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VOLUME 48 DECEMBER 1971 Numn 6
COMMENTARY
THE
SHIFT
TO
THE
LEFT
F
OR many years it appeared thatphysiol-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 ofhe-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 hasnot 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.
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 phosphategroups of 2,3-DPG and the imidazole
groups
of the
beta
chain
H-21 histidinesand
the
N terminal
end
of the
non-alpha
chain.”The
gamma chain of fetal hemoglo-bin lacks this histidine residue andthis may
be responsible
for its decreased
interaction with 2,3-DPG.Elsewhere in this issue of PlmzA’nucs,
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 affinityof 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 thatap-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 mightproduce 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 givespause 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
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.,
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5. Bunn, H. F., May, M. H., Kocholaty, W. F.,
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1969.
6. Anselmino, K. T., and Hoffman, F.: Die
Ursa-chen des Icterus Neonatorum. Arch. Gynak,
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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.
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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.
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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.
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balance in exchange transfusion. J. Obstet. Gynaec. Brit. Comm., 72:384, 1965.
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