Question: Is the stimulus to erythropoietin secretion a decrease in red cell mass or in oxygen content? Dr. Rambach: The red cell mass per se is probably not the regulatory mechanism, but absolute proof of that statement still has not been forthcoming. The general trend of experimental results, particularly in animals, but also in humans, suggests that it is the tissue oxygen saturation from which the stimulus originates. Dr. Buckingham: If our patient had a normal arterial blood oxygen with presumably a normal tissue oxygen, he would lose his erythrocytosis. One good way to produce a high erythropoietin titer in animals is to expose them intermittently to simulated altitudes of 20,000 feet. This is similar to what happens to this man when he lies down. He has eight-hour periods in which he stimulates his erythropoietin production. Dr. eugell, would you comment on altitude, hypoxia and hypoxemia? Dr. Cugell: Patients with chronic lung diseases do not have as great an increase in red cell mass and hemoglobin concentration for the same reduction in arterial p02 as is found in people who live at altitudes or who have congenital heart disease. 6 An explanation for this discrepancy is that patients with chronic lung disease have chronic infection resulting in suppression of red cell production. 6 In a later study of normal adults residing at sea level, 1,600 and 3,100 meters a linear relationship between arterial oxygen saturation and red cell mass was found. 7 Nine patients with obstructive lung disease exhibited a somewhat greater increase in red cell mass at comparable levels of arterial oxygen desaturation. The discrepancy between these reports may be attributable to variation in the degree of iron deficiency which may occur in pulmonary emphysema patients,8 the difference in occurrence of cor pulmonale, or to differences in patient selection procedures. 7 CHEST, VOL. 57, NO.4, APRIL 1970

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ERYTHROCYTOSIS AND HYPOXEMIA

Dr. Kettel: Is a 91 percent oxygen saturation compatible with a hematocrit of 57 percent? Dr. Gugell: According to the studies of Well and associates,7 the 95 percent confidence limit for normal men is a hematocrit of 55 percent at 91 percent oxygen saturation. Therefore, this hematocrit of 57 percent is a bit higher than would be expected from the observed saturation. Dr. Rambach: There is some data to suggest that if hypoxia is of appropriate duration and of sufficient degree there is a reduction in red cell production, and one wonders if in patients with chronic lung disease, there is not a narrow margin between an excess production of erythropoietin and depression of the bone marrow. Some years ago we produced acute hypoxia in animals, sustained it for half an hour, and demonstrated a very rapid drop in DNA synthesis in the bone marrow. However, if the hypOxia was continued for a longer period, erythropoietin production increased. Dr. Keitel: Is there data on normal individuals concerning the postural effects of erythropoietin production? Dr. Rambach: Not that I know of. Dr. Buckingham: Will erythropoietin studies in patients with chronic lung disease predict which patients will get secondary polycythemia? Dr. Rambach: I believe this has been attempted with no specific results. Dr. Buckingham: What are we going to do for this patient? Someone recommended we get him a Murphy bed to sleep in and leave it upright, or will losing weight accomplish the same thing? Dr. Rambach: His mild polycythemia represents

no danger. There is no need for specific treatment. If his red cell mass continues to increase then the treatment of choice is phlebotomy. It would be preferable to put the patient on a weight reduction diet and possibly some supplemental oxygen inhalation at night, or have him sleep standing up before considering phlebotomy. Patienfs wife (a physician)-Oh No!

Dr. Buckingham: Thank you for your comments. We will see what we can accomplish with cessation of smoking and weight reduction as a first step. REFERENCES

1 WHITFIELD, A.G.W., WATERHOUSE, J.A.H., AND ARNOIT, W.M.: The total lung volume and its subdivisions. A study in physiological norms. II The effect of posture, Brit. ]. Social Med., 4:86,1950. 2 TUCKER, D.H., AND SIEKER, H.O.: The effect of change in body position on lung volumes and intrapulmonary gas mixing in patients with obesity, heart failure, and emphysema, Amer. Rev. Resp. Dis., 82:787, 1960. 3 WADE, O.L., AND GILSON, J.C.: The effect of posture on diaphragmatic movement and vital capacity in normal subjects, with a note on spirometry as an aid in determining radiological chest volumes, Thorax, 6:103, 1951. 4 WARD, R.J., TOLAS, A.G., BENVENISTE, R.J., HANSEN, J.M., AND BONICA, J.J.: Effect of posture on normal arterial gas tensions in the aged, Geriatrics, 21:139, 1966. 5 WARD, H.P., BIGELOW, D.B., AND PETTY, T.L.: Postural hypoxemia and erythrocytosis, Amer. ]. Med., 45:880, 1968. 6 VANIER, T., DULFANO, M.J., Wu, C., AND DESFORGES, J.F.: Emphysema, hypoxia and polycythemic response, New Eng. J. Med., 269:169, 1963. 7 WElL, J.V., JAMIESON, G., BROWN, D.W., AND GROVER, R.F.: The red cell mass-arterial oxygen relationship in normal man, J. Clin. Invest., 47:1627, 1968. 8 FIELDING, J., AND ZoRAB, P.A.: Polycythemia and iron deficiency in pulmonary CCemphysema," Lancet, 2:284, 1964. Reprint requests: Dr. Cugell, 303 East Chicago Avenue, Chicago 60611.

FROM JOHN HUNTER TO CHARLES DARWIN John Hunter was the first great biologist of the modems, not alone because of his extraordinary powers of observation and the comprehensive sweep of his intellect, but chiefly because he first looked at life as a whole, and studied all of its manifestations, in order and disorder, in health and in disease. From John Hunter to Charles Darwin enonnous progress was made in every department of zoology and botany, and not only in the accumulation of facts relating to structure,

CHEST, VOL. 57, NO.4, APRIL 1970

but in the knowledge of function, so that the conception of phenomena of living matter was pro~essively widened. Then with the ORIGIN OF SPECIES came the awakening, and the theory of evolution has not only changed the entire aspect of biology, but has revolutionized every department of human thought. Osler, W.: Aequanimitas, Blakiston, Philadelphia, 1932