Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59

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Seminars in Fetal & Neonatal Medicine

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Neonatal hypotension: Dopamine or dobutamine?

Samir Gupta a, *, Steven M. Donn b
a
Department of Paediatrics, University Hospital of North Tees and University of Durham, Stockton-on-Tees, UK
b
Department of Pediatrics, Division of NeonatalePerinatal Medicine, C.S. Mott Childrens Hospital, University of Michigan Health System, Ann Arbor, MI,
USA

s u m m a r y
Keywords: Controversy surrounds the assessment of perfusion and the methods currently utilised to dene hypo-
Circulation tension, especially blood pressure. There is growing agreement to assess heart function when selecting
Dobutamine
inotropic therapy and use bedside tools such as echocardiography for assessing at-risk infants. Both
Dopamine
Hypotension
dopamine and dobutamine have comparative efcacy, and in certain disease states with immature
Inotrope myocardium there could be potential advantages in using dobutamine. The concomitant use of hydro-
Newborn cortisone has been shown to be benecial when escalating doses of rst-line inotropes are used. Other
inotropes require further study through randomised trials for their safety and efcacy to be established.
2013 Published by Elsevier Ltd.

1. Introduction
Neonatal hypotension is dened as a clinical condition of
abnormally low arterial blood pressure affecting perfusion. There is
little disagreement that inadequate perfusion or poor circulation
should be treated. However, disagreement abounds as to what
standards or thresholds should be utilised to trigger treatment of
such infants, and which agent or agents should be used [1].
The denition of hypotension in newborn has a number of
limitations. Unlike adults, newborn babies are delivered at different
gestational ages and there is no single accepted value that denes
low blood pressure. What to measure has been a subject of debate
and clinicians have used either systolic or mean blood pressure
values in newborn infants to dene hypotension [2]. For such a
common problem, with an absence of a single standard, clinicians
have adopted different approaches for managing hypotension in
newborn infants. A wide gestational age range, different patho-
physiologic states underlying poor perfusion, and the transition
from fetal to adult circulation further complicate the question, and
clinicians often nd it difcult to utilise the available data to make
informed choices for selecting the most appropriate inotrope [3].
Poor perfusion can result from persistence of fetal channels such
as the ductus arteriosus, loss of blood, immature myocardium, or
ischaemic damage after hypoxic injury, and as a manifestation of
sepsis or underlying heart disease. It is not possible to treat all of
* Corresponding author. Address: Department of Paediatrics and Neonatal
Medicine, University Hospital of North Tees, Hardwick Road, Stockton-on-Tees TS19
8PE, UK. Tel.: 44 (0) 1642 624232.
E-mail address: Samir.gupta@nth.nhs.uk (S. Gupta).
the above utilizing the same approach, and hence the selection of
specic inotrope requires more information than just a blood
pressure reading to target the therapy to the underlying problem.
With availability of bedside assessment tools such as echocardi-
ography, it is becoming clear that we need to modify our approach
and utilise more objective information before instituting treatment.
However, because of the limited techniques and skills for this
bedside assessment, blood pressure still remains the gold standard
to initiate or titrate the drugs used for managing poor perfusion.
In this review we limit the discussion to the controversy of
blood pressure, tools and techniques for non-invasive haemody-
namic assessments, and the current evidence regarding the use of
inotropes for managing neonatal hypotension. We suggest an
approach to manage poor perfusion. The recommendations should
be integrated with the advanced life support scheme (Neonatal Life
Support/Neonatal Resuscitation Program) and be amalgamated
with the stepwise approach of managing airway, breathing and
circulation [4].
2. The blood pressure controversy
Blood pressure is given great attention, as hypotension in the
newborn has been associated with impaired cerebral perfusion
and ischaemic damage [5]. The arterial pressure is determined
by two factors: the propulsion of blood from the heart (cardiac
output) and the resistance to the ow of this blood through the
blood vessels (arteriolar tone or vascular resistance). Thus
ow pressure O resistance, or pressure ow  resistance [6].
Low blood pressure could thus be caused by a decrease in ow
(cardiac output), a fall in resistance, or both. Measurement of ow,

1744-165X/$ e see front matter 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.siny.2013.09.006
 S. Gupta, S.M. Donn / Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59 55

however, requires advanced assessment techniques, and despite Table 1

advances in technology, this tool is still not widely available. The Methods for haemodynamic assessment.

resistance can only be calculated e not measured e but clinicians
routinely rely on blood pressure determinations to gauge the ad-
equacy of cardiac output and systemic perfusion. There could be
increase in resistance with a drop in cardiac output or vice versa
with minimal changes in blood pressure but considerable impair-
ment of tissue perfusion. The issue becomes even more compli-
cated when the fetal channels remain open during transitional
circulation.
The gold standard for determination of blood pressure is intra-
arterial measurement using an umbilical arterial catheter or pe-
ripheral arterial line. However, in many situations the clinician has
to rely on non-invasive blood pressure measurements. Often, too
little attention is paid to the accuracy of these measurements.
Although oscillometric methods of measuring blood pressure are
widely used, neonatal readings are of limited accuracy, and the
technique becomes least reliable when it needs to be most reliable
e in babies with clinically signicant hypotension. Fortunately,
there is good agreement between intravascular and indirect
Doppler measurements of systolic pressure, and between intra-
vascular and pulse oximetry technique measurements throughout
the blood pressure range [7,8].
What should be measured: systolic or mean pressures? The
systolic pressure is the amount of pressure that blood exerts on
arteries and vessels while the heart is beating, whereas the mean
pressure is the average arterial pressure during a single cardiac
cycle. Mean blood pressure is derived using systolic and diastolic
pressure values [(diastolic pressure  2) (systolic pressure) O 3].
The measurement of mean blood pressure was suggested because it
was thought to be free of the artefacts caused by resonance,
thrombi, and air bubbles, when measured intravascularly, but this
may not always be true. The correlation between systolic pressure
measurements in nearly 400 preterm babies in the rst 10 days and
their long-term outcomes at age 2 years in non-disabled children
suggest that values below the third percentile of systolic blood
pressure in the rst 4e24 h of life approximates the gestational age
(in weeks), and that these are associated with impairment in long-
term outcome [7]. Zubrow et al. [9] also observed similar ndings,
with the lower 95% condence limits equal to gestational age, but
with a narrow range. Yet, the majority of clinicians target a mean
blood pressure greater than the gestational age. Dempsey and
Barrington [10] criticised this notion, suggesting that the recom-
mendation was made without supporting data. Other studies have
reported a cut-off for acceptable mean blood pressure at 30 mmHg
based on the ndings that the lower limit of the cerebral blood ow
autoregulation was near 30 mmHg [11]. This hypothesis is, how-
ever, not supported by any substantial longitudinal long-term
outcome data. Additionally, there is a progressive rise in blood
pressure during the rst week of life in very preterm babies. This
uncertainty of what to measure is presently weighted by the ease
of use rather than the evidence, and a majority of clinicians still
seem to use the gestational age as the cut-off value of mean blood
pressure for the reasons described above.
3. Blood ow and systemic venous return
The adult cardiac physiology of systemic ow equals left ven-
tricular output does not hold true for newborn babies with open
fetal channels [12]. In these infants, the patent ductus arteriosus
(PDA), an extracardiac shunt, causes additional volume loading of
the left ventricle. Thus, left ventricular output (LVO) reects the
volume of blood perfusing the lungs and is the summation of right
ventricular output and the volume of blood shunting across the
PDA. In these situations the right ventricular output (RVO)
Clinical Non-invasive Invasive
Heart Heart rate Echocardiogram Intracardiac
(pump) Electrocardiogram catheterization
Non-invasive cardiac
output monitoring
Artery Pulse volume Non-invasive blood Intra-arterial
(after-load) pressure blood pressure
Capillary Capillary rell Pulse-oximetry e
Transcutaneous
oximetry
End-organ Urine output Near infra-red Arterial blood gas
(perfusion) Skin colour spectroscopy Mixed venous
Coreeperipheral saturation
temperature
difference
Lactate
Veins Jugular venous Echocardiography Central venous pressure
(pre-load) pressure
measured at the pulmonary valve equals the systemic ow, as it is
comprised of blood returning from the superior and inferior venae
cavae. However, in the presence of a patent foramen ovale (PFO), an
inter-atrial shunt, this RVO is overestimated depending on the
volume of shunt across the PFO [13]. These estimations of cardiac
output in preterm infants with open fetal channels should thus be
interpreted cautiously, keeping in mind the aforesaid physiologic
considerations.
Clinicians have been interested in the estimations of superior
vena cava (SVC) ow over the last decade. Fetal channels do not
affect SVC ow measurement and reect the venous return from
the upper body and brain [14]. The bedside measurements of SVC
ow using echocardiography correlated well with intraventricular
haemorrhage and poor outcome [14,15]. Clinicians adopted this
approach and started estimating the ventricular function and the
SVC ow to identify those babies who would benet from inotropic
support. A cut-off value of 40 ml/kg/min was suggested as a
threshold, and values below this in the rst 24 h were interpreted
as abnormal [14].
When the SVC ow measurements and simultaneous recording
of blood pressure were compared, the results pointed out the lim-
itations of blood pressure for making informed decisions for treat-
ment of hypotension. There was a group of babies in whom the
blood pressure was reported to be normal (mean BP >30 mmHg)
but their SVC ows were <40 ml/kg/min, suggesting poor cardiac
output with normal or increased vascular tone [16,17]. Such babies
benet from inotropic support early (rather than vasopressor sup-
port), such as extreme preterm babies with poor myocardial re-
serves and function. There was another group of babies with low
blood pressure but with normal SVC ow, suggesting normal or
high cardiac output with poor vascular tone. These babies are
usually identied clinically using vital signs and they benet from
inotropic support that improves vascular tone. Thus, isolated
assessment of blood pressure or measurement of SVC ow would
not help targeting the therapy to the underlying problem, but, when
combined, could help in selecting the appropriate drug and institute
the therapy directed to the pathology (problem-based therapy).
Recently, Groves et al. [17] challenged the measurement of SVC
ow. They compared the SVC diameters computed using echocar-
diography and magnetic resonance imaging (MRI). It was suggested
that SVC ow is not reproducible as the vessels cross-sectional area
is not circular but crescentic, indented by the adjacent aorta. Thus,
the physics of measurement introduces error in calculation.
How to assess perfusion to measure the effects of therapy is
another subject of debate. One can divide the methods for
56 S. Gupta, S.M. Donn / Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59

haemodynamic assessment into clinical, non-invasive, and invasive Table 2

methods. The evaluation can be directed to assessment of the heart, Mechanisms of action of dopamine.

arteriolar tone, capillary oxygenation, end-organ perfusion, capac- Adrenergic, dopaminergic and vasopressin receptors
itance and ow in central veins (Table 1). Using this approach, a a1/a2 b2 a1 b1/b2 DA1/DA2 V1a
detailed assessment of perfusion can be undertaken. However, for Vascular Vascular Cardiac Cardiac Vascular/cardiac Vascular
routine bedside decision-making, the busy clinician requires
Phenylephrine 0 0 0 0
pragmatic and sensitive methods. Various methods have been Norepinephrine 0/ 0 0
evaluated as part of research, but there are limited data to adopt a Epinephrine 0 0
particular approach. Dopaminea 0
Dobutamineb /0 0 0
The clinical signs to assess end-organ perfusion are widely used.
Isoprenaline 0 0 0
However, the sensitivity and specicity of these is poor in diag- Vasopressin 0 0 0 0 0
nosing or excluding low perfusion states [18]. Near-infrared spec- PDE-III inhibitors 0 0 0 0 0 0
troscopy (NIRS) is another tool that is mainly used for research and PDE-V inhibitors 0 0 0 0 0 0
can be utilised with encouraging results to assess cerebral perfu- a
Dopamine also has serotoninergic actions.
sion and oxygen extraction [19]. Bedside echocardiography is now b
Dobutamines efcacy is independent of afnity for adrenergic receptors.
increasingly used for assessing the contractility and function of
heart, and in a recent survey 75% of tertiary neonatal units in regarding the vasodilator effects in the renal, coronary, and cerebral
Europe had at least one clinician with echocardiography skills [20]. vascular beds [23].
In Europe and Australasia functional echocardiography is routinely Dobutamine is a synthetic catecholamine with predominantly
used to evaluate lling of the heart, computing cardiac outputs, and beta-adrenergic actions [22]. It has been suggested to offer the
assessing pulmonary hypertension and haemodynamically signi- same inotropic effects as dopamine without the tendency for pe-
cant PDA. The Targeted Neonatal Echocardiography consensus ripheral vasoconstriction (Fig. 2 and Table 2).
statement was published recently to develop standards of practice, The optimum doses of dopamine and dobutamine for treating
training, and accreditation [21]. Cardiac MRI for functional assess- hypotensive preterm infants are uncertain. Pharmacokinetic
ment of newborns is now being evaluated and initial reports seem studies demonstrate wide variations in plasma concentrations
promising. among individuals for a given dose of dopamine or dobutamine.
This is likely related to the differences in plasma clearance rates
4. Pharmacology of dopamine and dobutamine that are independent of birth weight and gestational age. In addi-
tion, there is poor correlation between plasma dopamine or
The two most widely used inotropes in the neonatal intensive dobutamine concentration and blood pressure responses [24]. Early
care unit are dopamine and dobutamine. Dopamine is a naturally studies of dopamine in infants and older children suggested that
occurring precursor of noradrenaline, and has specic dopami- high doses (>10 mg/kg/min) might be necessary to treat hypoten-
nergic actions in addition to well-recognised alpha- and beta- sion. Randomised controlled trials comparing dopamine with
adrenergic effects [22]. The inotropic and peripheral vasocon- either colloid infusion or corticosteroid therapy in hypotensive
strictor effects of dopamine predominate in the newborn period preterm infants demonstrated that successfully treated infants will
(Fig. 1 and Table 2). There is, however, considerable controversy respond at a median dose of 7.5e10 mg/kg/min [25]. However,

Fig. 1. Dose-dependent effects of dopamine in neonates. *Without adrenoreceptor downregulation. #Demonstrated effects in preterm neonates.
 S. Gupta, S.M. Donn / Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59
Fig. 2. Cardiovascular effects of dobutamine neonates. *Without adrenoreceptor downregulation. #Demonstrated effects in preterm neonates.
uncontrolled studies in preterm infants demonstrated that lower-
dose therapy (2e8 mg/kg/min) may also be effective in some in-
dividuals [26]. There are few studies of dobutamine in neonates. A
positive effect on left ventricular performance was demonstrated at
doses of 5 and 10 mg/kg/min in term and preterm infants [27].
5. Which inotrope: dopamine or dobutamine?
There is considerable controversy as to whether dopamine or
dobutamine should be the rst-line pharmacological agent for the
treatment of neonatal hypotension. Proponents of dopamine often
argue that it brings about a faster and more effective increase in
blood pressure. This is not surprising, since it is a potent vasocon-
strictor. However, proponents of dobutamine argue that because of
this intense vasoconstriction, tissue perfusion is further compro-
mised because of decreased blood ow.
Dopamine and dobutamine have been compared in randomised
controlled trials, but these hardly resolve the controversy. The re-
sults of Cochrane meta-analysis suggest the superiority of dopa-
mine over dobutamine [28]. The same conclusions are also
suggested in the European consensus guidelines for management
of neonatal respiratory distress syndrome [29]. The included
studies found benets of dopamine over dobutamine only for
short-term outcomes such as improvement in blood pressure.
However, there were no differences between the two drugs for
mortality by 28 days, severe intraventricular haemorrhage or per-
iventricular leucomalacia, and none of the studies reported any
long-term outcomes. Additionally, the majority of studies were
done in the early 1990s and the most recent published in 2000 [28].
The conclusion from just 209 babies enrolled in ve trials in this
review makes it difcult to draw any meaningful conclusions.
Additionally, most of the studies were done prior to the widespread
use of antenatal steroids and surfactant replacement therapy.
In the last decade studies have utilised assessment of ows in
addition to blood pressure measurements, and they have also
57
evaluated long-term outcomes. The study by Osborn et al. [30]
quantied SVC ow during rst 24 h and randomised very pre-
term babies to dobutamine or dopamine at 10 mg/kg/min after
giving one uid bolus of 10 ml/kg if SVC ow was <41 ml/kg/min.
They reported greater increase in blood ow with dobutamine
compared with dopamine at 24 h (RVO 295 vs 167 ml/kg/min,
P < 0.001) in 42 study infants. Almost 40% of babies failed to in-
crease or maintain SVC ow in response to either inotrope, even at
20 mg/kg/min. Subsequently, this group of investigators followed
the babies with low SVC ow up to 3 years age and reported that
early low SVC ow was associated with substantial rates of death,
morbidity, and developmental impairments. In this small study,
they found no difference in the combined outcome of death and
disability for infants assigned to either dopamine or dobutamine
[31]. In another study, Filippi et al. [32] compared endocrine effects
of dopamine and dobutamine in 35 hypotensive very-low-birth-
weight babies. They reported dobutamine did not alter any hor-
mone concentrations (TSH, T4, prolactin and growth hormone), but
dopamine produced reversible reduction of all these. Robel-Tillig
et al. [33] studied the effect of dobutamine in neonates with
myocardial dysfunction and reported that the drug improved car-
diac functional parameters after 20 min and maintained the in-
uence on blood ow in the anterior cerebral artery and superior
mesenteric artery 8e10 h after administration [33]. In refractory
hypotension and among infants requiring dopamine >10 mg/kg/
min, Ng et al. [34] reported advantages to adding low-dose hy-
drocortisone early in management, as it led to signicantly less
need for a second inotrope and also facilitated early weaning from
inotropic support.
The effect of dobutamine on CBF in preterm babies has not been
studied. Using Xe clearance, Lundstrom et al. [35] showed that
dopamine, although increasing LVO and MBP, did not increase CBF.
In an open-label observational study, Munro et al. [11] used NIRS to
show an increase in mean CBF after dopamine had been given to a
cohort of 12 preterm babies with MBP <30 mmHg. A large
58 S. Gupta, S.M. Donn / Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59
European-funded project (NEO-CIRC trial) is preparing to assess
safety and efcacy of dobutamine as a rst-line inotrope for all
gestational ages using assessment of SVC ow. Another European
FP7-funded HIP trial is currently in planning. This is a large prag-
matic, multinational, randomised trial of two different strategies
for the management of hypotension in extremely low-gestational-
age newborns comparing dopamine versus a restricted approach
using placebo (http://www.clinicaltrials.gov). The primary
outcome of the trial is to determine whether there is any difference
in the approach to improve survival without signicant brain injury
at 36 weeks of postmenstrual age (PMA) and survival without
moderate or severe neurodevelopmental disability at 2 years of
corrected age. A single centre trial (TOHOP) is currently recruiting
very preterm babies to assess routine management using inotropes
versus a restrictive approach for treating hypotension. It is hoped
that the results of these trials will address whether the currently
practised proactive approach of treating blood pressure has any
advantages over a more restrictive approach.
6. Other alternative inotropes
6.1. Adrenaline
Adrenaline infusions are frequently used in neonates for the
treatment of hypotension and pulmonary hypertension [36].
Adrenaline has both alpha- and beta-receptor agonist effects. At
low dose it is a potent inotrope, chronotrope, and systemic and
pulmonary vasodilator. At higher doses it has differential effects on
the systemic and pulmonary circulations, increasing systemic
pressure more than pulmonary pressure [37]. Animal studies
demonstrate improvement in cardiac output, myocardial perfusion,
and increased mesenteric vascular resistance [38]. Reported
adverse effects of adrenaline infusion in the neonate include in-
creases in peripheral vascular resistance leading to decreased car-
diac output and tissue perfusion, hypertension, tachycardia, and
severe tissue necrosis with extravasation [39]. There is a paucity of
published studies regarding the circulatory effects of adrenaline
infusion in the neonate.
6.2. Milrinone
Milrinone is a phosphodiesterase III inhibitor that increases the
bioavailability of cyclic adenosine monophosphate and has been
shown to improve pulmonary haemodynamics in animal models.
The drug was compared with placebo to assess the effectiveness in
prevention of low systemic blood ow in high-risk preterm infants.
In this double-blind, randomised, placebo-controlled trial 90 in-
fants born at <30 weeks of gestational age and age <6 h were
randomised to milrinone (loading dose 0.75 mg/kg/min for 3 h, then
maintenance 0.2 mg/kg/min until 18 h after birth) or placebo. The
primary outcome was maintenance of SVC ow 45 mL/kg/min
through the rst 24 h. The results showed no differences in pre-
venting low systemic blood ow [40]. However, in another small
pilot study in term infants with pulmonary hypertension, milrinone
was reported to improve oxygenation and pulmonary and systemic
haemodynamics in patients with suboptimal response to inhaled
nitric oxide [41]. More data are required for this promising drug.
6.3. Vasopressin
Arginine vasopressin (AVP) is a neuropeptide hormone secreted
by the posterior pituitary that regulates sodium homeostasis and
serum osmolality. AVP is released into the circulation in response to
high plasma osmolality or as a baroreceptor response to hypo-
volaemia. AVP mediates the cardiovascular and renal effects via at
least three known receptor subtypes (V1, V2 and V3). AVP exerts a
direct vasoconstrictive effect by acting on the V1 receptors that are
predominantly found on vascular smooth muscle cells and
myocardium. Currently, AVP and its analogue, terlipressin, are
increasingly being used as a rescue therapy for hypotension re-
fractory to high-dose catecholamine and corticosteroids in neo-
nates with sepsis [42], cardiogenic shock, necrotizing enterocolitis
[43], non-septic shock with acute renal injury, and systemic in-
ammatory response syndrome following surgery [44].
7. Conclusion
The choice of inotropes in clinical practice is still largely guided
by the clinicians personal preference rather than by the evidence
base, and the parameters utilised for decision-making are currently
debated. The objective role of echocardiography and other assess-
ment tools is now increasingly recognised when diagnosing
whether the problem is primarily pump, pre-load, or after-load.
Close monitoring and titration of inotropes is required with
objective bedside assessment with an aim to improve tissue
perfusion rather than chasing the numbers.
Practice points
 Blood pressure, though easy to measure, is only one
element of tissue perfusion and oxygen delivery.
 Controversy still exists over the threshold for
intervention.
 The most widely used pharmaceutical agents are dopa-
mine and dobutamine. Their mechanisms of action are
different, and sufficient comparative trials are lacking.
 Functional echocardiography and assessment of vena
cava flow are under-utilised technologies.
Research directions
 Establish the roles of functional echocardiography and
assessment of vena cava flow in the diagnosis and
treatment of neonatal hypotension.
 Clinical trials of dopamine versus dobutamine to assess
long-term outcomes.
 Evaluation of other vasoactive drugs, such as adrenaline,
milrinone, vasopressin, and hydrocortisone to develop an
evidence base for the treatment of neonatal hypotension.
Conict of interest statement
None declared.
Funding sources
None.
References
[1] Short BL, Van Meurs K, Evans JR. Summary proceedings from the cardiology
group on cardiovascular instability in preterm infants. Pediatrics 2006;117(3
Pt 2):S34e9.
[2] Sundaram JMP, Gupta S. Cardiovascular assessment and management practice
in neonatal intensive care units across United Kingdom. Arch Dis Child Fetal
Neonatal Ed 2008;93:272 (abstract).
[3] Evans N. Which inotrope for which baby? Arch Dis Child Fetal Neonatal Ed
2006;91:F213e20.
 S. Gupta, S.M. Donn / Seminars in Fetal & Neonatal Medicine 19 (2014) 54e59
[4] Wyllie J, Perlman JM, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al.
Part 11: neonatal resuscitation: 2010 international consensus on cardiopul-
monary resuscitation and emergency cardiovascular care science with treat-
ment recommendations. Resuscitation 2010;81(Suppl. 1):e260e87.
[5] Miall-Allen VM, de Vries LS, Whitelaw AG. Mean arterial blood pressure and
neonatal cerebral lesions. Arch Dis Child 1987;62:1068e9.
[6] Guyton AC, Hall JE. Guyton and Hall textbook of medical physiology with
student consult online access. 11th ed. Philadelphia: Elsevier Saunders; 2006.
ISBN 0-7216-0240-1.
[7] Systolic blood pressure in babies of less than 32 weeks gestation in the rst
year of life. Northern Neonatal Nursing Initiative. Arch Dis Child Fetal
Neonatal Ed 1999;80:F38e42.
[8] Langbaum M, Eyal FG. A practical and reliable method of measuring blood
pressure in the neonate by pulse oximetry. J Pediatr 1994;125:591e5.
[9] Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure
in infants admitted to neonatal intensive care units: a prospective multicenter
study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol 1995;15:
470e9.
[10] Dempsey EM, Barrington KJ. Treating hypotension in the preterm infant:
when and with what: a critical and systematic review. J Perinatol 2007;27:
469e78.
[11] Munro MJ, Walker AM, Bareld CP. Hypotensive extremely low birth weight
infants have reduced cerebral blood ow. Pediatrics 2004;114:1591e6.
[12] Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants
supported by mechanical ventilation: effect of interatrial shunting. J Pediatr
1994;125(5 Pt 1):778e85.
[13] Evans N, Iyer P. Incompetence of the foramen ovale in preterm infants sup-
ported by mechanical ventilation. J Pediatr 1994;125(5 Pt 1):786e92.
[14] Kluckow M, Evans N. Superior vena cava ow in newborn infants: a novel
marker of systemic blood ow. Arch Dis Child Fetal Neonatal Ed 2000;82:
F182e7.
[15] Kluckow M, Evans N. Low superior vena cava ow and intraventricular hae-
morrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F188e
94.
[16] Kluckow M, Evans N. Relationship between blood pressure and cardiac output
in preterm infants requiring mechanical ventilation. J Pediatr 1996;129:506e
12.
[17] Groves AM, Chiesa G, Durighel G, Goldring ST, Fitzpatrick JA, Uribe S, et al.
Functional cardiac MRI in preterm and term newborns. Arch Dis Child Fetal
Neonatal Ed 2011;96:F86e91.
[18] Osborn DA, Evans N, Kluckow M. Clinical detection of low upper body blood
ow in very premature infants using blood pressure, capillary rell time, and
central-peripheral temperature difference. Arch Dis Child Fetal Neonatal Ed
2004;89:F168e73.
[19] Caicedo A, Naulaers G, Lemmers P, van Bel F, Wolf M, Van Huffel S. Detection
of cerebral autoregulation by near-infrared spectroscopy in neonates: per-
formance analysis of measurement methods. J Biomed Opt 2012;17:117003.
[20] Roehr CC, Te Pas AB, Dold SK, Breindahl M, Blennow M, Rudiger M, et al.
Investigating the European perspective of neonatal point-of-care echocardi-
ography in the neonatal intensive care unit-a pilot study. Eur J Pediatr
2013;172:907e11.
[21] Mertens L, Seri I, Marek J, Arlettaz R, Barker P, McNamara P, et al. Targeted
Neonatal Echocardiography in the Neonatal Intensive Care Unit: practice
guidelines and recommendations for training. Writing Group of the American
Society of Echocardiography (ASE) in collaboration with the European Asso-
ciation of Echocardiography (EAE) and the Association for European Pediatric
Cardiologists (AEPC). J Am Soc Echocardiogr 2011;24:1057e78.
[22] Keeley SR, Bohn DJ. The use of inotropic and afterload-reducing agents in
neonates. Clin Perinatol 1988;15:467e89.
[23] Barrington KJ. Circulatory effects of dopamine in neonates. J Pediatr 1995;127:
843e4.
59
[24] Bhatt-Mehta V, Nahata MC, McClead RE, Menke JA. Dopamine pharmacoki-
netics in critically ill newborn infants. Eur J Clin Pharmacol 1991;40:593e7.
[25] Bourchier D, Weston PJ. Randomised trial of dopamine compared with hy-
drocortisone for the treatment of hypotensive very low birthweight infants.
Arch Dis Child Fetal Neonatal Ed 1997;76:F174e8.
[26] Seri I, Rudas G, Bors Z, Kanyicska B, Tulassay T. Effects of low-dose dopamine
infusion on cardiovascular and renal functions, cerebral blood ow, and
plasma catecholamine levels in sick preterm neonates. Pediatr Res 1993;34:
742e9.
[27] Stopfkuchen H, Queisser-Luft A, Vogel K. Cardiovascular responses to dobut-
amine determined by systolic time intervals in preterm infants. Crit Care Med
1990;18:722e4.
[28] Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive pre-
term infants. Cochrane Database Syst Rev 2000;(2):CD001242.
[29] Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European
consensus guidelines on the management of neonatal respiratory distress
syndrome in preterm infants e 2013 update. Neonatology 2013;103:353e68.
[30] Osborn D, Evans N, Kluckow M. Randomised trial of dobutamine versus
dopamine in preterm infants with low systemic blood ow. J Pediatr
2002;140:183e91.
[31] Osborn DA, Evans N, Kluckow M, Bowen JR, Rieger I. Low superior vena cava
ow and effect of inotropes on neurodevelopment to 3 years in preterm in-
fants. Pediatrics 2007;120:372e80.
[32] Filippi L, Pezzati M, Poggi C, Rossi S, Cecchi A, Santoro C. Dopamine versus
dobutamine in very low birthweight infants: endocrine effects. Arch Dis Child
Fetal Neonatal Ed 2007;92:F367e71.
[33] Robel-Tillig E, Knupfer M, Pulzer F, Vogtmann C. Cardiovascular impact of
dobutamine in neonates with myocardial dysfunction. Early Hum Dev
2007;83:307e12.
[34] Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E, et al. A double-blind,
randomised, controlled study of a stress dose of hydrocortisone for rescue
treatment of refractory hypotension in preterm infants. Pediatrics 2006;117:
367e75.
[35] Lundstrom K, Pryds O, Greisen G. The haemodynamic effects of dopamine and
volume expansion in sick preterm infants. Early Hum Dev 2000;57:157e63.
[36] Zaritsky A, Chernow B. Use of catecholamines in pediatrics. J Pediatr
1984;105:341e50.
[37] Barrington KJ, Finer NN, Chan WK. A blind, randomised comparison of the
circulatory effects of dopamine and epinephrine infusions in the newborn
piglet during normoxia and hypoxia. Crit Care Med 1995;23:740e8.
[38] Cheung PY, Barrington KJ, Pearson RJ, Bigam DL, Finer NN, Van Aerde JE.
Systemic, pulmonary and mesenteric perfusion and oxygenation effects of
dopamine and epinephrine. Am J Respir Crit Care Med 1997;155:32e7.
[39] Seri I. Circulatory support of the sick preterm infant. Semin Neonatol 2001;6:
85e95.
[40] Paradisis M, Evans N, Kluckow M, Osborn D. Randomised trial of milrinone
versus placebo for prevention of low systemic blood ow in very preterm
infants. J Pediatr 2009;154:189e95.
[41] McNamara PJ, Laique F, Muang- S, Whyte HE. Milrinone improves oxygena-
tion in neonates with severe persistent pulmonary hypertension of the
newborn. J Crit Care 2006;21:217e22.
[42] Leone M, Martin C. Role of terlipressin in the treatment of infants and neo-
nates with catecholamine-resistant septic shock. Best Pract Res Clin Anaes-
thesiol 2008;22:323e33.
[43] Bidegain M, Greenberg R, Simmons C, Dang C, Cotten CM, Smith PB. Vaso-
pressin for refractory hypotension in extremely low birth weight infants.
J Pediatr 2010;157:502e4.
[44] Filippi L, Poggi C, Serani L, Fiorini P. Terlipressin as rescue treatment of re-
fractory shock in a neonate. Acta Paediatr 2008;97:500e2.