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VOLUME 48 DECEMBER 1971 Numn 6

COMMENTARY

THE

SHIFT

TO

THE

LEFT

F

OR many years it appeared that

physiol-ogists, and phsiologists alone, puzzled over the causes and significance of altera-tions in the position of the

oxygen-hemoglo-bin equilibrium curve. The reports by

Benesch and Benesch1 and Chanutin and

Curnish2 in 1967, concerning the role of red cell organic phosphates in determining the

affinity of hemoglobin for oxygen, have

served to rekindle curiosity in this problem of oxygen transport and produced a common focus of clinical interest for neonatologists,

hematologists, biochemists, and the now

nearly forgotten physiologists.

The oxygen-hemoglobin equilibrium

curve of normal adult blood is depicted as the center curve in Figure 1. The P, the whole

blood

oxygen

tension at which hemo-globin is 50% saturated (pH 7.4, tempera-ture 37#{176}C), is approximately 27 mm Hg.

This equilibrium curve may be shifted to

the left or to the right by a variety of fac-tors which include pH, temperature, carbon dioxide tension, the intrinsic nature of the

hemoglobin, and the red cell content of

2,3-diphosphoglycerate (2,3-DPG) and

adenosine triphosphate (ATP). With a

de-crease in the affinity of hemoglobin for oxy-gen, a “right-shifted” curve, more oxygen is released from hemoglobin at any given par-tial pressure of oxygen. Conversely, a “left-shifted” curve denotes an increase in the af-finity of hemoglobin for oxygen and results in less oxygen release at any given oxygen tension. The oxygen-hemoglobin equilib-rium curve of the newborn’s blood is

“left-shifted,” with the usual P-0 at term approxi-mately 20 mm Hg.

In 1967,1,2 it was demonstrated that the affinity of a hemoglobin solution for oxygen could be decreased by its interaction with a

number of organic phosphates. Of the

or-ganic phosphates tested, 2,3-DPG and

ATP were found most effective in lowering oxygen affinity. Of the organic phosphates normally found in the human erythrocyte, 2,3-DPG is the one found in largest concen-tration and thus is quantitatively the most

important

with respect to modulation of

he-moglobin-oxygen

affinity.

The

content

of

2,3-DPG in red cells averages about 5.0

moles per milliliter of red blood cells and

adenosine

triphosphate

1.1 &moles per mil-liliter of red blood cells. In studying blood in a variety of clinical conditions” or under blood storage5 it has been demonstrated that in the blood of adults, the position of the oxygen-hemoglobin equilibrium curve, as reflected by the PIE,, correlates closely with the red cell 2,3-DPG content. This has

not been found to be true for blood

ob-tained from newborn infants.

In 1930, Anselmino and Hoffman6 first

observed that the oxygen affinity of human fetal blood was greater than that of mater-nal blood. The “left-shifted” fetal blood had a P50 value 6 to 8 mm Hg lower than that of the normal adult. Allen and associate..,7 showed that although intact fetal cells

pos-Supported by a grant from The John A. Hart-ford Foundation, Inc.

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20406080

854 THE SHIFT TO THE LEFT

80 .

60

40

20

Oxygen

Dissociation

P02 mmHg

Fic. 1. The oxygen dissociation curve of normal adult blood (center curve).

The P, the oxygen tension at 50% oxygen saturation, is approximately 27 mm Hg. As the curve shifts to the right, the oxygen affinity of hemo-globin decreases and more oxygen is released at a given oxygen tension. With

a shift to the left, the opposite effects are observed.

sessed a higher affinity for oxygen than did the red cells of adults, when adult and fetal hemoglobin solutions were dialyzed against the same surrounding buffer, the resulting oxygen affinities were identical. It was con-cluded that some dialyzable material, and not the hemoglobin itself, was responsible for the differences in oxygen affinity. This

puzzling observation was resolved by the

demonstration that the affinity of 2,3-DPG for fetal hemoglobin is considerably less than it is for adult hemoglobin and thus does not produce the same changes in

oxy-gen affinity when added or removed from

solutions of fetal hemoglobin.8-10 It appears that 2,3-DPG is bound in the internal cavity of the hemoglobin molecule

by the

forma-tion

of salt bonds between the phosphate

groups of 2,3-DPG and the imidazole

groups

of the

beta

chain

H-21 histidines

and

the

N terminal

end

of the

non-alpha

chain.”

The

gamma chain of fetal hemoglo-bin lacks this histidine residue and

this may

be responsible

for its decreased

interaction with 2,3-DPG.

Elsewhere in this issue of PlmzA’nucs,

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COMMENTARY

Clearly, as demonstrated from their equa-tion,l:I two infants with similar quantities of adult and fetal hemoglobin in their cells may have different P50 values depending on

the concentration of 2,3-DPG and,

con-versely, infants with identical red cell 2,3-DPC concentrations may have different P50 values if they happen to differ in their rela-tive percentages of fetal and adult

hemo-globin. Both the modulator (2,3-DPG) and

the substance modulated-adult or fetal he-moglobin-are crucial in this regard.

Of what real clinical significance is the

position of the oxygen-hemoglobin

equilib-rium curve? This question cannot be

an-swered with certainty at the present time, but accumulating evidence, some indirect,

suggests

that

changes

in the oxygen affinity

of hemoglobin may be of profound impor-tance.

The final step in oxygen transport is the

movenwnt of oxygen from the blood to the

tissues. This movement occurs by a process of diffusion. The rate of diffusion depends on the oxygen pressure gradient that exists between the capillary and the cell; the dis-tance between the closest perfusing capil-lary and the cell; and the impedance to dif-fusion provided by the tissue (the diffusion coefficient). As the partial pressure of

oxy-gen decreases, tissue oxygenation is

im-paired.

The

term

“critical

Po2”

has

been

introduced to indicate that level of oxygen pressure below which diffusion is impaired and organ function is disturbed. A critical Po2 cannot be a well defined value that

ap-plies

to all tissues

under

all conditions.

The

oxygen requirements of tissues vary, and in some tissues, such as striated muscle,

oxy-gen requirements are determined by the

level of activity. The critical Po2 for the

brain appears to be approximately 20 mm

Hg.14 With a “shift to the left” in the

posi-tion of the oxygen-hemoglobin equilibrium curve, oxygen is released at lower partial

pressures and this ultimately could result in

impaired diffusion.

At present it does not appear that the dif-ference in oxygen affinity between fetal and

maternal blood is crucial for intra-uterine

existence. The use of intra-uterinc

transfu-sions of adult blood does not appear to

compromise the fetus,15 although

evidence

accumulated in the study of intra-uterine transfusion of lambs suggests that it might

produce subtle hypoxic stress.16 Infants

have been born to mothers with abnormal hemoglobins. In these situations the oxygen affinity of the maternal blood was greater than that of the fetus’T

A “left-shifted curve” does result, how-ever, in physiologic changes. Individuals

with high affinity hemoglobins are poiy-cythemic,18 while individuals with low affin-ity hemoglobins tolerate without difficulty what would generally be regarded as ane-mia.19 A patient with a left-shifted curve” is

more limited in exercise ability. Because of the inability to release oxygen from

hemo-globin, such individuals must increase car-diac output in order to deliver sufficient

ox-ygen to meet metabolic demands.2#{176}

Studies in our laboratory indicate that the replacement of an infant’s blood with that of an adult results in the maintenance of a higher mixed central venous oxygen

tension. Similar results have been observed

both in the lamb’6 and in the pig.21 Whether this is of benefit remains to be de-termined. The reports of successful treat-ment of asphyxiated newborn infants by ex-change tranfusion22 and the observation that the respiratory distress syndrome is less

common

or better

tolerated

in infants re-ceiving intra-uterine transfusions2s gives

pause for reflection and should serve to

stimulate further observations in this par-ticular area.

The measurement of the “effective DPC

fraction” by the formula proposed by

Orza-lesi and Hay in this issue of the Journal

may ultimately become as common as a

calculation of the “base deficit” in the new-born nursery.

FRANK A. Ossu, M.D.

MARIA DELIVORIA-PAPADOPOULOS, M.D. Department of Pediatrics

University of Pennsylvania School of Medicine

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856 THE SHIFT TO THE LEFT

12.Orzalesi, M. M., and Hay, W. W.: The regula-REFERENCES

1. Benesch, R., and Benesch, R. E.: The effect of

organic phosphates from the human erythro-cyte on the allosteric properties of hemoglo-bin. Biochem. Biophys. Res. Commun., 26:

162, 1967.

2. Chanutin, A., and Curnish, R. R.: Effect of

or-ganic phosphates on the oxygen equilibrium

of human ervthrocvtes. Arch. Biochem.

Bio-phys., 121 :96, 1967.

3. Delivoria-Papadopoulos, M., Ronevic, N. P., and Oski, F. A.: Postnatal changes in oxygen transport of term, premature, and sick in-fants: The role of adult hemoglobin and red cell 2,3-diphosphoglycerate. Pediat. Res., 5: 235, 1971.

4. Oski, F. A., Gottlieb, A.

J.,

Miller, W. W., and Delivoria-Papadopoulos, M.: The effects of deoxygenation of adult and fetal hemoglobin on the synthesis of red cell

2,3-diphospho-glycerate and its in vivo consequences. J. Clin. Invest., 49:400, 1970.

5. Bunn, H. F., May, M. H., Kocholaty, W. F.,

and Shields, C. E.: Hemoglobin function in stored blood. J. Clin. Invest., 48:311,

1969.

6. Anselmino, K. T., and Hoffman, F.: Die

Ursa-chen des Icterus Neonatorum. Arch. Gynak,

143:477, 1930.

7. Allen, D. W., Wyman, J., and Smith, C. A.:

The oxygen equilibrium of fetal and adult

human hemoglobin. J. Biol. Chem., 203:84, 1953.

8. Bauer, C., Ludwig, I., and Ludwig, M.: Differ-ent effects of 2,3-diphosphoglycerate and adenosine triphosphate on oxygen affinity of adult and fetal human hemoglobin. Life Sci., 7:1339, 1968.

9. Syuma, I., and Shimizu, K.: Different re-sponses to organic phosphates of human fe-tal and adult hemoglobin. Arch. Biochem.,

129:404, 1969.

10. deVerdier, C. H., and Garby, L.: Low binding of 2,3-diphosphoglycerate to haemoglobin F.

Scand. J. Clin. Lab. Invest., 23:149, 1969. 11. Bunn, H. F., and Briehl, R. W.: The

interac-tion of 2,3-diphosphoglycerate with various human hemoglobins. J. Clin. Invest., 49: 1088, 1970.

tion of oxygen affinity of fetal blood: I. In vitro experiments and results in normal

in-fants. PEDIATRICS, 48:857, 1971.

13. Beer, R., Doll, E., and Wenner, C.: Die

Ver-schiedung der S#{228}uerstoffdissoziationskurve

des Blutes von Sauglingen wahrend der ersten Lebensmonate. Pflugers Arch. Ces. Physiol.,

265:526, 1958.

14. Opitz, E., and Schneider, M.: Uber die Sauer-stoffversogung des Gehirns und der Mecha-nisms von Mangeliverkungen. Ergebn. Phys-iol., 46:126, 1950.

15. Novy, M. J., Frigoletto, F. D., Easterday, C. L., Umansky, I., and Nelson, N. M.: Changes in cord blood oxygen affinity after intrauterine transfusions for erythroblastosis. New Eng. J. Med., 285:589, 1971.

16. Battaglia, F. C., Bowes, W., McGaughey, H. R.,

Makowski, E. L., and Meschia, C.: The

effect of fetal exchange transfusion with

adult blood upon fetal oxygenation. Pediat.

Res., 3:60, 1969.

17. Parer, J. T.: Reversed relationship of oxygen affinity in maternal and fetal blood. Amer. J.

Obstet. Gynec., 108:323, 1970.

18. Weatherall, D. J.: Polycythemia resulting from

abnormal hemoglobins. New Eng. J. Med.,

280:604, 1969.

19. Adamson, J. W., and Stamatoyannopoulos, C.:

Erythrocytosis associated with abnormal he-moglobins: Aspects of marrow regulation.

Blood, 30:848, 1967.

20. Oski, F. A., Marshall, B. E., Cohen, P. J.,

Sug-erman, H. J., and Miller, L. D.: Exercise

with anemia. The role of the left or right shifted oxygen-hemoglobin equilibrium curve. Ann. Intern. Med., 74:44, 1971.

21. Delivoria-Papadopoulos, M., Martens, R.,

Nov-natil, F., Cohen, R., and Forster, R. E., II.:

Effect of oxygen-hemoglobin affinity on tis-sue oxygen unloading following exchange transfusion of newborn piglets. Fed. Proc., 30(2), 1971.

22. MacRae, D. J., and Palarradji, D.: Acid-base

balance in exchange transfusion. J. Obstet. Gynaec. Brit. Comm., 72:384, 1965.

23. Westin, B., Nyberg, R., Miller, J. A., Jr., and

Wedenberg, E.: Hypothermia and transfu-sion with oxygenated blood in the treatment of asphyxia neonatorum. Acta Paediat.

(5)

1971;48;853

Pediatrics

Frank A. Oski and Maria Delivoria-Papadopoulos

THE SHIFT TO THE LEFT

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1971;48;853

Pediatrics

Frank A. Oski and Maria Delivoria-Papadopoulos

THE SHIFT TO THE LEFT

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