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Control of cerebral circulation in the high-risk Neonate.

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Control of Cerebral Circulation
in the High-Risk Neonate
0. Pryds, MD
A knowledge of neonatal cerebrovascular physiology is essential to the understanding of diseases that frequently affect
the subsequent development of the newborn brain. Recent observations indicate that the cerebral vessels of the healthy
newborn infant, even the very preterm, respond to physiological stimuli in the same manner as in the mature organism.
Thus, cerebral blood flow changes with changes in arterial carbon dioxide tension (Paco,), oxygen concentration
(Cao,), or glucose concentration, whereas cerebral blood flow remains constant at minor fluctuations in arterial blood
pressure. In pathological states, pressure autoregulation may become impaired, and in severe cases the vessels do not
react to chemical or metabolic stimuli. These infants are at high risk for developing cerebral lesions, and they may
be candidates for new “brain-protecting regimens.”
Pryds 0. Control of cerebral circulation in the high-risk neonate. Ann Neurol 1991;30321-329
The two major causes of brain injury and subsequent
neurological handicap in newborn infants are hypoxicischemic encephalopathy and intracranial hemorrhage.
Both types of lesions may be observed in the same
infant at autopsy, although germinal matrix hemorrhage is predominantly a lesion of the preterm infant,
whereas hypoxic-ischemic brain injury occurs independently of the gestational age 111. The pathophysiological mechanisms underlying these brain lesions are complex and partially unresolved. Within the last decades,
several risk factors have been related to the development of hypoxic-ischemic encephalopathy and intracranial hemorrhage. Most factors are accompanied by
alterations of cerebral blood flow (CBF), indicating that
perturbations of CBF may play an important role in
the pathogenesis. This theory is evidenced by the distribution of injury: Necrosis, indicating hypoxic-ischemic damage, is frequently found at the border zones
between end fields of major cerebral arteries. These
“watershed zones’’ may be hypoperfused when the arterial blood pressure declines in the absence of pressure-flow autoregulation r2). Ischemia may also occur
during asphyxia [3], during septicemia 147, in anemic
states with reduced blood oxygen concentration IS],
or during severe hyperventilation [6, 77. In contrast,
germinal matrix hemorrhage has been associated with
hyperperfusion states induced by hypercapnia, hypoxia, or hypertensive peaks IS-121.
Most brain lesions develop within the first days of
life 15, 13-15}; in this period the sick neonate experiences rapid and wide fluctuations of blood pressures
From the Department of Neonatology, State University Hospital,
Copenhagen, Denmark.
and blood gases due to prenatal catastrophes, birth
complications, resuscitation, mechanical ventilation,
and other reasons. At present, only sparse information
is available on the regulation of the cerebral circulation
in the newborn infant. This review attempts to organize the existing information with reference to investigations in animals and adult humans.
Estimation of Cerebral Blood Flow in
Newborn Infants
Few techniques are practical for quantitative CBF measurements in humans. A modification of the KetySchmidt method depends on the rate of extraction of
a diffusible, inert, and radioactive indicator from the
brain. The clearance is detected by means of external
scintillators placed over the skull. It is possible to administer the gamma ray-emitting gas xenon 133 (‘33Xe)
in the carotid artery [l6], in the inspiratory gas I171, or
intravenously 118-20). Clearance of positron-emitting,
inert isotopes as detected by positron emission tomography (PET) provides assessment of regional CBF [2 11,
and may also be extended to identify local metabolic
processes such as glucose consumption [22J Recently,
near-infrared spectrophotometry was used to estimate
CBF in neonates [23]. This noninvasive and nonradioactive technique detects changes in oxygenated
hemoglobin in the brain following a short pulse of
increased oxygen in the inspiratory gas. Regional
CBF has also been recorded by nonradioactive, xenon-enhanced, x-ray transmission computed tomograP ~ 1247.
Address correspondence to Dr Pryds, Department of Neonatology,
Rigshospitalet, Blegdamsvej, 2100 Copenhagen 8,Denmark.
Received Nov 30, 1990, and in revised form Feb 25, 1991. Accepted
for publication Feb 27, 1991.
Copyright 0 1991 by the American Neurological Association 321
Semiquantitative approaches for estimating CBF include Doppler ultrasonography for CBF velocity 1251,
venous occlusion plethysmography {26], and electrical
impedance plethysmography 127, 281.
Cerebral Blood Flow in Newborn Infants
In the normal brain, CBF is tightly coupled to the
cerebral metabolic demands [29}. The brain of the
newborn infant has few synaptic connections and
thereby low neuronal activity. Accordingly, the low cerebral metabolism is maintained by a global CBF in the
range of 10 to 20 ml/100 gm/min, which is approximately one third of the value for the healthy adult
brain C23, 30-331.
Regulation of Cerebral Blood Flow
Integrated brain function requires an efficient and
well-controlled circulation that responds appropriately
to the cerebral demands and to changes in perfusion
pressure and blood gases. CBF is basically determined
by two hemodynamic factors: (1) the net pressure gradient across the cerebral vascular bed (CPP), and (2)
the total resistance to blood flow in cerebral vascular
channels (CVR):CBF = CPP/CVR. Both variables
are in turn subject to the influence of numerous factors, which alter, regulate, or contribute to them.
These factors interact in a very complex mode, and
synergism as well as antagonism may be observed
in different conditions. Besides, hierarchical escape
mechanisms with overriding effect may occur in order
to ensure a sufficient supply of metabolites to the
brain. If the supply is reduced toward critical levels by
one factor, counteracting mechanisms may be invoked
to raise the CBF. Changes in blood flow are smaller in
neonates compared with adults, reflecting the lower
absolute CBF 134, 351, and more marked in cerebral
gray matter than in white matter {36]. Similarly, the
absolute change is attenuated by sedation and by hypothermia, which cause a reduction of the cerebral activity 1371. However, the relative changes in CBF are
almost identical in neonates and adults.
The Normal Brain
2.5 1
2.0 PER kPa paC02
1.5PER mmHg MABP
0.5 -
1.7 mM
The cerebral bloodflow (CBF) reactivity of healthy, preterm infants (mean values and 95% conjidence intmals). R e d s are
derived from f45,59, 79, 80, 118, 1261. MABP = mean arterial blood pressure; HGB = hemoglobin.
lated by oxygen; shortly after birth, the CBF changes
inversely with changes in hemoglobin concentration,
and increases with higher hemoglobin oxygen affinity
144). In preterm infants, investigated repeatedly during
the first 3 days of life, we observed that CBF increased
by a mean of 11.9%/1-mM decrease in hemoglobin
concentration, thereby providing a constant oxygen delivery to the brain 1451 (Fig). In accordance with the
active regulation of Cao,, hyperoxemia induces slight
cerebral vasoconstriction 146-481.
The mechanism by which tissue hypoxia leads to
vasodilation is not fully understood. A plausible hypothesis is that the response is mediated by a release
of vasoactive substances from the neural parenchyma
(see section on neuronal regulation). Alternatively, the
vascular response to hypoxia may be promoted by
release of endothelium-derived vasoactive substances
(see below) and via intrinsic actions on the smooth
muscles, as indicated by recent studies of isolated arterial segments [49, 501. This action, however, has not
been demonstrated in vivo [5 11.
Carbon dioxide has a pronounced
relaxant effect on the cerebrovascular smooth muscles.
Arterial hypercapnia causes a marked decrease in the
cerebrovascular resistance and increases CBF whereas
hypocapnia causes vasoconstriction and reduces CBF.
The effect of carbon dioxide on vascular smooth muscles is mediated via changes of the perivascular pH,
probably by activating the electrogenic sodium (Na+)
pump in the cell 1521. Inasmuch as carbon dioxide
diffuses readily across the blood-brain barrier, abrupt
changes in arterial carbon dioxide tension (Paco,) affect
the vascular resistance within 1 to 2 minutes 1431. This
acute effect of carbon dioxide on CBF is, however,
counteracted by an active regulation of the perivascular
Chemical Facton
In fetal and newborn animals, CBF increases
when the arterial oxygen tension (Pao2) decreases
markedly 136, 38, 391. Animal experiments have indicated that CBF is homeostatically regulated by the arterial oxygen concentration (Cao,), which is determined
by the hemoglobin concentration in the blood, the oxygen affinity of hemoglobin, and Pao, 139-42). Thus,
there is an almost linear relation between the cerebrovascular tone and Cao,. The temporal course of cerebrovascular dilation to hypoxia is rapid; it occurs within
30 to 60 seconds 1431.
The CBF of newborn infants appears to be modu322 Annals of Neurology Vol 30 No 3
Relative change in CBF
September 1991
p H causing the vessel diameter to normalize gradually
during the following 24 hours.
Under stable physiological conditions with normal
arterial blood pressure, normal Pao,, and Paco, ranging
between 3 and 9 kPa, CBF changes proportional to
changes in Paco,. In the healthy adult, CBF changes
by a mean of 30%;/1-kPa change in Paco, 153). Because the magnitude of response to changes in Paco,
depends on the actual vessel diameter, the carbon dioxide reactivity is attenuated at extreme hypocapnia or
hypercapnia. Severe hypocapnia may induce tissue
hypoxia that counteracts the vasoconstriction { 54).
Similarly, lower or absent carbon dioxide responses
may be observed when the cerebral vessels are dilated
because of hypercapnia, hypotension 15 51, or hypoglycemia C561.
Numerous studies have revealed that the cerebral
vessels of fetal and newborn animals are responsive to
acute changes in Paco, [34, 38, 54, 57, 581. Recently,
we demonstrated a CBF-carbon dioxide reactivity of
28.9%0/ 1 kPa in spontaneously breathing, preterm neonates studied 2 and 3 hours after birth {59] (see Fig).
On the other hand, the CBF-carbon dioxide reactivity was significantly lower in mechanically ventilated,
preterm infants in whom CBF changed 11 to 12%/
1-kPa change in Paco, shortly after birth. On the second day of life, however, the CBF-carbon dioxide reactivity attained normal adult levels 160, 61). Attenuated CBF-carbon dioxide reactivity has also been
demonstrated in ventilated, newborn animals during
the immediate postnatal period 162-651. This agedependent variation of the carbon dioxide reactivity is
most likely a physiological consequence of the hypercapnic state in utero. Chronic hypercapnia results in a
compensatory alkalosis of the perivascular pH, and the
high pH attenuates the carbon dioxide response when
studied at hypocapnic levels during mechanical ventilation 1661. In contrast, longer lasting ventilation with
chronic hypocapnia is accompanied by perivascular acidosis, which increases the CBF-carbon dioxide reactivity 146, 47, 677. The carbon dioxide reactivity may
be modified pharmacologically. Indomethacin, which is
used in preterm neonates for closure of a persistent
ductus arteriosus, attenuates the responsiveness of cerebral vessels to changes in Paco, {68).
Glucose is the major brain
substrate of the neonate although other metabolites,
such as lactate and hydroxybutyrate, may in part support the metabolism. Animal experiments, investigating the effect of hypoglycemia on CBF, demonstrated
cerebral hyperperfusion 169-7’41, a constant brain
perfusion 175-771, and cerebral hypoperfusion 178).
These conflicting results are difficult to interpret but
may be caused by the different techniques used with
varying speeds of blood glucose drop, and with varying
severity and duration of hypoglycemia. Furthermore,
hypoglycemia disrupts the pressure autoregulation, implying that minor drops of blood pressure may easily
abolish the hyperperfusion 1561.
In the newborn infant, CBF appears to be actively
coupled to the cerebral fuel demands: We demonstrated that blood glucose levels lower than 1.7 mM
are accompanied by a two- to threefold higher CBF
when compared with that in normoglycemic subjects
(see Fig). Furthermore, the hyperemia is reversed
after treatment with intravenous glucose 179,801. Similar escape mechanisms have been established in hypoglycemic adult humans 18 11. The underlying mechanism for the cerebral vasodilation is unknown, but
increased secretion of epinephrine with stimulation of
beta-receptors [SO, 82, 831 or liberation of vasoactive
amino acids may be involved 184, 851.
Pressure Autoregulation
Pressure autoregulation is defined as the occurrence of
vasodilation as cerebral perfusion pressure decreases
and the occurrence of vasoconstriction as cerebral perfusion pressure increases. Thus, due to vasomotor
function in the smaller resistance vessels, CBF is maintained relatively constant within a wide range of arterial
blood pressure (the autoregulatory plateau). The pressure at which CBF decreases significantly during hypotension is termed the lower limit of autoregulation.
In an analogous manner, the pressure at which CBF
increases significantly during hypertension is termed
the upper limit of autoregulation. These levels are not
fixed but depend on the actual diameter of the vessel
and thereby on Paco,, Cao,, the metabolic demands,
and the sympathetic activity. Pressure autoregulation
may be defective when the cerebral vessels are dilated
due to hypercapnia [86}, hypoxia 1863, hypoglycemia
[561, seizure activity {87), or the administration of vasodilating drugs. The temporal course of autoregulatory responses appears to be very rapid, occurring
within seconds [43). Several hypotheses have been offered to account for the mechanisms responsible for
cerebral autoregulation, and the myogenic theory has
been accepted as playing a major role. This hypothesis
supposes that there is an intrinsic mechanism in the
smooth muscle cells of the cerebral arterioles, which
respond to an increase in transmural pressure by vasoconstriction and to a decrease by vasodilation. Such
myogenic actions may be triggered by endotheliumderived vasoactive substances 188, 891. Alternatively,
the metabolic hypothesis of autoregulation suggests
that any changes in CBF initiated by changes in blood
pressure rapidly alter local concentrations of carbon
dioxide and other vasoactive metabolites, which in turn
affect the smooth muscle cells of the cerebral vessels
in a manner sufficient to maintain CBF constant.
Pressure autoregulation is fully developed in fetal
Neurological Progress: Pryds: Control of Cerebral Circulation in Neonates
and neonatal animals {38, 30-931. Because of the
lower arterial blood pressure in newborn animals, the
autoregulatory plateau is shifted to the left, when compared with the adult values 1901. In the newborn
infant, the autoregulatory plateau has not been established, although repetitive CBF investigations of
preterm infants with normal brains have revealed that
CBF is unaffected by physiological fluctuations of
mean arterial blood pressure (MABP) within the range
of 25 to 66 mm Hg {59-61} (see Fig). These observations were valid for infants of varying gestational ages
and postnatal ages, indicating that pressure-flow autoregulation is intact in the healthy neonate.
In contrast to these data on tissue perfusion, Doppler ultrasonography measurements of flow velocity
have been interpreted as indicating poorly developed
pressure autoregulation in the very-low-birth-weight
infant, with a gestational age of less than approximately
30 weeks 194, 951. However, this method is inadequate in determining autoregulation of cerebral perfusion, as it is decisive to determine the vascular diameter, which is subject to wide variations.
The role of changes in venous pressure and intracranial pressure (ICP) on the CBF regulation is probably minimal. The skull of newborn infants is very compliant, implying that only minor fluctuations of ICP
may OCCLU under normal conditions. Besides, a moderate increase of the venous pressure or ICP induces pial
vasodilation to maintain CBF constant in animals 196,
Neuronul Regulation
Measurements of local CBF during brain work, such
as perceptual mental and motor activity, have demonstrated a signlficant increase in regional cortical flow in
appropriate anatomical areas of the gray matter 198,
991. The underlying mechanism of the coupling between CBF and local cerebral metabolic requirements
is speculative. Extracellular accumulation of vasodilator
metabolites such as carbon dioxide, lactate, adenosine,
or potassium has been suggested as increased cerebral
activity (1) enhances glycolysis with carbon dioxide
production, (2) increases the degradation of ATP to
adenosine, and ( 3 ) induces an efflux of potassium. In
addition, if oxygen is consumed faster than it is delivered, lactate could accumulate. Alternatively, the regulation may be due to local reflex mechanisms that act
via connections from active neurons to adjacent precapillary vessels {loo, 1011.
An increase in focal cerebral flow accompanying increased cerebral activity has not yet been demonstrated
in the human neonate but studies have shown a close
relation between CBF and sleep state and between
CBF and electroencephalography (EEG)-detected activity 1102-1041.
The major cerebral arteries and arterioles are sup324 Annals of Neurology Vol 30 No 3
plied by sympathetic nerve fibers. Sympathetic stimulation results in slight vasoconstriction but the net effect
on CBF is only moderate, probably because of counteracting responses of the smaller resistance vessels (“dual
response”) 11051. Activation of the sympathetic nerves
shifts the autoregulatory plateau toward higher pressures, thereby protecting the brain against increases
in blood pressure. Under hypotension, however, high
sympathetic tone may be disadvantageous, as the upward shift of the lower limit of autoregulation may
result in brain ischemia 11061.
Several neuropeptides have been identified in nerve
fibers surrounding the cerebral vessels. The majority of
these peptides have distinct effects on cerebral vessels
11071, but their role in the CBF regulation remains to
be established.
The impact of sympathetic nerve activity on CBF
regulation in the newborn human brain is unknown.
Likewise, no studies have addressed the effect of circulating catecholamines. Probably, catecholamines modulate the tone of the greater arteries slightly by affecting
alpha- and beta-receptors 1108, 1091.
EndotheLium-Derived Vusouctiue Substances
Within the last decade it has been recognized that
endothelid cells manufacture very potent vasoactive agents that function on the underlying vascular
smooth muscles. Endothelium-derived contracting factor (EDCF) is a peptide [l 101, whereas endotheliumderived relaxing factor (EDRF) has been identified as
nitric oxide { 1111. Experiments on isolated arterial segments have demonstrated that the myogenic contraction to higher transmural pressures is dependent on
intact endothelium {88, 891, as is vasodilation induced
by increments in flow 1112) or hypoxia 149, 501. Although endothelium-derived vasoactive substances appear to act on cerebral resistance vessels in vivo { 1131151, their functions are far from clear. However, the
presence of local opposing mechanisms that respond
to changes in transmural pressure and flow may generate new concepts of circulatory control.
Phumucologicul Agents
Several pharmacological substances affect the cerebral
circulation in animals and adult humans 11161, but only
a few have been evaluated in the neonate. Indomethacin is a potent cerebral vasoconstrictor that reduces
CBF by 20 to 40% in preterm infants, when it is given
in therapeutical doses of 0.20 mg/kg {117-119} (see
Fig). Aminophylline has a minor constricting effect on
the cerebral vessels in adults {120, 1211. Several studies using Doppler ultrasonography were unable to
identify a direct effect of aminophylline and caffeine
on CBF of neonates, partly because of a confounding
variation of Paco, {122-1253. However, when changes
in Paco, were adjusted for, we found that CBF de-
September 1991
creased by a mean of 13.3% after intravenous administration of aminophylline 11261 (see Fig).
The Unhealthy Brain
Pathological states following hypoxic-ischemic episodes, brain contusion, or inflammation may result in
impaired regulation of CBF. After severe insults, the
cerebral vessels become unresponsive to changes in
MABP 1127, 1281, Paco, 11291, and Cao, 1130, 1311.
Defective regulation implies that CBF increases exponentially with increasing MABP and that CBF does not
adjust to chemical stimuli or to changes of the cerebral
metabolic demands. Apparently, the CBF regulatory
systems have varying vulnerabilities; pressure autoregulation is generally believed to be lost before carbon
dioxide reactivity, which again is lost before Cao, reactivity 1129, 132).
Indications of impaired pressure autoregulation of
CBF have been observed in newborn infants. In 1979,
Lou and colleagues reported a proportional relation
between CBF and MABP in 19 patients 11331, and
other studies indicated an increasing CBF with increasing MABP after blood transfusion 194, 134, 1351.
These observations were supported in a recent study
including repeated measurements of CBF at different
levels of MABP and Paco,. In mechanically ventilated,
preterm infants with subsequent severe hemorrhage of
the germinal layer, CBF changed by a mean of 4.0%/
1-mm Hg change in MABP, and CBF was unresponsive to changes in Paco, [601. The varying vulnerability
of the regulatory mechanisms was substantiated in another study of asphyxiated, term infants. Mild cerebral
lesions developed in patients with impaired pressure
autoregulation but with intact carbon dioxide reactivity. Although the timing of cerebral lesions in relation
to the measurement of vasoreactivity was less precise,
infants with subsequent evidence of extensive brain
damage had absent CBF regulation with regard to
changes in blood pressure, Paco,, and metabolic demands { 1361. These latter infants had a markedly high
CBF despite isoelectric EEG activity and thereby a presumably low cerebral metabolism. The pathophysiological mechanisms underlying postasphyxial cerebral uncoupling and hyperperfusion are unclear inasmuch as
few studies on animals have identified delayed brain
hyperemia after ischemia { 137). Conversely, most investigations of CBF in the postischemic period have
reported the “no reflow phenomenon” with delayed
cerebral hypoperfusion lasting for several hours 1138140). It has been speculated that this delayed hypoperfusion may enhance the cerebral damage 1141, 1421,
although others have found the hypoperfusion coupled
to a depressed cerebral function 11431. It is unknown
whether the “no reflow phenomenon” exists in humans, as CBF has not been investigated shortly after
asphyxial or ischemic episodes. Delayed cerebral hy-
peremia, on the other hand, may be observed even a
few hours after the insult E25, 136, 144-1491. Speculative mechanisms underlying the hyperemia are complete loss of tone in resistance vessels, accumulation of
vasoactive metabolites such as adenosine and lactate,
or liberation of the excitatory amino acids, glutamate
and aspartate.
It appears that the cerebral vessels of the healthy newborn infant, preterm as well as term, respond to physiological stimuli in the same manner as in the mature
organism even shortly after birth. In pathological
states, the CBF regulation may become impaired, implying that the vessels are unresponsive to changes in
MABP, and in more severe cases also to changes in
Paco,, Cao,, and metabolic demands. Although the
role of perinatal asphyxia is unmistakable in term infants, the underlying factors are still obscure in the
preterm neonate. In immature infants, there is no relation between defective regulation of CBF and the commonly used indicators of perinatal asphyxia [60]. However, abruption of the placenta prior to delivery has
been documented to be a risk factor, indicating that
undetected prenatal asphyxia or liberation of vasoactive substances from the placenta into the fetal circulation may be involved {7, 14, 601.
There seems to be a relation between vasoparalysis
and subsequent severe intracranial hemorrhage in the
preterm infant [GO], but the relationship to hypoxicischemic brain damage is probably more complicated
as these lesions may have been induced prior to the
vasoparalytic state. Short-lasting and isolated impairment of pressure autoregulation does not appear to
warrant a poor prognosis El501, but absent pressure
autoregulation will increase the risk of vascular lesions:
A defect in regulation of the vessel diameter with
changing perfusion pressure may induce ischemia during hypotension, whereas high blood pressure will be
transmitted unhampered to the poorly supported capillaries and increase the risk of rupture 111, 12, 60, 95,
The carbon dioxide and Cao, reactivities are more
robust compared with the pressure vasoreactivity, and
their absence is an indicator of severe cerebrovascular
pathology. Thus, this state is associated with subsequent evidence of extensive brain damage {136, 147,
15 11. Moreover, because carbon dioxide is a powerful
coupler between CBF and cerebral demands, and oxygen delivery should be adjusted sufficiently, infants
with impaired carbon dioxide and Cao, reactivities are
exposed to additional cerebral insults during hypermetabolic conditions such as seizure activity, which is common after asphyxia. Hypoglycemia may also be deleterious to infants with defective regulation of CBF and
inability to induce compensatory hyperperfusion.
Neurological Progress: Pryds: Control of Cerebral Circulation in Neonates
Knowledge of the cerebral hemodynamics may have
important implications for neonatal care. Unfortunately, none of the available methods for CBF measurements have been able to detect the ischemic
threshold of CBF to justify interventions. Notwithstanding, it seems advisable (1) to maintain normal arterial blood pressure as hypotension may make the capillaries more vulnerable to higher transmural pressures
[152), (2) to avoid abrupt changes in blood pressure,
and (3) to avoid conditions with vasodilation and impaired pressure autoregulation (hypoxia, hypercapnia,
hypoglycemia, etc.). On the other hand, demonstration
of absent CBF-carbon dioxide reactivity, or uncoupling between CBF and metabolic demands, may facilitate identification of infants at high risk of cerebral
damage. These infants may be candidates for “brainprotecting regimens” including administration of free
radical scavengers { 139, 153, 1547 or glutamate antagonists Cl55, 1561.
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