In the recent article by Stark et al,(1) the authors provide only
circumstantial evidence that carbon
monoxide (CO) contributes to the apparent “dysregulated” microvascular
blood flow in preterm male
infants. However, they are beginning to “connect the dots” in a line of
logic
implicating CO in the
hemodynamic instability of biologically “disadvantaged” male infants,(2)
who,
more often than female
infants, experience pathophysiologic processes, such as
periventricular/intraventricular hemorrhage.
In their paper,(1) the authors reveal that lower gestational age and male
gender are associated with
increases in CO bound to hemoglobin or carboxyhemoglobin (COHb), which
is further correlated
directly with increases in microvascular blood flow. Thus, our original
observation that COHb could be
related indirectly to blood pressure in infants with respiratory distress
syndrome may need to be
considered in a larger context.(3) It appears that CO-induced
vasorelaxation
may be developmentally
regulated or reactive to various stimuli, such as hypoxia or
infection(,4,5)
which may be characterized
as oxidative in nature. However, not all sources of CO production may be
regulated, such as photo-
oxidation(6) or lipid peroxidation(7) caused by exposure to light or
oxygen,
respectively. It could be
speculated that the fleeting “vascular” rashes associated with
phototherapy
are the result of local CO
production in the skin. Thus, for a small, translucent baby, intense
exposure
to phototherapy lights for
extended periods after birth, might have deadly consequences in some
cases.(8)
Although guanosine 3’-5’-cyclic monophosphate (cGMP) and nitric oxide
(NO) are probably
important in the regulation of blood pressure in preterm infants, the
elevation in cGMP in sick preterm
infants with RDS does not appear to be due solely to NO.(3,9) Moreover, CO
can cause vasorelaxation
not only acting through cGMP, but, depending upon the vascular source or
tissue, also through
blocking the cytochrome P450-mediated production of endothelin-1, a
vasoconstrictor,(10) or by
activation of calcium-dependent potassium channels.(11) Moreover, the non-
enzymatic sources of CO
may create circumstances that can overwhelm what is usually a tightly
regulated heme oxygenase
(HO)/CO system, more than making up for CO’s less potent activation of
soluble guanylyl cyclase
(sGC).(7)
We agree with the authors that the associations that they have found
are
intriguing, and that the
sources of CO in preterm infants are not fully elucidated. We suspect that
they include the enzymatic
source (HO) via the heme catabolic pathway, as evidenced by the cord blood
findings, but also non-
enzymatic sources, which contribute to the pathophysiology of a failed
hemodynamic transition in
some sick infants(.4,5) A terrible irony could be that the same HO pathway
that is up-regulated to
protect the relatively antioxidant-deficient newborn, can also generate CO
in
such large amounts
(adding to the even larger amounts caused by oxidative reactions involving
O2 and light), to contribute
to the dysregulation of microvascular flow.
Yet, a mystery still remains. Why do male infants start with higher
COHb
in their cord blood?
Information about their hemoglobin concentration would help clarify
whether
the CO source might be
from a relatively larger red blood cell mass or blood volume. In fact,
even the
latter can now be
estimated using biotin labeling and fluorescence-activiated cell sorting
(FACS) technologies.(12) If
there were no gender difference in hemoglobin concentrations, then a
COHb/Hb ratio might expose a
hemolytic cause.(13) If there were no gender difference in the ratio, then
a
non-enzymatic source
would seem more likely responsible since the catabolism of other heme
proteins represents such a
small part (∼20%) of CO production. Finally, the new CO-oximeters
make it unlikely that the elevations
in COHb correlated with gestational age represent an artifact of
spectroscopy,
with fetal hemoglobin
being misidentified as COHb,(14) in addition to being more accurate at
COHb
≤ 2.5% than we have
previously reported.(15)
The authors make another provocative, and entirely logical
suggestion,
that a metalloporphyrin
might be a pharmacologic solution to reduce the excessive CO production in
preterm infants,
especially male ones, addressing not only their propensity for jaundice
and
bilirubin-induced
neurologic injury, but also their propensity for increased or dysregulated
microvascular flow. Although
the evidence is certainly not sufficient for proposing an indication for
metalloporphyrin treatment,
there is more evidence to support the use of a metalloporphyrin as the
primary therapeutic approach
to infants <750 grams at risk for hyperbilirubinemia, who are
translucent and
may be at risk for
phototoxicity when undergoing phototherapy.(8) In this regard, the use of
a
photo-inert drug would
be ideal because the chance of generating CO from photo-oxidation would
be avoided, during
inhibition of the enzymatic production of CO while still improving
microvascular tone. Such an
approach is biologically plausible as vasodilatation can be reduced
through
inhibition of HO in the
setting of CO-induced dilatation (e.g., the inhibition of the normal
dilatation
of the abdominal aorta in
pregnant mice).(16) Although hypotension has not been observed in the
infants treated with tin
mesoporphyrin (SnMP), the infants have been larger and more mature. In the
context of a dysregulated
microvascular system, the effects could be dramatic. Imagine mitigating
the
risk for bilirubin-induced
injury and many of the other morbidities affecting the tiny, immature
infant
with the same targeted
therapeutic intervention! Unfortunately, targets are never singular or
simple;
they are always in a
context. There will always be trade-offs for our pharmacologic cleverness.
Until we know what they
are, we will not know whether they represent greater or lesser risks than
the
ones our tiny patients
already face.
References
1. Stark MJ, Clifton VL, Wright IM. Carbon monoxide is a significant
mediator of cardiovascular status
following preterm birth. Pediatrics. 2009;124:277-284.
2. Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA,
Shankaran S,
et al. Sex differences in
outcomes of very low birthweight infants: The newborn male disadvantage.
Arch Dis Child Fetal
Neonatal Ed. 2000;83:F182-185.
3. Krediet TG, Cirkel GA, Vreman HJ, Wong RJ, Stevenson DK,
Groenendaal
F, et al. End-tidal carbon
monoxide measurements in infant respiratory distress syndrome. Acta
Paediatr. 2006;95:1075-1082.
4. Moncure M, Brathwaite CE, Samaha E, Marburger R, Ross SE.
Carboxyhemoglobin elevation in
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concentrations in paediatric sepsis
syndrome. Arch Dis Child. 2003;88:889-890.
6. Vreman HJ, Knauer Y, Wong RJ, Chan ML, Stevenson DK. Dermal carbon
monoxide excretion in
neonatal rats during light exposure. Pediatr Res. 2009;66:66-69.
7. Vreman HJ, Wong RJ, Sanesi CA, Dennery PA, Stevenson DK.
Simultaneous
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system. Can J Physiol Pharmacol. 1998;76:1057-1065.
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11. Kaide JI, Zhang F, Wei Y, Jiang H, Yu C, Wang WH, et al. Carbon
monoxide
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13. Kaplan M, Na'amad M, Kenan A, Rudensky B, Hammerman C, Vreman HJ,
et al. Failure to predict
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14. Mahoney JJ, Wong RJ, Vreman HJ, Stevenson DK. Fetal hemoglobin of
transfused neonates and
spectrophotometric measurements of oxyhemoglobin and
carboxyhemoglobin. J Clin Monit.
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15. Mahoney JJ, Vreman HJ, Stevenson DK, Van Kessel AL. Measurement
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comparison with
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16. Zhao H, Wong RJ, Doyle TC, Nayak N, Vreman HJ, Contag CH, et al.
Regulation of maternal and
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751.
Conflict of Interest:
None declared
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