Lung 154, 299-305 (1978)

The Oxyhemoglobin Dissociation Curve in Type A and Type B COPD Everett M. Murphy, Roger C. Bone, F. Charles Dennis A. Diederich, and William E. Ruth Department of Medicine, Kansas City, Kansas

University

of Kansas

Hiller,

Medical

Center,

Abstract. Patients with chronic obstructive pulmonary disease (COPD) have been clinically separated into Type A and Type B COPD. Type A patients are characterized by the presence of anatomical emphysema or an increased total lung capacity, low sputum production, late onset of cough, rare hypercapnia, rare cot pulmonale and absent polycythemia. In contrast, Type B patients are characterized by roentgenographic evidence of chronic inflammation or smaller total lung capacity, significant sputum production, frequent hypercapnia with cor pulmonale and the presence of polycythemia. We studied whole blood oxygen transport (P50, 2, 3-DPG, and ATP) in II Type A patients and 13 Type B patients. Whole blood oxygen transport was not different in the two groups of patients. Type A patients with higher hemoglobin values had a lower 2, 3-DPG. Type A patients with a higher hemoglobin value also had a higher ATP level. In all patients, Type A and Type B, 2, 3-DPG was inversely related to hemoglobin concentration. Despite other distinguishing clinical and laboratory characteristics, whole blood oxygen transport was not different in Type A and Type B patients. Key words: Airway 2, 3-DiphosPhoglycerate

obstruction - P50

- Emphysema

- Oxygen

transport

-

Introduction position of the oxyhemoglobin dissociation curve, expressed as the P50, is a reflection of oxygen affinity for hemoglobin. The P50 is the tension at which hemoglobin is 50% saturated with oxygen. Multiple factors affect the The

~Paper presented at the 41st Annual Scientific Assembly College of Chest Physicians, October 26-28, 1975.

of the American

0341-2040/78/0154/0299/$ 01.~0

300

position of the oxyhernoglobin dissociation curve such as the Bohr effect, temperature changes, oxygen tension, and carbon dioxide [1,6]. The intraerythrocytic organophosphates, namely 2, 3-diphosphoglycerate (2, 3-DPG) and adenosine triphosphate (ATP), have been demonstrated to play a prominent role in decreasing red cell oxygen affinity [2]. Patients with chronic obstructive pulmonary disease (COPD) are currently classified in terms of their clinical appearance, that is, Type A COPD or "pink puffer" and Type B COPD or "blue bloater, " with interferences made concerning the course of illness and prognosis [4] . Little attention has been paid to the position of the oxyhemoglobin dissociation curve and its bearing on the clinical differentiation of the two groups of patients and the compensatory effect of the different hemoglobin concentrations, arterial oxygen tension and carbon dioxide tension. Since Type A and B patients with COPD have different hemoglobin concentrations, arterial oxygen tensions and carbon dioxide tensions, one might expect the oxyhemoglobin dissociation curve to be different. We are not aware of any study which evaluates the oxyhemo globin dissociation curve in these two clinical subtypes of patients with COPD. The purposes of this study were to evaluate the parameters of whole blood oxygen transport in Type A and Type B COPD, to identify the relationship between whole blood oxygen transport and hemoglobin concentration and arterial oxygen tension in patients with stable COPD.

Methods A total of 24 patients were selected with the following specific criteria: (I) COPD with an FEV 1 being less than i. 5 liters and (2) stable respiratory status. Patients were clinically separated into Type A and Type B COPD in accordance with published criteria [4]. Type A COPD patients had a late onset of symptoms with scanty sputum production, roentgenographic evidence of emphysema, rare cot pulmonale and increased lung volumes with a markedly reduced diffusing capacity. Type B COPD patients, however, had an early onset of cough with sputum production greater than I0 ml in 24 h, prominent broncho-vascular markings on chest roentgenograrn, chronic cor pulmonale, moderately increased residual volume with a normal total lung capacity, persistently elevated arterial carbon dioxide tension and occasional polycythemia. Patients were selected from a much larger group of a clinic population of several hundred patients with COPD, most of whom could not be classified into Type A or Type B categories but had characteristics of both Type A and Type B COPD. Parameters mea sured in each patient group included the P50, 2, 3-DPG, ATP, hemoglobin, hematocrit, PaO2, PaCO 2 and FEV I. 2, 3-DPG was determined by an automated enzymatic method [5]. ATP was determined by a luciferase method [3]. P50 determination was performed using Instrumentation Laboratory co oximeter and blood gas analyzer and reported for pH 7.4; normal P50 is 26. 5 tort.

301

Table

i. Epidemiologic

and oxygen

transport

d~a

Patient

FVC

FEVI

PaO2

PaCO2

type

(liter)

(liter)

(mmHg)

(mmHg)

(gm/I 00 ml)

59

34

ii.I

1.15 0.89 0.83 2.30 1.75 1.63 3.65 2.48 2.81 1.55

0.41 0.36 0.28 1.40 0.85 0.76 0.78 1.13 1.24 0.45

50 66 57 76 73 76 65 58 64 64

36 40 50 42 38 33 33 31 32 36

16.3 14.0 12.4 Ii.0 14.4 ii.0 14.5 14.1 13.8 12.3

1.90 0.90

.77 .39

64.36 8.24

36.82 5.55

13.17 1.73

2. 09 i. 77 i. 90 i. 72 0. 83 2. 36 2. 19 3.40 i. 40 3. 60 i. 45 3.41 i. 45

0. 67 0. 77 0. 59 0. 52 0.43 0. 76 i. 14 1.15 0. 35 i. 25 0. 50 i. 16 0. 50

60 74 67 52 67 82 62 76 51 56 53 65 53

39 36 62 48 54 40 30 41 37 37 47 37 47

19. 6 14. 6 15. 2 17. 0 15. 9 15. 2 17. 2 17.4 16. 7 16. 7 17. 2 16. 8 17. 2

2.12 .86

. 76 .30

62. 36 9.88

43.93 9.49

16. 38 1.63

A

Mean

± SD

a

B

Mean

a

_+ SD

a

Hemoglobin

Standard deviation

Results Of the 24 patients selected, II w e r e categorized as T y p e A patients and 13 as Type B patients. The epidemiologic characteristics and oxygen transport data are presented in Table i. Type A and Type B patients had similar

302 a

Table

P

2. Mean

values of oxygen

50

2, 3-DPG ATP

(~M/gmHb)

(uM/gmHb)

transport

parameters

in patient groups

Type

A

Type

B

27.4

+ 0.4

27.9

+ 1.6

17.2

+ 0. 6

17.2

+ 3.9

4. 6 + 0.2

4. 6 + I. 2

a

Mean

+ SD

values for the P50 as well as the 2,3-DPG and ATP((Table 2). The 2,3-DPG, ATP and P50 for these patients were increased above normal control values in our laboratory and published normal values [3] . The mean values for the hemoglobin in Type A patients were 13.2 -+ i. 8 gm%; in Type B patients they were 16 f i. 6 gin%. All patients had an arterial oxygen tension greater than 50 rnmHg, with a mean of 63.6 +- 9 mmHg. The mean FEV 1 for all patients was . 76 +_ . 34 liters. When 2, 3-DPG and ATP were compared with hemoglobin within each patient group, Type A patients demonstrated an inverse relationship between 2, 3-DPG and hemoglobin (P < 0. 05). In Type A patients a direct relationship was found between ATP and hemoglobin (P < 0. 05). In Type B patients a similar relationship existed between 2, 3-DPG and hemoglobin; however, the values were not statistically significant. The parameters of whole blood oxygen transport were also evaluated by combining both groups of patients. A similar inverse relationship existed between 2,3-DPG and hemoglobin (P < 0. 05); however, no significant relationship was apparent between P50 or ATP and the hemoglobin concentration.

Discussion T h e position of the oxyhemoglobin dissociation curve is an expression of oxygen affinity for hemoglobin (Fig. i). A right-shifted curve enhances the unloading of oxygen in the tissues. A left-shifted curve reflects increased oxygen affinity for hemoglobin and enhances the loading of oxygen in the pulmonary capillary bed. T h e left curve, however, interferes with unloading of oxygen in the tissues. Both 2, 3 - D P G a n d A T P are a m o n g the major factors associated with a right-shifted curve. T h e role of 2, 3 - D P G is quantitatively m o r e important since it comprises approximately 6 0 % of the organophosphates of the red cell [8]. Although the literature has reported increased levels of 2, 3 - D P G in small n u m b e r s of patients with C O P D [7], the data in our study repre-

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POz (mrn Hg) Fig. i. T h e position of the o x y h e m o g l o b i n dissociation curve is expressed as the PS0" T h e left curve represents n o r m a l red cells with a P S 0 of 26. 5. T h e right curve has a P S 0 of 36. 5. T h e arterial oxygen tension displayed is 90 m m H g , almost complete saturation. T h e m i x e d - v e n o u s oxygen tension is 40 m m H g . T h e left curve is capable of releasing an oxygen content of 4.5 v o l u m e s %. T h e right curve, however, is capable of releasing 7.2 v o l u m e s %, a 6 0 % increase in the a m o u n t of oxygen available to the tissues. It is apparent that the right-shifted curve, with its property of enhanced unloading of oxygen at the tissue-capillary level, is m u c h m o r e advantageous at this saturation

sent information collected in a group of patients with C O P D w h o w e r e not in respiratory failure and w e r e nonacidotic. T h e s e data suggest that C O P D with a c o m p r o m i s e d respiratory status (but not in acute respiratory failure) will c o m p e n s a t e by shifting the o x y h e m o g l o b i n dissociation curve to the right by m e a n s of an elevated 2, 3 - D P G , enhancing oxygen unloading at the tissue level. T h e inverse relationship between 2, 3 - D P G and h e m o g l o b i n in patients with C O P D has been described in n o r m a l volunteers as well as in patients with various types of a n e m i a [9]. O n e postulated m e c h a n i s m for this inverse relationship can be explained by referring to the metabolic pathway of 2, 3 - D P G p r o d u c t i o n (Fig. 2). This figure s h o w s that patients with a low h e m o g l o b i n concentration will have elevated levels of 2, 3 - D P G resulting in enhanced oxygen unloading. Chronic hypoxemia, which occurs with a d v a n c e d C O P D , might be expected to result in reduced affinity of h e m o g l o b i n for oxygen by causing increased 2, 3 - D P G production. This would occur as an adaptive m e c h a n i s m to increase oxygen delivery to the tissues. Conversely, this adaptive shift impairs oxygen loading at the lungs, an obvious detrimental result. Possibly the reason no difference in oxygen delivery is seen with T y p e 7k and B patients results f r o m conflicting homeostatic m e c h a n i s m s acting to deliver oxygen to the tissues and increase oxygen loading at the lungs. These may cancel the effect of each other, resulting in similar oxyhemoglobin dissociation curves in the two groups of patients.

304

GLUCOSE t 1 5 DPGf-~

ADP ' A 4 --~ ~ s F . . . . OPG yPHOSPHOGLYCERATE~ ~(:~ A KINASE ~," ~ ATP

~ALKALOSIS MUTASE

2,3 DPG + DEOXYHEMOGLOBIN+ FREE 2,3 DPG j ~ ' ~ - - - - - 2 , 3 DI:~3 PHOSPHATASE 3 PG

LACTATE~,

,~

PYRUVATE

Fig. 2. The metabolic pathway of 2, 3-DPG production. 2, 3-DPG is a product of the erythrocytic glycolytic pathway, i, 3-DPG is converted to 2, 3DPG by the enzyme DPG mutase. 2, 3-DPG preferentially binds with reduced hemoglobin or deoxyhemoglobin. Once the oxyhemoglobin is saturated, unbound or free 2,3-DPG accumulates. It is known that an increased deoxyhemoglobin fraction compared to oxyhemoglobin results in a higher intracellular pH. T w o situations affect the e n z y m e D P G mutase: (I) an increased free D P G inhibits the e n z y m e and (2) an increased intracellular p H activates the enzyme. With a low hemoglobin there is a reduced venous oxygen saturation or an increased a m o u n t of reduced hemoglobin or deoxyhemoglobin. T h e increased deoxyhemoglobin binds m o r e 2, 3 - D P G and results in a lower free D P G . Therefore the increased intracellular pH, a result of the increased deoxyhemoglobin fraction, and a low free D P G result in more 2, 3-DPG production with activation of the enzyme DPG mutase

In summary, Type A and Type B patients with COPD do not have different patterns of whole blood oxygen transport, despite their distinctive clinical and laboratory characteristics. In all patients, Type A and Type 2, 3-DPG has an inverse relationship with hemoglobin concentration.

B,

References i. Bauer, C. : O n the respiratory function of haemoglobin. Rev. Physio !. P h a r m a c o l . 70, 1-31 (1974) 2. Benesch, R., Benesch, R . E . : T h e effect of organic phosphate f r o m h u m a n erythrocytes on the allosteric properties of hemoglobin. B i o c h e m . Biophys. Res. C o m m . 26, 182-187 (1967) 3. Beutler, E. : R e d Cell M e t a b o l i s m - M a n u a l of Biochemical Methods. N e w York: G r u n e & Stratton 1971 4. B u r r o w s , B., Niden, A . H . , Fletcher, C . M . , Jones, N.L. :Clinical types of chronic obstructive lung disease in L o n d o n and Chicago. A m e r . Rev. Resp. Dis. 90, 14-27 (1964) 5. Grisolia, S., Moore, K., Lugue, J., Grady, H. : A u t o m a t e d p r o c e d u r e for m i c r o estimation of 2,3-diphosphoglycerate. Annal. B i o c h e m . 3_1, 325 (1969)

305

6. Kilmartin, J.V. , Rossi-Bernardi, L. : Interaction of hemoglob in with hydrogen ions, carbon dioxide and organic phosphate. Physiol. Rev. 53, 836-890 (1973) 7. Oski, F.K., Gottlieb, A.J., Miller, W . W . , Delivoria-Papadopoulos, IV[. R e d cell 2, 3-diphosphoglycerate levels in subjects with chronic hypoxemia. N. Engl. J. Med. 280, 1165-1166 (1969) 8. Oski, F.K., Gottlieb, A.J., Miller, W . W . , Delivoria-Papadopoulos, M. : T h e effects of deoxyhemoglobin of adult and fetal hemoglobin on the synthesis of red cell 2, 3-diphosphoglycerate and its in vivo consequences. J. Clin. Invest. 49, 400-407 (1970) 9. T h o m a s , H . M . , Lafrak, S.S., Irwin, R.S., Fritts, H . W . , Caldwell, P. R. B. : T h e oxyhemoglobin dissociation curve in health and disease. A m e r . J. Med. 57, 331-348 (1974)

Accepted for publication: 18 October 1977

Roger C. Bone, M.D. University of Kansas Medical 39th & Rainbow Boulevard Kansas City, Kansas 66103 USA

Center