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Polycythemia vera and arterial oxygen saturation
The American VOL. 34
Journal APRIL
of Medicine
1963
No.
4
Editorial Polycythemia
Vera
and Arterial
Oxygen
Saturation of the arterial oxygen saturation has become an important part of the evaluation of patients presenting with polycythemia. Such analysis permits separation of cases of polycythemia vera from polycythemia secondary to what may be inapparent causes of hypoxemia, such as intracardiac shunt, A-V shunt in the lung, significant but not obvious pulmonary insufficiency, methemoglobinemia, or the presence of other abnormal hemoglobins. The finding of a normal arterial oxygen saturation strongly suggests that the polycythemia is of the primary type. However, there are other causes for a polycythemic blood picture with a normal arterial oxygen saturation. These include renal disease (particularly hypernephroma), cerebellar hemangioblastomas, Cushing’s syndrome, fibroid uterus and chemical poisons (such as cobalt or phosphorus). In normal man, the arterial oxygen saturation, as determined by the Van Slyke technic, has generally been found to be 95 to 98 per cent. In young adults, Comroe’s figures [I] are 97.4 per cent + standard deviation (S.D.) 2.1, a figure with which almost all laboratories agree. A selected review of the recorded values for arterial oxygen saturation in patients with polycythemia vera reveals that the arterial oxygen saturation ordinarily exceeded 95 per cent. However, in a few patients figures were as low as 80 per cent, and in some others values fell in the borderland of 91 to 93 per cent. These reports pose several problems. (1) Are cases of apparent polycythemia vera in which the
D
arterial oxygen saturation is below 90 per cent bona fide? (2) What is the lower limit of normal arterial oxygen saturation for polycythemia Vera? (3) What is the mechanism for the borderline low arterial oxygen saturation in cases which appear unequivocally to be polycythemia Vera? Alleged Polycythemia Vera with Low Arterial Oaygen Saturation. In cases alleged to be polycythemia vera values for arterial oxygen saturations have been recorded as low as 79 [Z], 65 [.?] and 83.5 per cent [4]. In the light of subsequent experience, certain sources of possible error may account for these low values. One such study [4] employed “arterialized” ear lobe blood. Although a check was made in a small number of cases in which arterial blood was studied simultaneously, the possibility of admixture of venous blood in some instances cannot be excluded. It should be noted further that results of pulmonary function tests were not reported in any of these cases. Another study [2], utilizing analysis by the Van Slyke and Neil1 method of blood tonometrically equilibrated with appropriate gases to obtain accurate measurement of oxygen capacity, yielded values for twelve normal subjects of 94.0 to 97.5 per cent with a mean of 95.9 per cent. Allowing for a systematic error of approximately 2 per cent by the tonometer method, an even higher mean figure would be obtained. Of seventeen patients with polycythemia assumed to be primary because of the absence of specific causes, the arterial oxygen saturation was 30
ETERMINATION
435
Editorial per cent or less in four. Of these, the one with the lowest arterial oxygen saturation value (79.5 per cent) had a significant scoliosis, a history of pulmonary hemorrhage and abnormal pulmonary function test results. The second, a sixty year old man with an arterial oxygen saturation of 86.1 per cent, was reported to have atria1 fibrillation and arteriosclerotic heart disease. No results of pulmonary function tests were reported in this patient. Two additional patients, both aged fourteen, with arterial oxygen saturations of 90 and 80.5 per cent, respectively, had no apparent cardiac or pulmonary disease. The carbon dioxide tension in each of these patients was 30 mm. Hg. The pH values were alkalotic, which suggests the likelihood of hyperventilation during the study. It is possible that an alveolar-capillary block syndrome or perhaps an unrecognized shunt was present. In 1951 Newman et al. [3] described the results of pulmonary function tests in five patients with polycythemia assumed to be primary. In three the arterial oxygen saturation was normal. In the fourth it was 69 per cent, and the authors regarded the patient as having possible respiratory center damage. However, the patient’s weight of 350 pounds argues strongly for a diagnosis of the Pickwickian syndrome, a suggestion which is supported by the narcoleptic behavior of the patient. (At the time of their report this syndrome was not yet appreciated.) The fifth patient, with an arterial oxygen saturation of 65 per cent, falls into the category of alveolar hypoventilation believed by the authors to be on a basis of central nervous system involvement. However, the patient’s “obesity precluded adequate examination for splenomegaly.” Furthermore, in patients with alveolar hypoventilation due to central nervous system damage, the maximum breathing capacity is normal; in this patient it was not. It is possible that this was another instance of the Pickwickian syndrome. The selected cases cited illustrate the need for precise evaluation of patients with polycythemia of undetermined origin. In those with arterial oxygen unsaturation of marked degree, careful and complete testing of cardiopulmonary function is essential, particularly when hematologic investigation does not demonstrate the ancillary peripheral blood and bone marrow findings of classic polycythemia Vera, and splenomegaly is absent.
Arterial Oxygen Saturation in Unequivocal Cases of Polycythemia Vera. In most of the selected studies reviewed [ 7-51, the arterial oxygen saturation in the majority of patients was normal, i.e ., greater than 95 per cent. Exclusion of obviously questionable cases, particularly those in which the diagnosis was in doubt from the data presented or in which insufficient cardiopulmonary data are available, leaves the greatest number with either normal arterial oxygen saturation or with values between 92 and 94 per cent. In the studies by Fisher et al. [5] thirteen patients with polycythemia were evaluated on the basis of pulmonary function test results. In ten of the thirteen, the arterial oxygen saturation was greater than 95 per cent; in two it was 94.3 and 94.6 per cent, respectively; and in one it was 93.4 per cent. It should be stressed that in these patients the clinical diagnosis of polycythemia vera was based on the presence of polycythemia, leukocytosis, increased platelets and a palpable spleen. It is interesting to note that when these rigorous criteria for the diagnosis of polycythemia vera are used, no unusually low values for arterial oxygen saturations are encountered. Similarly [S] in twenty-four patients regarded as having polycythemia vera and also studied with extensive evaluation of pulmonary function, arterial oxygen saturation exceeded 95 per cent in nineteen. In the five remaining cases the values were 94.7, 94.5, 94.0, 92.3 and 92 per cent. It would appear, then, that in valid cases of polycythemia vera (and this should be true of cases of polycythemia vera without all the clinical criteria) a normal arterial oxygen saturation is the rule, but a few borderline values between 91 and 93 per cent may be encountered; figures below this level should suggest a search for a cause for oxygen unsaturation. Rarely, alveolar hypoventilation, due to a change in the central nervous system presumably on a vascular (thrombotic) basis, may develop in a patient with polycythemia Vera. In such cases oxygen unsaturation is, of course, due to the alveolar hypoventilation. The hypoxemia in turn may augment the polycythemia [S-S]. Borderline Low Oxygen Saturation in Polvcythemia Vera. As already noted, patients with validated polycythemia vera may give values for oxygen saturation ranging between 91 and 93 per cent, raising the question as to the possible AMERICAN JoURNAL
OF
MEDICINE
Editorial mechanism for these borderline figures. Such possibilities include (1) effect on lung function per se in respect to diffusing capacity or ventilation-perfusion relationships; (2) overloading of oxygen transport mechanism by the increased hemoglobin flow; (3) analytic error; and (4) the effect of age on what is considered to be the normal oxygen saturation. Dz&sing cap&y: The earliest study of diffusing capacity of the lung in patients with polycythemia vera was carried out by Harrop [9]. He reported a reduction in the DLO* in such patients as compared with control data. In the light of modern technics the methodology for the carbon monoxide procedure employed is open to question. Furthermore, in more recent studies, the diffusing capacity of the lung for oxygen has been reported to be normal in three of three cases in one such study [3] and four of four cases in another [6]. Ventilation-perfusion relationships: Hypoventilation relative to blood flow could account for the decrease in oxygen saturation. Alveolar hypoventilation due to central nervous system involvement secondary to polycythemia vera suggests the possibility that such a mechanism may play a role in the patients in whom mild degrees of unsaturation are found. Alveolar ventilation, however, is normal in the cases reported with such borderline saturation [5,6]. Impairment of distribution of inspired gas, while a theoretical possibility, is excluded by the universal finding of normal mixing of inspired air [3,5,6]. Furthermore, uneven ventilation would be reflected in abnormally increased venous admixture. When studied [3], this was normal as measured by a normal A-a oxygen gradient on breathing 21 per cent oxygen at sea level. The possibility has been suggested [6] that the increased blood volume may result in opening of additional pulmonary capillaries, with disturbed ventilation-perfusion relationship resulting in an increased venous admixture. Such a possibility is ruled out by the finding of borderline low arterial oxygen saturation in patients whose blood volume has been reduced to normal; moreover, as previously stated, the venous admixture, when it has been measured, is normal. Overloading of oxygen transport: Another theory is that the high hemoglobin flow in the pulmonary capillaries in polycythemia vera may exceed the oxygen transport maximum. Once VOL. 34,
APRIL. 1963
again the presence of borderline arterial oxygen unsaturation in patients whose blood volume has been reduced to normal negates this possibility. Analytic error: Overestimation of the oxygen capacity may account for a measured reduction in the oxygen saturation. Such errors may relate to (1) the presence of “inactive” hemoglobin; (2) oxygen consumption by the polycythemic blood, making oxygen content smaller; (3) systematic error in the tonometer method of determining oxygen capacity; and (4) shifts in the oxyhemoglobin dissociation curve. In regard to “inactive” hemoglobin, addition of sodium hyposulfite to blood results in an increase in the capacity of the hemoglobin to bind carbon monoxide, and this portion of the hemoglobin has been called “inactive” [70]. In 60 per cent of normal subjects this fraction was found to be less than 0.5 volumes per cent of carbon monoxide capacity, a figure which was regarded as within the limits of error of the method of determination used. In the remaining 40 per cent, however, values ranged from 0.5 to 2.5 volumes per cent. It should be noted that these values varied from day to day, for which no reason could be found. In thirty-five patients with a variety of diseases no condition was encountered in which a high “inactive” hemoglobin was characteristic [70]. A theoretical possibility exists that in polycythemia vera there may be a higher than normal quantity of “inactive” hemoglobin which could account for a reduced “borderline” arterial oxygen saturation. This would be true only if, on exposure to air and rotation during measurement of the oxygen capacity, “inactive” hemoglobin becomes active, resulting in an increased capacity. A similar situation may prevail due to the presence of increased carboxyhemoglobin in the blood, particularly in heavy smokers [ 7 71. Dissociation of such carboxyhemoglobin on rotation of blood exposed to air could result in an increase in the oxygen capacity and a low estimate of arterial oxygen saturation. It has been calculated that “inactive” hemoglobins could result in an overestimate of the oxygen capacity of about 2 per cent and an underestimate of the oxygen saturation of a similar order [ 771. Since this same systematic error in determining oxygen capacity would apply, according to present knowledge, to both normal and polycythemic blood, analytic error could not explain the borderline values unless the
Editorial possibility that polycythemic blood has more “inactive” hemoglobin is valid. It has been demonstrated that in vitro consumption of oxygen by blood cells will occur if the blood is allowed to stand. It has been suggested that this consumption may be increased in polycythemia vera and occasionally may play a role in producing a lower oxygen saturation.. Cooling the blood, or better, immediate determination of the oxygen values precludes significant error from this source. Our own observations of borderline low arterial oxygen saturation in patients with polycythemia, when determinations were made immediately after collection of blood, would suggest that oxygen consumption by the blood cells is not a major factor. In calculating the oxygen saturation, appropriate correction must be made by subtracting the dissolved oxygen from. the oxygen content and oxygen capacity. To eliminate possible error in making the appropriate estimate of dissolved oxygen, tonometry may be employed. In a study of polycythemia vera employing this procedure [5] no saturation below 93.4 per cent was obtained. In using the tonometric method there may be a systematic error due to adherence of plasma to the walls of the tonometer vessel, apart from any change in “inactive” hemoglobin. Appropriate corrections may be made for this. The oxyhemoglobin dissociation curve may be affected by several factors. A shift in pH may give lower saturations for isobaric oxygen values. In polycythemia vera no demonstrable change in acid-base balance has been found [Z] and in the studies here considered pH values were generally within normal limits. Abnormal hemoglobins also may modify the shape of the dissociation curve; these include a variety of hemoglobinopathies, such as hemoglobin M and S, but no abnormal hemoglobin has been demonstrated in polycythemia Vera. Studies of oxyhemoglobin dissociation curves in patients with polycythemia vera indicate them to be normal [Z] and thus not a factor in patients with somewhat reduced oxygen saturation. As is well recognized, a moderate reduction in pulmonary function occurs normally in aged subjects. Thus Greifenstein et al. [I] found in such persons a reduction in vital capacity and an increase in functional residual volume, residual volume, and the ratio of residual volume to total capacity. In addition, they
reported some unevenness in the intrapulmonary mixing of inspired gases in older normal subjects. There is also a reduction in the maximum diffusing capacity with age [YZ]. It is of interest that Comroe’s group nevertheless found no significant difference in the arterial oxygen saturation, carbon dioxide tension or pH as compared with young individuals [ 71. The mean value for arterial oxygen saturation for healthy young adults was 97.4 f SD. 2.1 while in older subjects it was 96.5 + S.D. 1.68. This would give the lower level of normal as 93.2 per cent in young adults as compared to 93.14 per cent in older normal subjects. Although polycythemia vera is encountered chiefly in older subjects, the age factor cannot account for the borderline values of saturation between 91 and 93 per cent. The figures of 93 and 94 per cent, however, must be considered within the normal range. In summary, polycythemia vera is not associated with significant reductions in arterial oxygen saturation, and cases in which significant arterial oxygen unsaturation has been reported are suspect. In unequivocal cases of polycythemia vera the arterial oxygen saturation is above 93 per cent but in a few instances the values may range from 91 to 93 per cent. Polycythemia vera does not significantly affect lung function except in those rare instances in which vascular thromboses in the respiratory center create a syndrome of primary alveolar hypoventilation. Factors such as lung diffusion, distribution of inspired gases and oxygen transport probably do not contribute to the borderline values obtained. There appears to be no evidence that “inactive” hemoglobin plays a greater role in patients with pblycythemia than in normal control subjects. The ‘arterial oxygen saturation is slightly but not significantly reduced in the older age groups to which most patients with polycythemia vera belong. Thus when the arterial oxygen saturation is less than 93 per cent, and certainly when less than 91 per cent, evidence of some cardiopulmonary abnormality or hemoglobin variant should be sought as the underlying cause for polycythemia. RICHARD A. BADER, M.D. MORTIMER E. BADER, M.D. AND JOEL L. DUBERSTEIN,M.D. Department of Medicine Mount Sinai Hospital New York, New York AMERICAN
JOURNAL
OF
MEDICINE
Editorial REFERENCES
7. 1. GREIFENSTEIN, F. E., KING, R. M., LATCH, S. D. and
2.
3.
4.
5.
6.
COMROE,J. H., JR. Pulmonary function studies in healthy men and women 50 years and older. J. A@. Physiol., 4: 641, 1952. CASSELS, D. E. and MORSE, M. The arterial blood gases, the oxygen dissociation curve, and the acidbase balance in polycythemia vera. J. Clin. Invest., 33: 52, 1953. NEWMAN, W., FELTMAN, J. A. and DEVLIN, B. Pulmonary function studies in polycythemia vera. Am. J. Med., 11: 706, 1951. WASSERMAN,L. R., DOBSON,R. L. and LAWRENCE, J. H. Blood oxygen studies in patients with polycythemia and in normal subjects. J. Clin. Invest., 28: 60, 1949. FISHER, M. J., BEDELL, G. N. and SEEBOHM,P. M. Differentiation of polycythemia vera and secondary polycythemia by arterial oxygen saturation and pulmonary function tests. J. Lab. &? Clin. Med., 50: 455, 1957. RATTO, O., BRISCOE,W. A., MORTON, J. W. and COMROE, J. H., JR. Anoxemia secondary to
VOL.
34,
APRIL
1963
8.
9.
10.
11.
12.
polycythemia and polycythemia secondary to anoxemia. Am. J. Med., 19: 958, 1955. RICHTER, T., WEST, J. R. and FISHMAN, A. P. The syndrome of alveolar hypoventilation and primary depression of the respiratory center. Neul England J. Med., 256: 1165, 1957. PARE, P. and LOWENSTEIN,L. Polycythemia associated with disturbed function of the respiratory center. Blood, 11: 1077, 1956. HARROP, G. A., JR. and HEATH, E. H. Pulmonary gas diffusion in polycythemia vera. J. Clin. Inuest., 4: 53, 1927. AMMUNDSEN, E. Studies on presence of non-carbon monoxide combining (inactive) hemoglobin in blood of normal persons. J. Biol. Chem.? 138: 563, 1941. ROUGHTON, F. J. W., DARLING, R. C. and ROOT, W. S. Factors effecting the determination of oxygen capacity, content and pressure in human arterial blood. Am. J. M. SC., 132: 228, 1944. COHN, J. E., CARROLL, D. E., ARMSTRONG,B. W., SHEPARD, R. H. and RILEY, R. L. Maximal diffusing capacity of the lung in normal male subjects of different ages. J. A@. Physiol., 6: 588, 1954.
Journal APRIL
of Medicine
1963
No.
4
Editorial Polycythemia
Vera
and Arterial
Oxygen
Saturation of the arterial oxygen saturation has become an important part of the evaluation of patients presenting with polycythemia. Such analysis permits separation of cases of polycythemia vera from polycythemia secondary to what may be inapparent causes of hypoxemia, such as intracardiac shunt, A-V shunt in the lung, significant but not obvious pulmonary insufficiency, methemoglobinemia, or the presence of other abnormal hemoglobins. The finding of a normal arterial oxygen saturation strongly suggests that the polycythemia is of the primary type. However, there are other causes for a polycythemic blood picture with a normal arterial oxygen saturation. These include renal disease (particularly hypernephroma), cerebellar hemangioblastomas, Cushing’s syndrome, fibroid uterus and chemical poisons (such as cobalt or phosphorus). In normal man, the arterial oxygen saturation, as determined by the Van Slyke technic, has generally been found to be 95 to 98 per cent. In young adults, Comroe’s figures [I] are 97.4 per cent + standard deviation (S.D.) 2.1, a figure with which almost all laboratories agree. A selected review of the recorded values for arterial oxygen saturation in patients with polycythemia vera reveals that the arterial oxygen saturation ordinarily exceeded 95 per cent. However, in a few patients figures were as low as 80 per cent, and in some others values fell in the borderland of 91 to 93 per cent. These reports pose several problems. (1) Are cases of apparent polycythemia vera in which the
D
arterial oxygen saturation is below 90 per cent bona fide? (2) What is the lower limit of normal arterial oxygen saturation for polycythemia Vera? (3) What is the mechanism for the borderline low arterial oxygen saturation in cases which appear unequivocally to be polycythemia Vera? Alleged Polycythemia Vera with Low Arterial Oaygen Saturation. In cases alleged to be polycythemia vera values for arterial oxygen saturations have been recorded as low as 79 [Z], 65 [.?] and 83.5 per cent [4]. In the light of subsequent experience, certain sources of possible error may account for these low values. One such study [4] employed “arterialized” ear lobe blood. Although a check was made in a small number of cases in which arterial blood was studied simultaneously, the possibility of admixture of venous blood in some instances cannot be excluded. It should be noted further that results of pulmonary function tests were not reported in any of these cases. Another study [2], utilizing analysis by the Van Slyke and Neil1 method of blood tonometrically equilibrated with appropriate gases to obtain accurate measurement of oxygen capacity, yielded values for twelve normal subjects of 94.0 to 97.5 per cent with a mean of 95.9 per cent. Allowing for a systematic error of approximately 2 per cent by the tonometer method, an even higher mean figure would be obtained. Of seventeen patients with polycythemia assumed to be primary because of the absence of specific causes, the arterial oxygen saturation was 30
ETERMINATION
435
Editorial per cent or less in four. Of these, the one with the lowest arterial oxygen saturation value (79.5 per cent) had a significant scoliosis, a history of pulmonary hemorrhage and abnormal pulmonary function test results. The second, a sixty year old man with an arterial oxygen saturation of 86.1 per cent, was reported to have atria1 fibrillation and arteriosclerotic heart disease. No results of pulmonary function tests were reported in this patient. Two additional patients, both aged fourteen, with arterial oxygen saturations of 90 and 80.5 per cent, respectively, had no apparent cardiac or pulmonary disease. The carbon dioxide tension in each of these patients was 30 mm. Hg. The pH values were alkalotic, which suggests the likelihood of hyperventilation during the study. It is possible that an alveolar-capillary block syndrome or perhaps an unrecognized shunt was present. In 1951 Newman et al. [3] described the results of pulmonary function tests in five patients with polycythemia assumed to be primary. In three the arterial oxygen saturation was normal. In the fourth it was 69 per cent, and the authors regarded the patient as having possible respiratory center damage. However, the patient’s weight of 350 pounds argues strongly for a diagnosis of the Pickwickian syndrome, a suggestion which is supported by the narcoleptic behavior of the patient. (At the time of their report this syndrome was not yet appreciated.) The fifth patient, with an arterial oxygen saturation of 65 per cent, falls into the category of alveolar hypoventilation believed by the authors to be on a basis of central nervous system involvement. However, the patient’s “obesity precluded adequate examination for splenomegaly.” Furthermore, in patients with alveolar hypoventilation due to central nervous system damage, the maximum breathing capacity is normal; in this patient it was not. It is possible that this was another instance of the Pickwickian syndrome. The selected cases cited illustrate the need for precise evaluation of patients with polycythemia of undetermined origin. In those with arterial oxygen unsaturation of marked degree, careful and complete testing of cardiopulmonary function is essential, particularly when hematologic investigation does not demonstrate the ancillary peripheral blood and bone marrow findings of classic polycythemia Vera, and splenomegaly is absent.
Arterial Oxygen Saturation in Unequivocal Cases of Polycythemia Vera. In most of the selected studies reviewed [ 7-51, the arterial oxygen saturation in the majority of patients was normal, i.e ., greater than 95 per cent. Exclusion of obviously questionable cases, particularly those in which the diagnosis was in doubt from the data presented or in which insufficient cardiopulmonary data are available, leaves the greatest number with either normal arterial oxygen saturation or with values between 92 and 94 per cent. In the studies by Fisher et al. [5] thirteen patients with polycythemia were evaluated on the basis of pulmonary function test results. In ten of the thirteen, the arterial oxygen saturation was greater than 95 per cent; in two it was 94.3 and 94.6 per cent, respectively; and in one it was 93.4 per cent. It should be stressed that in these patients the clinical diagnosis of polycythemia vera was based on the presence of polycythemia, leukocytosis, increased platelets and a palpable spleen. It is interesting to note that when these rigorous criteria for the diagnosis of polycythemia vera are used, no unusually low values for arterial oxygen saturations are encountered. Similarly [S] in twenty-four patients regarded as having polycythemia vera and also studied with extensive evaluation of pulmonary function, arterial oxygen saturation exceeded 95 per cent in nineteen. In the five remaining cases the values were 94.7, 94.5, 94.0, 92.3 and 92 per cent. It would appear, then, that in valid cases of polycythemia vera (and this should be true of cases of polycythemia vera without all the clinical criteria) a normal arterial oxygen saturation is the rule, but a few borderline values between 91 and 93 per cent may be encountered; figures below this level should suggest a search for a cause for oxygen unsaturation. Rarely, alveolar hypoventilation, due to a change in the central nervous system presumably on a vascular (thrombotic) basis, may develop in a patient with polycythemia Vera. In such cases oxygen unsaturation is, of course, due to the alveolar hypoventilation. The hypoxemia in turn may augment the polycythemia [S-S]. Borderline Low Oxygen Saturation in Polvcythemia Vera. As already noted, patients with validated polycythemia vera may give values for oxygen saturation ranging between 91 and 93 per cent, raising the question as to the possible AMERICAN JoURNAL
OF
MEDICINE
Editorial mechanism for these borderline figures. Such possibilities include (1) effect on lung function per se in respect to diffusing capacity or ventilation-perfusion relationships; (2) overloading of oxygen transport mechanism by the increased hemoglobin flow; (3) analytic error; and (4) the effect of age on what is considered to be the normal oxygen saturation. Dz&sing cap&y: The earliest study of diffusing capacity of the lung in patients with polycythemia vera was carried out by Harrop [9]. He reported a reduction in the DLO* in such patients as compared with control data. In the light of modern technics the methodology for the carbon monoxide procedure employed is open to question. Furthermore, in more recent studies, the diffusing capacity of the lung for oxygen has been reported to be normal in three of three cases in one such study [3] and four of four cases in another [6]. Ventilation-perfusion relationships: Hypoventilation relative to blood flow could account for the decrease in oxygen saturation. Alveolar hypoventilation due to central nervous system involvement secondary to polycythemia vera suggests the possibility that such a mechanism may play a role in the patients in whom mild degrees of unsaturation are found. Alveolar ventilation, however, is normal in the cases reported with such borderline saturation [5,6]. Impairment of distribution of inspired gas, while a theoretical possibility, is excluded by the universal finding of normal mixing of inspired air [3,5,6]. Furthermore, uneven ventilation would be reflected in abnormally increased venous admixture. When studied [3], this was normal as measured by a normal A-a oxygen gradient on breathing 21 per cent oxygen at sea level. The possibility has been suggested [6] that the increased blood volume may result in opening of additional pulmonary capillaries, with disturbed ventilation-perfusion relationship resulting in an increased venous admixture. Such a possibility is ruled out by the finding of borderline low arterial oxygen saturation in patients whose blood volume has been reduced to normal; moreover, as previously stated, the venous admixture, when it has been measured, is normal. Overloading of oxygen transport: Another theory is that the high hemoglobin flow in the pulmonary capillaries in polycythemia vera may exceed the oxygen transport maximum. Once VOL. 34,
APRIL. 1963
again the presence of borderline arterial oxygen unsaturation in patients whose blood volume has been reduced to normal negates this possibility. Analytic error: Overestimation of the oxygen capacity may account for a measured reduction in the oxygen saturation. Such errors may relate to (1) the presence of “inactive” hemoglobin; (2) oxygen consumption by the polycythemic blood, making oxygen content smaller; (3) systematic error in the tonometer method of determining oxygen capacity; and (4) shifts in the oxyhemoglobin dissociation curve. In regard to “inactive” hemoglobin, addition of sodium hyposulfite to blood results in an increase in the capacity of the hemoglobin to bind carbon monoxide, and this portion of the hemoglobin has been called “inactive” [70]. In 60 per cent of normal subjects this fraction was found to be less than 0.5 volumes per cent of carbon monoxide capacity, a figure which was regarded as within the limits of error of the method of determination used. In the remaining 40 per cent, however, values ranged from 0.5 to 2.5 volumes per cent. It should be noted that these values varied from day to day, for which no reason could be found. In thirty-five patients with a variety of diseases no condition was encountered in which a high “inactive” hemoglobin was characteristic [70]. A theoretical possibility exists that in polycythemia vera there may be a higher than normal quantity of “inactive” hemoglobin which could account for a reduced “borderline” arterial oxygen saturation. This would be true only if, on exposure to air and rotation during measurement of the oxygen capacity, “inactive” hemoglobin becomes active, resulting in an increased capacity. A similar situation may prevail due to the presence of increased carboxyhemoglobin in the blood, particularly in heavy smokers [ 7 71. Dissociation of such carboxyhemoglobin on rotation of blood exposed to air could result in an increase in the oxygen capacity and a low estimate of arterial oxygen saturation. It has been calculated that “inactive” hemoglobins could result in an overestimate of the oxygen capacity of about 2 per cent and an underestimate of the oxygen saturation of a similar order [ 771. Since this same systematic error in determining oxygen capacity would apply, according to present knowledge, to both normal and polycythemic blood, analytic error could not explain the borderline values unless the
Editorial possibility that polycythemic blood has more “inactive” hemoglobin is valid. It has been demonstrated that in vitro consumption of oxygen by blood cells will occur if the blood is allowed to stand. It has been suggested that this consumption may be increased in polycythemia vera and occasionally may play a role in producing a lower oxygen saturation.. Cooling the blood, or better, immediate determination of the oxygen values precludes significant error from this source. Our own observations of borderline low arterial oxygen saturation in patients with polycythemia, when determinations were made immediately after collection of blood, would suggest that oxygen consumption by the blood cells is not a major factor. In calculating the oxygen saturation, appropriate correction must be made by subtracting the dissolved oxygen from. the oxygen content and oxygen capacity. To eliminate possible error in making the appropriate estimate of dissolved oxygen, tonometry may be employed. In a study of polycythemia vera employing this procedure [5] no saturation below 93.4 per cent was obtained. In using the tonometric method there may be a systematic error due to adherence of plasma to the walls of the tonometer vessel, apart from any change in “inactive” hemoglobin. Appropriate corrections may be made for this. The oxyhemoglobin dissociation curve may be affected by several factors. A shift in pH may give lower saturations for isobaric oxygen values. In polycythemia vera no demonstrable change in acid-base balance has been found [Z] and in the studies here considered pH values were generally within normal limits. Abnormal hemoglobins also may modify the shape of the dissociation curve; these include a variety of hemoglobinopathies, such as hemoglobin M and S, but no abnormal hemoglobin has been demonstrated in polycythemia Vera. Studies of oxyhemoglobin dissociation curves in patients with polycythemia vera indicate them to be normal [Z] and thus not a factor in patients with somewhat reduced oxygen saturation. As is well recognized, a moderate reduction in pulmonary function occurs normally in aged subjects. Thus Greifenstein et al. [I] found in such persons a reduction in vital capacity and an increase in functional residual volume, residual volume, and the ratio of residual volume to total capacity. In addition, they
reported some unevenness in the intrapulmonary mixing of inspired gases in older normal subjects. There is also a reduction in the maximum diffusing capacity with age [YZ]. It is of interest that Comroe’s group nevertheless found no significant difference in the arterial oxygen saturation, carbon dioxide tension or pH as compared with young individuals [ 71. The mean value for arterial oxygen saturation for healthy young adults was 97.4 f SD. 2.1 while in older subjects it was 96.5 + S.D. 1.68. This would give the lower level of normal as 93.2 per cent in young adults as compared to 93.14 per cent in older normal subjects. Although polycythemia vera is encountered chiefly in older subjects, the age factor cannot account for the borderline values of saturation between 91 and 93 per cent. The figures of 93 and 94 per cent, however, must be considered within the normal range. In summary, polycythemia vera is not associated with significant reductions in arterial oxygen saturation, and cases in which significant arterial oxygen unsaturation has been reported are suspect. In unequivocal cases of polycythemia vera the arterial oxygen saturation is above 93 per cent but in a few instances the values may range from 91 to 93 per cent. Polycythemia vera does not significantly affect lung function except in those rare instances in which vascular thromboses in the respiratory center create a syndrome of primary alveolar hypoventilation. Factors such as lung diffusion, distribution of inspired gases and oxygen transport probably do not contribute to the borderline values obtained. There appears to be no evidence that “inactive” hemoglobin plays a greater role in patients with pblycythemia than in normal control subjects. The ‘arterial oxygen saturation is slightly but not significantly reduced in the older age groups to which most patients with polycythemia vera belong. Thus when the arterial oxygen saturation is less than 93 per cent, and certainly when less than 91 per cent, evidence of some cardiopulmonary abnormality or hemoglobin variant should be sought as the underlying cause for polycythemia. RICHARD A. BADER, M.D. MORTIMER E. BADER, M.D. AND JOEL L. DUBERSTEIN,M.D. Department of Medicine Mount Sinai Hospital New York, New York AMERICAN
JOURNAL
OF
MEDICINE
Editorial REFERENCES
7. 1. GREIFENSTEIN, F. E., KING, R. M., LATCH, S. D. and
2.
3.
4.
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