Pediatric Anesthesia ISSN 1155-5645

REVIEW ARTICLE

Cerebral blood flow in the neonate

Laszlo Vutskits1,2
1 Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland
2 Department of Fundamental Neuroscience, Geneva University Medical School, Geneva, Switzerland

Keywords Summary
autoregulation; brain; development; cerebral
blood flow; hypotension; neonate Ensuring adequate oxygenation of the developing brain is the cornerstone of
neonatal critical care. Despite decades of clinical research dedicated to this
Correspondence issue of paramount importance, our knowledge and understanding regarding
Laszlo Vutskits, Department of the physiology and pathophysiology of neonatal cerebral blood flow are still
Anesthesiology, Pharmacology and
rudimentary. This review primarily focuses on currently available human
Intensive Care, University Hospital of
clinical and experimental data on cerebral blood flow and autoregulation in
Geneva, 4, rue Gabrielle-Perret-Gentil, 1211
Geneva 4, Switzerland the preterm and term infant. Limitations of systemic blood pressure values as
Email: laszlo.vutskits@unige.ch surrogates for monitoring adequate cerebral oxygen delivery are discussed.
Particular emphasis is placed on the high interindividual variability in cere-
Section Editor: Andy Wolf bral blood flow values, vasoreactivity, and autoregulatory thresholds making
the applications of normative values highly questionable. Technical and ethi-
Accepted 11 October 2013
cal difficulties to conduct such trials leave us with a near complete lack of
knowledge on how pharmacological and surgical interventions impact on
doi:10.1111/pan.12307
cerebral autoregulation. The ensemble of these works argues for the necessity
of highly individualized care by taking advantage of continuous bedside mon-
itoring of cerebral circulation. They also point to the urgent need for further
studies addressing the exciting but difficult issue of cerebral blood flow auto-
regulation in the neonate.
modulation of ion-channels and underlying signaling
Introduction
pathways in the developing brain? If not, to what extent
One particularly important concept in neonatal care is changes in systemic parameters, including blood pres-
the pronounced vulnerability of the developing brain to sure, acid-base, temperature and glucose homeostasis,
pharmacological and physiological insults. This issue determine neurological outcome in the perioperative set-
gains ample clinical relevance in the context of providing ting? We currently do not have a clear answer to these
anesthesia to the neonate and young infant. Exposure to issues. The neurobiological basis for general anesthetics-
the wide variety of pharmacological substances during induced specific impairment of brain development is well
the perioperative period has a direct impact on neuro- established (3). Less is known, however, about the
transmitter systems function and can indirectly lead to impact of changing whole-body homeostasis on the
major perturbations of systemic physiological parameters immature nervous system. The present review will focus
maintaining whole-body homeostasis. An ever-increasing on how systemic hypotension in the perioperative period
body of experimental work demonstrates developmental might affect cerebral blood flow (CBF) and oxygen
stage-dependent neurotoxicity and altered synaptic plas- delivery to the immature brain. Technical considerations
ticity following administration of general anesthetics (1). on the measurement of CBF along with the available
Recent clinical epidemiological data also suggest an knowledge on cerebral autoregulation will be discussed
association between exposure to anesthesia/surgery dur- both in the healthy and in the critically ill neonate.
ing early stages of life and subsequently altered neurode-
velopmental outcome (2). There are two important and
Systemic hypotension in the neonate
related questions precluding the interpretation of these
observations. Do the unwanted negative effects of gen- Appropriate blood pressure management of the neonate
eral anesthesia are specifically related to drug-induced is a difficult and highly controversial issue. Indeed,

22 © 2013 John Wiley & Sons Ltd

Pediatric Anesthesia 24 (2014) 22–29
L. Vutskits
neither consensus on the definition of systemic hypoten-
sion nor agreement on the best approach to treat the
perceived abnormalities are available (4). This is most
probably explained by the fact that despite the existence
of detailed normative values for blood pressure based
on weight or age (5–11), the physiological blood pres-
sure range that allows adequate organ perfusion is
essentially unknown (4). Several factors account for this
uncertainty. First, reported ‘normal’ blood pressure
values might be significantly influenced by institution-
specific management strategies, especially in low birth
weight premature neonates (4). Second, the type of non-
invasive arterial pressure monitor, the size of the infant,
and the extremity where the measure is taken have been
shown to have an important impact on the obtained
results either in awake or in anesthetized subjects (12–
15). Last but not least, there is also evidence that sys-
temic blood pressure and cardiac output may be poorly
correlated in sick preterm neonates (16–18). For exam-
ple, given the limited myocardial reserve in the neonate,
it is conceivable that the increased afterload associated
with higher systemic pressures (and thus with increased
vascular resistance) may reduce cardiac output and
systemic flow (16). In an attempt to establish guidelines
for blood pressure management in the neonate, the joint
working group of the British Association of Perinatal
Medicine and the Research Unit of the Royal College of
Physicians suggested that ‘a mean arterial blood pres-
sure equivalent to the gestational age in weeks is ade-
quate as a minimum value’ (19). While the paucity of
scientific foundations underlying this statement has been
emphasized by the working group itself, these rules are
now widely accepted in clinical practice.
There are no clear data demonstrating that, in young
infants, keeping blood pressure in the physiological
range would improve outcome (20,21). Nevertheless,
some clinical reports suggest an association between low
systemic arterial blood pressure and brain injury. In a
prospective observational study, including 33 infants of
<31 gestational weeks, mean arterial blood pressure val-
ues of <30 mmHg for over an hour were significantly
associated with severe hemorrhage, ischemic cerebral
lesions, or death within 48 h (22). In line with these
observations, subsequent studies in neonates have also
found an association between systemic hypotension but
not hypertension and intraventricular hemorrhage and
neurodevelopmental outcome (23,24). A potential rela-
tionship between blood pressure variability and intra-
ventricular hemorrhage has also been evoked but this
remains controversial (9,25–27).
Although not evidence based, systolic blood pressure
values are preferentially used in the management of
hypotension in neonates and children (28,29). A recent
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Pediatric Anesthesia 24 (2014) 22–29
Cerebral blood flow in the neonate
survey amongst members of the Society for Pediatric
Anesthesia and the Association of Paediatric Anaesthe-
sists reveals that the majority of pediatric anesthesiolo-
gists quote 45–50 mmHg as a threshold value for
systolic blood pressure in neonates and consider a
20–30% decrease from baseline values as clinically sig-
nificant (29). Recent analysis of perioperative records in
a noncardiac pediatric surgical population indicates that
up to 27% of children between 1 and 5 years of age
develops hypotension prior to surgical incision (30). To
our knowledge, no available data exist on the incidence
of perioperative hypotension in neonates, and multicen-
tric data collection/analysis is urgently needed to resolve
this issue.
Cerebral blood flow: how to measure and what
are the normal values in the neonate?
There is no general agreement on the best approach to
measure CBF. Nevertheless, it is important to note that,
despite their methodological diversity, all these measure-
ment methods yield fairly comparable results on cere-
bral circulation. In their pioneering series of work in the
1940s, Kety and Schmidt used nitrous oxide and took
advantage of the Fick principle stating that the rate of
uptake and clearance of an inert diffusible gas is propor-
tional to blood flow (31). The invasive nature of this
measurement technique, necessitating repeated blood
draws from the internal jugular veins, together with the
fact that equilibrium of nitrous oxide between the circu-
lation and the brain tissue occurs very slowly, however,
largely limited its use even in the experimental setting.
Since the 1960s and the advent of radioisotope imaging,
the Kety-Schmidt method was gradually replaced by the
tracing and measurement of the strong gamma emitter
Xenon-133, a freely diffusible inert gas that does not
interfere with cerebral metabolism (32). More recently,
due to the important development of noninvasive imag-
ing technologies, single photon emission computed
tomography (SPECT) and magnetic resonance imaging
(MRI) are increasingly used to study cerebral blood flow
(33,34). Despite the important and detailed information
they may provide, these methodologies cannot be easily
applied in the clinical settings where continuous bedside
measurement of cerebral blood flow would be needed to
guide clinical decision making. There are currently two
major measurement techniques allowing the assessment
of CBF with relative ease in the operating room: trans-
cranial Doppler ultrasonography (TCD) and near-infra-
red spectroscopy (NIRS). TCD was introduced into
clinical practice in 1982 and allows continuous monitor-
ing of cerebral blood flow velocity at the bedside (35).
Although this method does not give direct quantitative
23
Cerebral blood flow in the neonate
information on CBF, it provides a valuable tool to (i)
follow qualitative changes in flow velocities, (ii) measure
cerebrovascular resistance, and (iii) determine lower lim-
its of CBF autoregulation (36,37). Assessment of cere-
bral circulation using NIRS is based on the high degree
of transparency of brain tissue in the near-infrared range
(38,39). By measuring oxygenated and de-oxygenated
hemoglobin, this method provides continuous on-line
information on the oxygenation state of brain tissue.
Importantly, NIRS has also been validated to measure
CBF (40,41) as well as autoregulation (42).
In healthy adult human volunteers, CBF values are in
the range of 40–50 ml/100 g
min 1 (43). The most chal-
lenging and important issue are however to determine
the lower limits of CBF that still maintains physiological
brain function. In experimental studies on adult
baboons, neurotransmission is ceased when perfusion
rate is decreased to levels around 20 ml/100 g
min 1,
and irreversible neuronal damage has been reported
under 10 ml/100 g
min 1 even under normoxic condi-
tions (44,45). In line with these animal data, PET mea-
surements from patients with varying degree of cerebral
ischemia indicate that normal neurological functions are
preserved at values above 19 ml/100 g
min 1, while irre-
versible tissue damage occurred under flow rates of
15 ml/100 g
min 1 (46).
Determining physiological CBF values in neonates
faces important challenges. Indeed, to avoid artifacts, all
currently available techniques require repeated measure-
ments in relatively still subjects. This is of course very
difficult to achieve in healthy neonates without inducing
some level of sedation which, in itself, might change
CBF. Both sedation and the possible need for proce-
dure-related invasive equipment (e.g., intravenous lines)
raise ethical concerns. Last but not least, physiological
differences related to gestational age together with
potential adaptive changes in flow occurring during the
early postnatal period further complicate the establish-
ment of appropriate normative values. Given the ensem-
ble of these technical and ethical difficulties, it is thus
not surprising that the majority of studies focused on
neonates necessitating medical care following birth. In
their initial study in 1979, Lou et al. assessed CBF in 19
neonates (29–36 weeks of gestational age) with ‘varying
degrees of respiratory distress syndrome’ using the Xe-
133 clearance technique (47). In this cohort, CBF was
found to be in the range of 30–55 ml/100 g
min 1 in the
least affected infants presenting systolic blood pressures
of 60–65 mmHg. In contrast, in infants who had
asphyxia at birth and/or important respiratory distress,
CBF was found to be below 20 ml/100 g
min 1. Com-
parable values of CBF were obtained in a group of 15
preterm infant with <1250 g birth weight and of whom
24
L. Vutskits
10 neonates developed intraventricular hemorrhage
(48). In a subsequent cohort of 42 premature neonates
(28–33 weeks of gestation), important differences in
PET-measured CBF have been demonstrated between
spontaneously breathing infants (CBFmean 20 ml/
100 g
min 1) and those requiring mechanical ventilation
(CBFmean 12 ml/100 g
min 1) (49). Whether these
differences are due to the health status of these infants
or are rather the result of mechanical ventilation on
CBF in this patient population remains unclear. More
recently, Meek et al. used serial NIRS recordings to
study CBF in mechanically ventilated preterm neonates
(24–31 w) with apparently normal brains during the first
3 days following birth (41). The range of NIRS-mea-
sured CBF during the first 24 postnatal hours varied
between 6.3 and 15.2 ml/100 g
min 1, an observation
that is consistent with data obtained using the aforemen-
tioned Xe-133 and PET imaging techniques in compara-
ble patient populations. In all patients, there was a
significant increase in CBF values over the first 72 h
which most probably represents a normal adaptive
response of cerebral circulation to postnatal life as mean
arterial blood pressure, CO2, and hematocrit values
remained stable over this same period. As stated above,
due to ethical and technical constraints, little is known
about normal physiological values of CBF in healthy
term neonates. Using Doppler sonography, Fenton
et al. measured cerebral blood flow velocity (CBFV) in
the anterior and middle cerebral arteries of 128 healthy
term neonates during the first week of postnatal life
(50). They have found an important decrease in cerebro-
vascular resistance during the first 24 h following birth,
and this was accompanied by a nearly twofold gradual
increase in CBFV through the first 4 days of postnatal
life.
Reporting mean CBF values does not reflect the
important amount of interindividual variability of CBF
being present even in within a relatively homogenous
patient population. In a consecutive series of 25 mechan-
ically ventilated neonates, CBF varied between 4.3 and
18.9 ml/100 g
min 1 (51). This huge interindividual var-
iability is further emphasized by positron emission
tomography measurements, where CBF varied between
9 and 73 ml/100 g
min 1 in 14 term neonates, and
between 4.9 and 23 ml/100 g
min 1 in 16 preterm
infants (52). Of utmost interest, all infants in this study
those had CBF values inferior to 10 ml/100 g
min 1 in
the early postnatal period appeared normal at subse-
quent neurological examinations (52). These observa-
tions thus suggest that, in contrast to adults (46), even
very low CBF levels in the early postnatal period might
be sufficient to maintain CNS function, at least in cer-
tain patients. In line with this hypothesis, a combination
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Pediatric Anesthesia 24 (2014) 22–29
L. Vutskits
of Xe-133 measurement of CBF together with ampli-
tude-integrated electroencephalogram in 20 mechani-
cally ventilated preterm infants (27–33 w) during the
first 48 h following birth revealed the presence of corti-
cal electrical activity at flow rates as low as 3 ml/
100 g
min 1 (53). Also, measurements of visual evoked
potentials in 32 premature neonates of <29 weeks of age
revealed that neither the latency nor the amplitude of
these potentials were affected at episodes of CBF as low
as 4.5 ml/100 g
min 1 as long as arterial O2 tension
exceeded 5 kPa (54). The fact that cerebral functions
may persist at even very low CBF in infants does not,
however, mean that low cerebral flow can harmlessly
supported in this patient population in general. Indeed,
although it is ethically unacceptable to conduct such
studies, the high interindividual variability in CBF may
imply that a given individual with relatively high CBF
values at rest might not tolerate low CBF rates.
The majority of studies addressing CBF in the neo-
nate measured global flow. As the preterm infant is at
high risk of white matter injury, and ischemia is consid-
ered as the major cause to induce this morbidity, an
important question is whether CBF is quantitatively
comparable between the cerebral gray and white matter.
Only few works investigated this question in neonatal
populations. They show that cerebral blood flow in the
white matter is only one fifth of that measured in the
gray matter. Additionally, blood flow to the white mat-
ter is selectively reduced at low arterial blood pressure
values. Altogether, these data suggest that hypotensive
episodes could selectively induce cerebral white matter
ischemia in sick neonatal populations.
Relationship between systemic blood pressure
and cerebral blood flow: the autoregulation
concept
Cerebral blood flow autoregulation is referred to the
intrinsic ability of cerebral vessels to maintain constant
cerebral blood flow despite changes in cerebral perfusion
pressure. Initial studies defined the lower limits of the
autoregulatory plateau at around 50–60 mmHg of mean
arterial blood pressure in adult human subjects (55–57).
These values are repeatedly reported in the majority of
currently available textbooks and are generally used by
clinicians as acceptable lower blood pressure thresholds
in the perioperative period. The lower limit of cerebral
autoregulation (LLA) has, however, been seriously chal-
lenged as the publication of these pioneering data (58).
Indeed, more recent studies suggest that the lower limit
of autoregulatory threshold is rather situated at the
80–90 mmHg mean systemic blood pressure range
(37,42,59–61). Most importantly, both early and late
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Pediatric Anesthesia 24 (2014) 22–29
Cerebral blood flow in the neonate
observations report huge interindividual variability in
these values. This, in turn, raise the question whether
any given LLA value can be applied to a broad patient
population (58).
Cerebral autoregulation is a complex feedback-based
homeostatic process composed of at least two mecha-
nisms operating at different time scales: a rapid response
to pressure pulsations followed by a slow response to
changes in mean pressure (36). To gain insights into
these homeostatic mechanisms, one should experimen-
tally lower/raise systemic blood pressure and simulta-
neously record CBF. The rapid component, also called
dynamic cerebral autoregulation, occurs over a period
of seconds and can be tested by measuring recovery of
CBF (or CBFV as a validated surrogate) after a rapid
transient decrease in systemic blood pressure induced by
deflation of large thigh cuffs (36). In contrast, the slow
‘static’ component of autoregulation is evaluated by
serial static measurements of CBF over a period of min-
utes following pharmacological stepwise manipulation
of systemic blood pressure levels. Early CBF measure-
ment techniques could only give information on the
static component of autoregulation. Today, both MRI,
TCD, and NIRS technologies have the ability to record
instantaneous changes in CBF and thus can be used for
detailed assessment of autoregulation.
Early experimental observations in fetal and newborn
lambs suggest that cerebral autoregulation is preserved
in a mean arterial blood pressure range of 40–80 mmHg
in neonates (62,63). Whether similar autoregulatory
curves can also be present in the healthy neonate is cur-
rently unknown as it is ethically unacceptable to study
cerebral autoregulation in human neonates by experi-
mentally inducing significant changes in systemic blood
pressure. Therefore, in these patient populations, our
knowledge on CBF autoregulation is principally based
on monitoring spontaneously occurring events at the
neonatal intensive care unit. The first clinical observa-
tions on autoregulation in premature human neonates
showed a linear relationship between CBF and arterial
blood pressure in all infants independently of the sever-
ity of their distress (47) (64). Other works, however,
found no correlation between CBF and arterial blood
pressure values in clinically stable mechanically venti-
lated neonates (51,65). Indeed, these infants have been
shown to maintain constant cerebral perfusion in mean
systemic blood pressure ranges of 25–40 mmHg (65).
Pyrds et al. investigated CBF autoregulation in 57
mechanically ventilated preterm infants with normal
brain sonograms and found that 10 neonates in this
group displayed pressure passive flow (66). Of utmost
interest, in this study, all neonates with impaired
CBF autoregulation subsequently developed severe
25
Cerebral blood flow in the neonate
intracranial hemorrhage while no or only mild bleeding
occurred in the presence of intact autoregulation. Mea-
suring the gradient of CBF velocity response to transient
systemic blood pressure peaks can be used to study
dynamic autoregulation in infants (67). Using this tech-
nology in 25 neonates undergoing intensive care, it has
been shown that all preterm infants had absent dynamic
autoregulation. In contrast, this dynamic component
was present in term infants without neurological impair-
ment (67). More recent works, using coherence analysis
between continuous bedside NIRS and systemic arterial
pressure measurements, suggest that autoregulation can
transiently be impaired in any critically ill neonate (68–
71). The frequency of impaired autoregulation is associ-
ated with low gestational age and birth weight as well as
with systemic hypotension (71). Importantly, a link
between increased periods of impaired autoregulation
and bad neurological outcome has also been demon-
strated (68,70,71).
Factors affecting cerebral blood flow and
autoregulation
Arterial CO2 and O2 tensions are major determinants of
CBF (72). In healthy adult normocapnic volunteers,
1 kPa increase in arterial CO2 tension induces a
concomitant 30% change in CBF. The effect of CO2 is
principally mediated through changes in pH and thus in
H+ concentrations. The hypercapnia-induced increase
in H+ concentration of the perivascular space increases
K+ outflow from smooth muscles cells of cerebral arter-
ies and arterioles, leading thereby to the relaxation of
these cells and to related vasodilatation (73,74). In con-
trast, the hypocapnia-induced decrease in H+ concen-
tration leads to vasoconstriction of cerebral vessels. The
molecular mechanisms underlying arterial O2 tension-
mediated regulation of CBF are different to those oper-
ating for CO2 and requires an intact endothelium and
NO production (75). Hypoxia can also induce tissue
lactacidosis, and the resulting increase in H+ concentra-
tions provides a link between CO2- and O2-mediated
regulation of CBF.
The reactivity of CBF to changes in arterial CO2 ten-
sion appears to be present even in the preterm neonate.
Early studies, using the venous occlusion plethysmogra-
phy technique, revealed that inhalation of 2% CO2 in
sleeping term infants results in an approximately 40%
increase in cerebral blood flow while breathing of 100%
O2 induces a 30% decrease in this parameter on average
(76). Reporting mean values, however, does not reflect
the important interindividual variability in cerebral
blood vessel reactivity to CO2 and O2 in this population.
Indeed, in this same study, the increase in CBF to 2%
26
L. Vutskits
increase in CO2 varied between 21 and 170%, and, to
100% in O2 between 22 and 45%. In apparently healthy
preterm infants (34 weeks of gestation), the same venous
occlusion plethysmography technique reveals that CBF
reactivity to 1 kPa of CO2 is between 10 and 100% with
an average of 60% and administration of 100% O2
reduces CBF by approximately 15% (77). Comparable
results have been found using Xe-133 measurements in
16 mechanically ventilated preterm neonates where the
95% confidence interval of CO2-CBF reactivity was 13–
146% with a mean of 67% per kPa change (51). Doppler
ultrasound assessment of CBF in ventilated preterm
neonates (≦33w) also describes important interindividu-
al variability with a median rise of 44% per kPa increase
in CO2 during the 1st 24 h after birth and a 53%
increase thereafter (78). Of utmost interest, some infants
in this particularly vulnerable population did not
increase or even decreased CBF in response to increased
CO2 suggesting that CO2-CBF reactivity might be
absent under certain circumstances (78). In line with this
possibility, Pryds et al. examined CBF responses to CO2
in 57 preterm infant under mechanical ventilation dur-
ing the 1st 48 h following birth and found that CO2
reactivity was absent in those infants who subsequently
developed intracranial hemorrhage (66). In patients,
however, who persistently had good cerebral ultra-
sound, Xe-133 measurements revealed an 11% increase
in CBF in response to 1 kPa increase in CO2 during the
first day of extrauterine life, and this reactivity increased
to an average of 33% by the 2nd day (66). The acute
CO2-induced rapid changes in CBF are most probably
not persistent. In adults, it has been shown that compen-
satory mechanisms lead to the normalization of cerebro-
spinal fluid pH, and, as a consequence, of CBF over the
period of hours. Whether such adaptive mechanisms
occur in the human neonate has not been studied so far.
No study specifically addressed the impact of general
anesthetics on CBF and autoregulation in neonatal
populations. In healthy adults, propofol and, to some
extent, sevoflurane have been reported to decrease CBF,
while isoflurane and desflurane (up to 1.5 MAC) do not
exert such effects (79,80). Ketamine, in contrast, induces
a significant increase in CBF (81). Dose-dependent
impairment of both dynamic and static components of
cerebral autoregulation is observed upon exposure to
isoflurane and desflurane but not under propofol anes-
thesia (79). Static cerebral autoregulation remains intact
with up to 1.5 MAC of sevoflurane, and the dynamic
component is also better preserved with this volatile
agent compared with isoflurane (82,83). Dexmedetomi-
dine has been reported to weaken both dynamic and sta-
tic aspects of autoregulation (84). Fentanyl is the only
anesthetic/analgesic drug being studied for its effects on
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Pediatric Anesthesia 24 (2014) 22–29
L. Vutskits Cerebral blood flow in the neonate

cerebral blood flow in critically ill premature neonates.
Infusion of this drug up to 3 lg
kg 1 over 15 min did
not affect CBFV as evaluated by Doppler ultrasound
measurements (85).
Despite the fact that many patients at the neonatal
intensive care units receive vasopressors to increase
systemic blood pressure, the association between the
treatment for hypotension and improved outcome is still
controversial (86). Indeed, as the majority of drugs with
inotropic effects also have an impact on vasoconstric-
tion, it is plausible to think that they could induce cere-
bral vasoconstriction and, thereby, worsen outcome. In
line with this possibility, retrospective chart reviews
suggest an association between early introduction of ino-
tropic support in preterm infants with hypotension and
increased morbidity including intraventricular hemor-
rhage, periventricular leucomalacia as well as severely
impaired neurodevelopment (87,88). Based on these
observations, it remained unclear whether the need for
inotropic support is a marker or cause of these disabili-
ties. Several studies revealed the absence of CBF autore-
gulation in hypotensive preterm neonates and showed
linear changes between increased CBF and mean arterial
pressure following the administration of dopamine
(89–91). In a randomized controlled trial aimed to treat
systemic hypotension in low birth weight preterm neo-
nates, low doses of dopamine and epinephrine have
shown comparable efficacy to increase CBF (92). Neuro-
developmental follow-up of this population revealed dif-
ferences neither between the dopamine and epinephrine
groups nor in comparison with control groups (93). Alto-
gether, these data argue for the safe use of vasopressors,
at least in low doses, in these vulnerable populations.
Little is known about whether surgery and/or the
related perioperative management might impair cerebral
autoregulation. Indeed, 13% of infant undergoing
cardiopulmonary bypass and open heart surgery had
impaired autoregulatory response at 6 and 24 h
following surgery (94). Also, there was a higher preva-
lence of impaired autoregulation following surgery in
infants requiring surgical closure of patent ductus arteri-
osus compared with those who received pharmacologi-
cal treatment for closure (95). The reasons for this
association are unknown. Surgery-induced systemic
inflammatory would be one plausible candidate. Never-
theless, recent investigations showed no association
between systemic inflammation and altered CBF autore-
gulation in preterm human infants (96).
Conclusions
Despite decades of investigations, our understanding on
physiological and pathophysiological mechanisms
underlying CBF, and its autoregulation in the neonate is
still scarce. Monitoring of systemic blood pressure prob-
ably does not provide precise information on CBF and,
most importantly, on cerebral oxygenation. The high in-
terindividual variability on autoregulatory thresholds,
CBF values, and cerebral vasoreactivity further compli-
cates clinical decision making. Recent developments of
bedside measurement techniques allowing continuous
monitoring of cerebral circulation and oxygen supply
will provide valuable means in the next future to ade-
quately tailor individual patient management. Using
these technologies, prospective clinical investigations
and trials are urgently needed to gain insights into the
biology of CBF autoregulation in these particularly
vulnerable neonatal patient populations.
Acknowledgments
This research was carried out without funding.
Conflict of interest
No conflicts of interest declared.

References
1 Jevtovic-Todorovic V, Absalom AR, Blom-
gren K et al. Anaesthetic neurotoxicity and
neuroplasticity: an expert group report and
statement based on the BJA Salzburg Semi-
nar. Br J Anaesth 2013; 111: 143–151.
2 DiMaggio C, Sun LS, Ing C et al. Pediatric
anesthesia and neurodevelopmental impair-
ments: a Bayesian meta-analysis. J Neuro-
surg Anesthesiol 2012; 24: 376–381.
3 Vutskits L. General anesthesia: a gateway to
modulate synapse formation and neural
plasticity? Anesth Analg 2012; 115:
1174–1182.
4 Short BL, Van Meurs K, Evans JR. Sum-
mary proceedings from the cardiology group
on cardiovascular instability in preterm
infants. Pediatrics 2006; 117: S34–S39.
5 Tan KL. Blood pressure in full-term healthy
neonates. Clin Pediatr (Phila) 1987; 26: 21–
24.
6 Tan KL. Blood pressure in very low birth
weight infants in the first 70 days of life.
J Pediatr 1988; 112: 266–270.
7 Park MK, Lee DH. Normative arm and calf
blood pressure values in the newborn. Pedi-
atrics 1989; 83: 240–243.
8 Shortland DB, Evans DH, Levene MI.
Blood pressure measurements in very low
birth weight infants over the first week of
life. J Perinat Med 1988; 16: 93–97.
9 Bada HS, Korones SB, Perry EH et al.
Mean arterial blood pressure changes in
premature infants and those at risk for intra-
ventricular hemorrhage. J Pediatr 1990; 117:
607–614.
10 Zubrow AB, Hulman S, Kushner H et al.
Determinants of blood pressure in infants
admitted to neonatal intensive care units: a
prospective multicenter study. Philadelphia

© 2013 John Wiley & Sons Ltd 27

Pediatric Anesthesia 24 (2014) 22–29
Cerebral blood flow in the neonate
Neonatal Blood Pressure Study Group.
J Perinatol 1995; 15: 470–479.
11 Cayabyab R, McLean CW, Seri I. Definition
of hypotension and assessment of hemody-
namics in the preterm neonate. J Perinatol
2009; 29: S58–S62.
12 Dannevig I, Dale HC, Liestol K et al. Blood
pressure in the neonate: three non-invasive
oscillometric pressure monitors compared
with invasively measured blood pressure.
Acta Paediatr 2005; 94: 191–196.
13 Gevers M, van Genderingen HR, Lafeber
HN et al. Accuracy of oscillometric blood
pressure measurement in critically ill neo-
nates with reference to the arterial pressure
wave shape. Intensive Care Med 1996; 22:
242–248.
14 Crossland DS, Furness JC, Abu-Harb M
et al. Variability of four limb blood pressure
in normal neonates. Arch Dis Child Fetal
Neonatal Ed 2004; 89: F325–F327.
15 Short JA. Noninvasive blood pressure mea-
surement in the upper and lower limbs of an-
aesthetized children. Paediatr Anaesth 2000;
10: 591–593.
16 Kluckow M, Evans N. Relationship between
blood pressure and cardiac output in preterm
infants requiring mechanical ventilation.
J Pediatr 1996; 129: 506–512.
17 Kluckow M, Evans N. Superior vena cava
flow in newborn infants: a novel marker of
systemic blood flow. Arch Dis Child Fetal
Neonatal Ed 2000; 82: F182–F187.
18 Evans N, Iyer P. Assessment of ductus arteri-
osus shunt in preterm infants supported by
mechanical ventilation: effect of interatrial
shunting. J Pediatr 1994; 125: 778–785.
19 Development of audit measures and guide-
lines for good practice in the management of
neonatal respiratory distress syndrome.
Report of a Joint Working Group of the Brit-
ish Association of Perinatal Medicine and the
Research Unit of the Royal College of Physi-
cians. Arch Dis Child 1992; 67: 1221–1227.
20 Osborn DA, Evans N. Early volume expan-
sion for prevention of morbidity and mortal-
ity in very preterm infants. Cochrane
Database Syst Rev 2004; 2: CD002055.
21 Osborn DA, Paradisis M, Evans N. The
effect of inotropes on morbidity and mortal-
ity in preterm infants with low systemic or
organ blood flow. Cochrane Database Syst
Rev 2007; 1: CD005090.
22 Miall-Allen VM, de Vries LS, Whitelaw AG.
Mean arterial blood pressure and neonatal
cerebral lesions. Arch Dis Child 1987; 62:
1068–1069.
23 Watkins AM, West CR, Cooke RW. Blood
pressure and cerebral haemorrhage and
ischaemia in very low birthweight infants.
Early Hum Dev 1989; 19: 103–110.
24 Goldstein RF, Thompson RJJ, Oehler JM
et al. Influence of acidosis, hypoxemia, and
28
hypotension on neurodevelopmental out-
come in very low birth weight infants. Pediat-
rics 1995; 95: 238–243.
25 Miall-Allen VM, de Vries LS, Dubowitz LM
et al. Blood pressure fluctuation and intra-
ventricular hemorrhage in the preterm infant
of less than 31 weeks’ gestation. Pediatrics
1989; 83: 657–661.
26 Perry EH, Bada HS, Ray JD et al. Blood
pressure increases, birth weight-dependent
stability boundary, and intraventricular hem-
orrhage. Pediatrics 1990; 85: 727–732.
27 D’Souza SW, Janakova H, Minors D et al.
Blood pressure, heart rate, and skin tempera-
ture in preterm infants: associations with
periventricular haemorrhage. Arch Dis Child
Fetal Neonatal Ed 1995; 72: F162–F167.
28 Haque IU, Zaritsky AL. Analysis of the evi-
dence for the lower limit of systolic and mean
arterial pressure in children. Pediatr Crit
Care Med 2007; 8: 138–144.
29 Nafiu OO, Voepel-Lewis T, Morris M et al.
How do pediatric anesthesiologists define
intraoperative hypotension? Pediatr Anesth
2009; 19: 1048–1053.
30 Nafiu OO, Kheterpal S, Morris M et al. Inci-
dence and risk factors for preincision hypo-
tension in a noncardiac pediatric surgical
population. Pediatr Anesth 2009; 19:
232–239.
31 Schmidt CF, Kety SS. Recent studies of cere-
bral blood flow and cerebral metabolism in
man. Trans Assoc Am Physicians 1947; 60:
52–58.
32 Lassen NA, Ingvar DH. The blood flow of
the cerebral cortex determined by radioactive
krypton. Experientia 1961; 17: 42–43.
33 Zauner A, Muizelaar JP. Measuring cerebral
blood flow and metabolism. In: Reilly P,
Bullock R, eds. Head Injury. London:
Chapman & Hall, 1997: 217–227.
34 McGehee BE, Pollock JM, Maldjian JA.
Brain perfusion imaging: how does it work
and what should I use? J Magn Reson Imag-
ing 2012; 36: 1257–1272.
35 Aaslid R, Markwalder TM, Nornes H. Non-
invasive transcranial Doppler ultrasound
recording of flow velocity in basal cerebral
arteries. J Neurosurg 1982; 57: 769–774.
36 Aaslid R, Lindegaard KF, Sorteberg W et al.
Cerebral autoregulation dynamics in
humans. Stroke 1989; 20: 45–52.
37 Larsen FS, Olsen KS, Hansen BA et al.
Transcranial Doppler is valid for
determination of the lower limit of cerebral
blood flow autoregulation. Stroke 1994; 25:
1985–1988.
38 Jobsis FF. Noninvasive, infrared monitoring
of cerebral and myocardial oxygen suffi-
ciency and circulatory parameters. Science
1977; 198: 1264–1267.
39 Ferrari M, Giannini I, Sideri G et al. Contin-
uous non invasive monitoring of human
L. Vutskits
brain by near infrared spectroscopy. Adv Exp
Med Biol 1985; 191: 873–882.
40 Edwards AD, Richardson C, van der Zee P
et al. Measurement of hemoglobin flow and
blood flow by near-infrared spectroscopy.
J Appl Physiol 1993; 75: 1884–1889.
41 Meek JH, Tyszczuk L, Elwell CE et al. Cere-
bral blood flow increases over the first three
days of life in extremely preterm neonates.
Arch Dis Child Fetal Neonatal Ed 1998; 78:
F33–F37.
42 Olsen KS, Svendsen LB, Larsen FS. Valida-
tion of transcranial near-infrared spectros-
copy for evaluation of cerebral blood flow
autoregulation. J Neurosurg Anesthesiol
1996; 8: 280–285.
43 Ito H, Kanno I, Kato C et al. Database of
normal human cerebral blood flow, cerebral
blood volume, cerebral oxygen extraction
fraction and cerebral metabolic rate of
oxygen measured by positron emission
tomography with 15O-labelled carbon
dioxide or water, carbon monoxide and
oxygen: a multicentre study in Japan.
Eur J Nucl Med Mol Imaging 2004; 31:
635–643.
44 Astrup J, Symon L, Branston NM et al. Cor-
tical evoked potential and extracellular K+
and H+ at critical levels of brain ischemia.
Stroke 1977; 8: 51–57.
45 Morawetz RB, Crowell RH, DeGirolami U
et al. Regional cerebral blood flow thresh-
olds during cerebral ischemia. Fed Proc 1979;
38: 2493–2494.
46 Powers WJ, Grubb RLJ, Darriet D et al.
Cerebral blood flow and cerebral metabolic
rate of oxygen requirements for cerebral
function and viability in humans. J Cereb
Blood Flow Metab 1985; 5: 600–608.
47 Lou HC, Lassen NA, Friis-Hansen B.
Impaired autoregulation of cerebral blood
flow in the distressed newborn infant. J Pedi-
atr 1979; 94: 118–121.
48 Ment LR, Ehrenkranz RA, Lange RC et al.
Alterations in cerebral blood flow in preterm
infants with intraventricular hemorrhage.
Pediatrics 1981; 68: 763–769.
49 Greisen G. Cerebral blood flow in preterm
infants during the first week of life. Acta Pae-
diatr Scand 1986; 75: 43–51.
50 Fenton AC, Shortland DB, Papathoma E
et al. Normal range for blood flow velocity
in cerebral arteries of newly born term
infants. Early Hum Dev 1990; 22: 73–79.
51 Greisen G, Trojaborg W. Cerebral blood
flow, PaCO2 changes, and visual evoked
potentials in mechanically ventilated, pre-
term infants. Acta Paediatr Scand 1987; 76:
394–400.
52 Altman DI, Powers WJ, Perlman JM et al.
Cerebral blood flow requirement for brain
viability in newborn infants is lower than in
adults. Ann Neurol 1988; 24: 218–226.
© 2013 John Wiley & Sons Ltd
Pediatric Anesthesia 24 (2014) 22–29
L. Vutskits
53 Greisen G, Pryds O. Low CBF, discontinu-
ous EEG activity, and periventricular brain
injury in ill, preterm neonates. Brain Dev
1989; 11: 164–168.
54 Pryds O, Greisen G. Preservation of single-
flash visual evoked potentials at very low
cerebral oxygen delivery in preterm infants.
Pediatr Neurol 1990; 6: 151–158.
55 McCall ML. Cerebral circulation and metab-
olism in toxemia of pregnancy; observations
on the effects of veratrum viride and apreso-
line (1-hydrazinophthalazine). Am J Obstet
Gynecol 1953; 66: 1015–1030.
56 Lassen NA. Cerebral blood flow and oxygen
consumption in man. Physiol Rev 1959; 39:
183–238.
57 Moyer JH, Morris G. Cerebral hemodynam-
ics during controlled hypotension induced by
the continuous infusion of ganglionic block-
ing agents (hexamethonium, pendiomide and
arfonad). J Clin Invest 1954; 33: 1081–1088.
58 Drummond JC. The lower limit of autoregu-
lation: time to revise our thinking? Anesthesi-
ology 1997; 86: 1431–1433.
59 Strandgaard S. Autoregulation of cerebral
blood flow in hypertensive patients. The
modifying influence of prolonged antihyper-
tensive treatment on the tolerance to acute,
drug-induced hypotension. Circulation 1976;
53: 720–727.
60 Waldemar G, Schmidt JF, Andersen AR
et al. Angiotensin converting enzyme inhibi-
tion and cerebral blood flow autoregulation
in normotensive and hypertensive man.
J Hypertens 1989; 7: 229–235.
61 Olsen KS, Svendsen LB, Larsen FS et al.
Effect of labetalol on cerebral blood flow,
oxygen metabolism and autoregulation in
healthy humans. Br J Anaesth 1995; 75:
51–54.
62 Purves MJ, James IM. Observations on the
control of cerebral blood flow in the sheep
fetus and newborn lamb. Circ Res 1969; 25:
651–667.
63 Papile LA, Rudolph AM, Heymann MA.
Autoregulation of cerebral blood flow in the
preterm fetal lamb. Pediatr Res 1985; 19:
159–161.
64 Lou HC, Lassen NA, Friis-Hansen B. Low
cerebral blood flow in hypotensive perinatal
distress. Acta Neurol Scand 1977; 56: 343–
352.
65 Tyszczuk L, Meek J, Elwell C et al. Cerebral
blood flow is independent of mean arterial
blood pressure in preterm infants undergoing
intensive care. Pediatrics 1998; 102: 337–341.
66 Pryds O, Greisen G, Lou H et al. Heteroge-
neity of cerebral vasoreactivity in preterm
infants supported by mechanical ventilation.
J Pediatr 1989; 115: 638–645.
67 Boylan GB, Young K, Panerai RB et al.
Dynamic cerebral autoregulation in sick new-
born infants. Pediatr Res 2000; 48: 12–17.
© 2013 John Wiley & Sons Ltd
Pediatric Anesthesia 24 (2014) 22–29
68 Tsuji M, Saul JP, du Plessis A et al. Cerebral
intravascular oxygenation correlates with
mean arterial pressure in critically ill prema-
ture infants. Pediatrics 2000; 106: 625–632.
69 Soul JS, Hammer PE, Tsuji M et al. Fluctu-
ating pressure-passivity is common in the
cerebral circulation of sick premature infants.
Pediatr Res 2007; 61: 467–473.
70 Alderliesten T, Lemmers PM, Smarius JJ
et al. Cerebral oxygenation, extraction, and
autoregulation in very preterm infants who
develop peri-intraventricular hemorrhage.
J Pediatr 2013; 162: 698–704.e2.
71 Wong FY, Leung TS, Austin T et al.
Impaired autoregulation in preterm infants
identified by using spatially resolved
spectroscopy. Pediatrics 2008; 121: e604–
e611.
72 Kety SS, Schmidt CF. The effects of altered
arterial tensions of carbon dioxide and oxy-
gen on cerebral blood flow and cerebral oxy-
gen consumption of normal young men.
J Clin Invest 1948; 27: 484–492.
73 Aalkjaer C, Poston L. Effects of pH on vas-
cular tension: which are the important mech-
anisms? J Vasc Res 1996; 33: 347–359.
74 Persson PB. Modulation of cardiovascular
control mechanisms and their interaction.
Physiol Rev 1996; 76: 193–244.
75 Greisen G, Vannucci RC. Is periventricular
leucomalacia a result of hypoxic-ischaemic
injury? Hypocapnia and the preterm brain.
Biol Neonate 2001; 79: 194–200.
76 Rahilly PM. Effects of 2% carbon dioxide,
0.5% carbon dioxide, and 100% oxygen on
cranial blood flow of the human neonate.
Pediatrics 1980; 66: 685–689.
77 Leahy FA, Cates D, MacCallum M et al.
Effect of CO2 and 100% O2 on cerebral
blood flow in preterm infants. J Appl Physiol
1980; 48: 468–472.
78 Levene MI, Shortland D, Gibson N et al.
Carbon dioxide reactivity of the cerebral cir-
culation in extremely premature infants:
effects of postnatal age and indomethacin.
Pediatr Res 1988; 24: 175–179.
79 Strebel S, Lam AM, Matta B et al. Dynamic
and static cerebral autoregulation during iso-
flurane, desflurane, and propofol anesthesia.
Anesthesiology 1995; 83: 66–76.
80 Kaisti KK, Langsjo JW, Aalto S et al.
Effects of sevoflurane, propofol, and adjunct
nitrous oxide on regional cerebral blood
flow, oxygen consumption, and blood vol-
ume in humans. Anesthesiology 2003; 99:
603–613.
81 Strebel S, Kaufmann M, Maitre L et al.
Effects of ketamine on cerebral blood flow
velocity in humans. Influence of pretreatment
with midazolam or esmolol. Anaesthesia
1995; 50: 223–228.
82 Gupta S, Heath K, Matta BF. Effect of
incremental doses of sevoflurane on cerebral
Cerebral blood flow in the neonate
pressure autoregulation in humans. Br J Ana-
esth 1997; 79: 469–472.
83 Summors AC, Gupta AK, Matta BF.
Dynamic cerebral autoregulation during
sevoflurane anesthesia: a comparison with
isoflurane. Anesth Analg 1999; 88: 341–345.
84 Ogawa Y, Iwasaki K, Aoki K et al. Dex-
medetomidine weakens dynamic cerebral au-
toregulation as assessed by transfer function
analysis and the thigh cuff method. Anesthe-
siology 2008; 109: 642–650.
85 Hamon I, Hascoet JM, Debbiche A et al.
Effects of fentanyl administration on general
and cerebral haemodynamics in sick newborn
infants. Acta Paediatr 1996; 85: 361–365.
86 Azhan A, Wong FY. Challenges in under-
standing the impact of blood pressure man-
agement on cerebral oxygenation in the
preterm brain. Front Physiol 2012; 3: 471.
87 Fanaroff JM, Wilson-Costello DE, Newman
NS et al. Treated hypotension is associated
with neonatal morbidity and hearing loss in
extremely low birth weight infants. Pediatrics
2006; 117: 1131–1135.
88 Kuint J, Barak M, Morag I et al. Early trea-
ted hypotension and outcome in very low
birth weight infants. Neonatology 2009; 95:
311–316.
89 Seri I, Rudas G, Bors Z et al. Effects of low-
dose dopamine infusion on cardiovascular
and renal functions, cerebral blood flow, and
plasma catecholamine levels in sick preterm
neonates. Pediatr Res 1993; 34: 742–749.
90 Munro MJ, Walker AM, Barfield CP. Hypo-
tensive extremely low birth weight infants
have reduced cerebral blood flow. Pediatrics
2004; 114: 1591–1596.
91 Lundstrom K, Pryds O, Greisen G. The hae-
modynamic effects of dopamine and volume
expansion in sick preterm infants. Early Hum
Dev 2000; 57: 157–163.
92 Pellicer A, Valverde E, Elorza MD et al. Car-
diovascular support for low birth weight
infants and cerebral hemodynamics: a ran-
domized, blinded, clinical trial. Pediatrics
2005; 115: 1501–1512.
93 Pellicer A, Bravo MC, Madero R et al. Early
systemic hypotension and vasopressor
support in low birth weight infants: impact
on neurodevelopment. Pediatrics 2009; 123:
1369–1376.
94 Bassan H, Gauvreau K, Newburger JW et al.
Identification of pressure passive cerebral
perfusion and its mediators after infant car-
diac surgery. Pediatr Res 2005; 57: 35–41.
95 Chock VY, Ramamoorthy C, Van Meurs
KP. Cerebral autoregulation in neonates with
a hemodynamically significant patent ductus
arteriosus. J Pediatr 2012; 160: 936–942.
96 Hahn GH. Testing impact of perinatal
inflammation on cerebral autoregulation in
preterm neonates: evaluation of a noninva-
sive method. Dan Med J 2013; 60: B4628.
29