Eur J Pediatr

DOI 10.1007/s00431-016-2794-7

ORIGINAL ARTICLE

Noradrenaline in preterm infants

with cardiovascular compromise
Kirsten Rowcliff 1 & Koert de Waal 2,3 & Abdel-Latif Mohamed 1,4 & Tejasvi Chaudhari 1,4

Received: 31 August 2016 / Revised: 4 October 2016 / Accepted: 7 October 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract Noradrenaline (NA) is beneficial in the treatment of
term newborns with cardiovascular compromise due to sepsis
or pulmonary hypertension, but experiences with NA in pre-
term infants are limited. The aim of this study is to describe the
efficacy and safety of NA in preterm infants. Patient records of
preterm infants 32 weeks gestation admitted to two hospi-
tals between 2004 and 2015 and who received NA were
reviewed for perinatal morbidities and mortality. Clinical de-
tails were collected at the time of NA use, and response on
blood pressure, perfusion and oxygenation was documented
as well as possible side effects. Forty-eight infants with pri-
mary diagnoses of sepsis (63 %) and pulmonary hypertension
(23 %) received NA. Normotension was achieved at a median
of 1 h in all but one infant at a median dose of 0.5 mcg/kg/min.
Infants who died (46 %) were of younger gestational age and
had worse cardiovascular function at start of NA compared to
infants who survived. Tachycardia was common (31 %), but
no additional effects were found on kidney or liver function.
Conclusion: NA appears to be tolerated safely by preterm
infants with no major side effects. However, effectiveness
needs to be studies further in structured trials.
What is Known:
Noradrenaline is beneficial in the treatment of term newborns and
infants with cardiovascular compromise.
Noradrenaline is known for its potent vasoconstrictive effects and,
therefore, infrequently used in preterm infants.
What is New:
Noradrenaline used in relative low dose and as first or second line
support increases blood pressure in preterm infants with
cardiovascular compromise.
Tachycardia was common, but no additional side effects were found.

Keywords Noradrenaline . Preterm infant . Hypotension

Communicated by Patrick Van Reempts

* Koert de Waal
koert.dewaal@hnehealth.nsw.gov.au
Abbreviations
Kirsten Rowcliff NA Noradrenaline
u5743796@anu.edu.au NDI Neurodevelopmental impairment
Abdel-Latif Mohamed SVR Systemic vascular resistance
Abdel-Latif.Mohamed@act.gov.au
Tejasvi Chaudhari
Tejasvi.Chaudhari@act.gov.au Introduction
1
Australia National University, Canberra, ACT, Australia Cardiovascular compromise is a frequent complication in pre-
2
Department of Neonatology, John Hunter Childrens Hospital, term infants and associated with increased mortality and mor-
Lookout road, Newcastle, NSW 3205, Australia bidity. Common causes of cardiovascular compromise in pre-
3
University of Newcastle, Newcastle, NSW, Australia term infants are transitional hypotension, septic or cardiogenic
4
Department of Neonatology, Canberra Hospital, Canberra, ACT, shock or pulmonary hypertension. Short-term and long-term
Australia complications include intraventricular haemorrhage,

periventricular leucomalacia, neurodevelopmental disability,
renal impairment and organ failure [5, 21].
Treatment is directed at restoring cardiovascular stabil-
ity. Blood pressure is often the only continuous parameter
available to clinicians caring for preterm infants, and thus,
treatment is often focussed on normalising hypotension.
There is a wide variability in the definition of cardiovas-
cular compromise and hypotension in preterm infants
which is reflected by an equally wide variety in treatment
rates of between 16 and 98 % in one study. [12] Not only
treatment rates varied but also treatments received.
Surveys on cardiovascular support in preterm infants
showed that volume expansion, dopamine or dobutamine
remain as the most frequently used first line therapies but
with a wide variability in second line treatments [19, 22].
Noradrenaline (NA) is a naturally occurring sympathomi-
metic amine that acts on myocardial and vascular alpha- and
beta-adrenergic receptors. It has decreased affinity for 2
adrenoreceptor and therefore causes a more pronounced pe-
ripheral vasoconstriction combined with positive inotropic ef-
fects [20]. NA is commonly used in older infants and adults
with septic shock [4]. In a large randomised trial in adults with
shock, NA was equally effective compared to dopamine and
showed less adverse events. [3] NA increased perfusion pres-
sure and tissue oxygenation in full-term newborn infants with
septic shock refractory to fluid loading and dopamine or do-
butamine [23]. NA was also effective in newborn infants with
pulmonary hypertension and could improve oxygenation
through a decrease in pulmonary to systemic artery pressure
ratio and improved cardiac performance [24]. However, the
clinical experiences with NA in preterm infants are limited [6,
25]. The aim of this study is to review our clinical use of NA in
preterm infants 32 weeks gestation and to describe its effec-
tiveness and safety in this population.
Methods
Patient population
This retrospective cohort study was undertaken at the
Canberra Hospital (ACT, Australia) and the John Hunter
Childrens Hospital (NSW, Australia) and approved by the
ACT and Hunter New England Health Human research ethics
committees (ETHLR.15.125). Infants 32 weeks gestation
who were admitted to these units between 2004 and 2015
and who received NA were included in this study. Both units
serve as a level 4 referral centre for neonatal intensive care and
admitted a total of 3573 infants 32 weeks gestation during
the study period. Perinatal demographics, neonatal morbid-
ities and mortality of all infants of this gestational age are
collected prospectively for the NICUS database (http://www.
psn.org.au/nicus) which contributes to the Australian and New
Eur J Pediatr
Zealand Neonatal Network (ANZNN). Neonatal morbidities
were defined according to the ANZNN 2014 data dictionary
(http://anznn.net/dataresources/datadictionaries). Patient
records were reviewed for clinical data, including vital signs,
medications, fluid intake and laboratory biochemistry test
results. Further details were collected before and during the
use of NA, including the use of additional cardiovascular
medications, the dose and duration of NA, respiratory
support measures and selected laboratory parameters. If
arterial access was available, we calculated an oxygenation
index from FiO2 mean airway pressure / arterial PaO2.
Urine output pre-NA was defined as the urine output in the
preceding 6 h.
For the purpose of this study, we defined hypotension as a
mean blood pressure (MBP) < infants postconceptional age
for more than 30 min, and a response to NA was determined
when MBP reached above the gestational age in weeks of the
neonate for at least 30 min.
Safety was detemined by reviewing the possible side ef-
fects of NA. This included the development of tachycardia
(>200/min) and/or hypertension (systolic blood pressure
>95th percentile for postconceptional) after NA was started
and laboratory indicators of kidney and liver damage.
Long-term follow-up was reviewed for neurodevelopmental
impairment. Mild impairment was defined as 1 to 2 SD on
the Bayley-III developmental test for any of the five subscales
(cognitive, expressive language, receptive language, fine motor
or gross motor score) and moderate to severe impairment as
more than 2 SD and/or cerebral palsy, deafness or blindness.
Statistics
Statistical analyses were performed using SPSS (IBM
Statistics version 22.0). Data was explored for normal distri-
bution and repoted accordingly. Data is presented as median
(interquartile range) or number (%). Wilcoxon-signed rank
test and Mann-Whitney U test were used where appropriate.
Multiple logistic regression analysis was performed to identify
the independent influence of duration of NA, maximum NA
dose and time to normalisation of blood pressure on mortality
after controlling for significant confounding factors. All p-
values were two sided, with p < 0.05 considered significant.
Results
Forty-eight preterm infants received NA during the 11-year
study period. The median gestation was 27 weeks, and in two-
thirds of these infants, the cardiovascular compromise was
due to sepsis. All included infants had hypotension prior to
NA administration, and 40 infants had additional signs of poor
perfusion such as a raised lactate >3 mmol/l or oliguria.
Eur J Pediatr
Additional details on patient demographics and details on NA
use can be found in Tables 1 and 2.
The median postnatal age at administration of NA was
1.5 days (IQR 114) and ranged from 1 to 86 days. NA was
used for a median of 29 h, although in one patient, it was used
for more than 9 days. NA was the first line inotrope in 5
infants, the second line inotrope in 15 infants, the third line
inotrope in 25 infants and the fourth line inotrope in 3 infants.
In 3 infants, NA was used as sole inotrope. These were all
more recent cases with pulmonary hypertension due to
prolonged rupture of membranes as primary diagnosis.
NA was started at a median dose of 0.4 mcg/kg/min and
increased by 0.10.2 mcg/kg/min every 15 min until blood
pressure started to increase. In all but one infant blood pres-
sure could be restored after the start of NA. The response was
prompt at a median of 1 h and at a relative low median dose of
0.5 mcg/kg/min.
The effect of NA on cardiovascular parameters and oxy-
genation in the first 24 h of its use is presented in Fig. 1.
Systolic, mean and diastolic blood pressure significantly in-
creased (p < 0.001), and FiO2 and the oxygenation index
decreased (p < 0.05) within 3 h after start. The increased blood
pressure did not lead to immediate improvement of pH, lactate
or urine output.
Fifteen infants (31 %) developed tachycardia after NA was
started, and one infant developed a brief period of hyperten-
sion. Urea and creatinine were significantly increased 24 h
after NA was started (median increase +3.6 mmol/l and
+12 mol/l respectively), remained high by 48 h and returned
to baseline within 1 week. One infant showed a 300 % in-
crease in creatinine which recovered during the intensive care
Table 1 General demographics for the 48 preterm infants who received
noradrenaline for cardiovascular compromise
Gestational age (weeks) 27 (2630)
Birth weight (grammes) 952 (7261450)
Male 18 (38 %)
Antenatal steroids 43 (90 %)
APGAR 5 min 7 (58)
Clinical diagnosis
Hypotension 48 (100 %)
Sepsis 32 (67 %)
Pulmonary hypertension 11 (23 %)
Mortality 22 (46 %)
IVH grade 3 or 4 22 (25 %)
PVL 2 (4 %)
NEC stage 2b or above 12 (25 %)
ROP stage 2 or above 12 (25 %)
Data is presented as median (IQR) or n (%)
IVH intraventricular haemorrhage, PVL periventricular leucomalacia,
NEC necrotising enterocolitis, ROP retinopathy or prematurity
Table 2 Details of noradrenaline use in 48 preterm infants with
cardiovascular compromise
Age at start NA (days) 1.5 (1-14)
Starting dose (mcg/kg/min) 0.4 (0.20.5)
Maximum dose (mcg/kg/min) 0.7 (0.41.0)
Dose at MBP restoration (mcg/kg/min) 0.5 (0.30.7)
Time to MBP restoration (h) 1 (12)
Total duration of NA (h) 29 (1144)
Additional medications
Other inotropes 45 (94 %)
iNO 19 (40 %)
Prostin 1 (2 %)
Hydrocortisone 29 (60 %)
Data is presented as median (IQR) or n (%)
NA noradrenaline, MBP mean blood pressure, iNO inhaled nitric oxide
stay. Alanine aminotransferase values did not change over
time in any infant.
Although NA was effective in increasing blood pressure,
mortality was high in this cohort. Twenty-two of the 48 infants
died (46 %). Most died during the acute phase of their disease,
and four died later due to additional complications of prema-
turity. As expected, mortality was higher in the younger ges-
tational age infants with indications of more severe cardiovas-
cular compromise and more severe hypoxia (Table 3). Blood
pressure, pH, lactate and parameters of oxygenation did not
improve to the same extent in the infants who died compared
to the survivors. After controlling for gestation, birth weight,
lactate and pH at the start of NA infusion, we found no sig-
nificant difference in duration of noradrenaline (p = 0.408),
maximum noradrenaline dose (p = 0.260) or time to normal-
isation (p = 0.708) between infants who survived and died.
Infants with pulmonary hypertension as primary diagnosis
were started on NA earlier and continued for longer.
Parameters at start were not different compared to infants
without pulmonary hypertension (Table 4). Blood pressure
increased similar in each group after 3 h of NA, but the oxy-
genation index decreased only in the infants with pulmonary
hypertension (from 17 to 8).
Follow-up at 1 year corrected gestational age was available
for 22 of the 26 surviving infants. Four infants had mild and
five infants moderate to severe neurodevelopmental
impairment.
Discussion
The purpose of this study was to determine the efficacy and
safety of NA in preterm infants. We found that NA was effec-
tive in improving blood pressure in the majority of preterm
infants at a median dose of 0.5 mcg/kg/min, including those
 Eur J Pediatr

Fig. 1 Effect of noradrenaline on selected circulatory, perfusion and oxygenation parameters. The data is presented as median, IQR (box) and range
(whiskers). SBP systolic blood pressure, DBP diastolic blood pressure, UO urine output, MAP mean airway pressure

refractory to first line inotropes. After blood pressure normal-
ised, it remained normal until NA was ceased suggesting a
sustained effect of NA on the cardiovascular system.
Although not all significant, additional parameters of oxygen-
ation and perfusion improved suggesting that NA may im-
prove organ perfusion. However, improvement in blood pres-
sure was not associated with survival. Mortality and
neurodevelopmental impairment in survivors were high in this
cohort, and it is unclear from this retrospective study design if
this is due to the selection of patients receiving NA or due to
the use of NA itself.
There is limited evidence in the published literature on
the safety and efficacy of NA in preterm infants. Van Balen
et al. reported improvement in blood pressure in 75 infants
with a mean gestational age of 34 weeks without causing
significant side effects. Nearly half of these babies received

Table 3 Comparison of median

(IQR) variables between preterm Variable Survived Died p value
infants with cardiovascular
compromise who received Gestation (weeks) 29 (2631) 26 (2628) 0.043
noradrenaline that died versus Birth weight (grammes) 1250 (7981703) 800 (6641117) 0.043
those that survived Age at start NA (days) 1 (19) 6 (124) 0.668
Total duration of NA (h) 33 (1746) 23 (742) 0.385
Maximum number of inotropes 2 (23) 3 (23) 0.578
Parameters at start of NA
Mean blood pressure (mmHg) 24 (1527) 25 (2029) 1.000
Lactate (mmol/l) 2.6 (1.74.6) 5.0 (2.58.4) 0.043
pH 7.25 (7.187.28) 7.14 (6.997.22) 0.003
Heart rate (bpm) 173 (162199) 175 (165186) 0.772
Oxygenation index 17 (455) 19 (6.565) 0.892

NA noradrenaline
Eur J Pediatr
Table 4 Comparison of median
(IQR) variables between preterm Variable
infants with pulmonary
hypertension (PPHN) as primary Gestation (weeks)
diagnosis versus those that did not Birth weight (grammes)
have PPHN Age at start NA (days)
Total duration of NA (h)
Maximum number of inotropes
Parameters at start of NA
Mean blood pressure (mmHg)
Lactate (mmol/l)
pH
Heart rate (bpm)
Oxygenation index
NA noradrenaline
additional medications to achieve normotension [25].
Mortality was not reported. Derleth et al. reported im-
provement in blood pressure in 29 babies with a gestational
age ranging from 22 to 38 weeks following use of NA in
addition to dopamine. Mortality was reported at 48 %,
comparable to our findings [6]. Both abstracts did not re-
port on long term complications of NA use, and added a
word of caution due to the perceived vasoconstrictive ef-
fects of NA. Further evidence on the use of NA is available
for more mature newborns with sepsis and shock.
Tourneux et al. showed in a cohort of 22 newborns
>35 weeks gestation with septic shock refractory to vol-
ume expansion and other inotropes that NA could increase
blood pressure and urine output and reduce lactate [23].
They used a NA dose ranging from 0.2 to 2.0 mcg/kg/
min, and only four infants died.
NA is an endogenous catecholamine that increases
systemic vascular resistance (SVR) via activation of 1
receptors. Cardiac output is increased by activation of
cardiac 1 receptors to improve contractility, and 1 me-
diated venoconstriction to help increase venous return
and preload [17]. In view of its predominant 1 activity,
NA is the preferred vasopressor for treatment of septic
shock in children and adults which is characterised by a
low SVR [4]. Preterm infants with late onset sepsis com-
monly present with similar pathophysiology of high car-
diac output and low SVR, but the pathophysiology in
preterm infants with cardiovascular compromise immedi-
ately after birth is less uniform [7]. Preterm infants with
cardiovascular compromise during the transitional period
can have variable cardiac output, SVR and also variable
pulmonary vascular resistance depending on the severity
of pulmonary hypertension. The ideal treatment and sup-
portive medications for preterm infants with cardiovascu-
lar compromise remain difficult to determine and might
change with progression of time and underlying disease
progression.
PPHN No PPHN p value
29 (2831) 27 (2530) 0.090
1250 (8801670) 880 (6641375) 0.061
1 (11) 4 (119) 0.028
38 (3058) 24 (1043) 0.048
2 (23) 3 (23) 0.776
26 (2232) 24 (2030) 0.279
3.6 (1.35.5) 3.3 (2.07.2) 0.524
7.23 (7.067.27) 7.21 (7.127.28) 0.980
170 (165180) 175 (160191) 0.410
17 (730) 9 (424) 0.111
NA has recently been described in newborns with pul-
monary hypertension, our second most common cause of
cardiovascular compromise. Jaillard et al. evaluated pul-
monary vascular responses to NA in 15 lambs, 9 of which
had pulmonary hypertension created by antenatal ligation
of the ductus arteriosus [11]. They found that NA signif-
icantly reduced pulmonary vascular resistance and in-
creased pulmonary blood flow in comparison to the con-
trol group and concluded that NA may improve postnatal
adaptation by increasing both systemic blood pressure and
pulmonary blood flow. Tourneux et al. evaluated effect of
NA on respiratory and circulatory changes in 18 mechan-
ically ventilated infants with pulmonary hypertension and
oxygenation problems [24]. They found a significant re-
duction in the pulmonary to systemic pressure ratio in
addition to an increase in both the systemic blood pres-
sure and the left ventricular output. It is likely that the
NA-induced pulmonary vasodilatory effect was mediated
through the activation of vascular 2 adrenoceptors [14,
15, 24, 26]. These findings may suggest that NA may be
the preferred inotrope in newborn infants with pulmonary
hypertension and prompted an increased use of NA in
both our centres where NA is now used as first line
inotrope in term and preterm infants with pulmonary hy-
pertension and cardiovascular compromise. In the four
preterm infants with pulmonary hypertension due to pre-
term prolonged rupture of membranes included in this
cohort, the cardiovascular compromise could be managed
with NA as primary inotrope.
In comparison to other inotropes like dopamine and
adrenaline, NA is less likely to cause tachycardia due to
its effect on vagal tone on the cardiac conduction system
[16]. However, in preterm infants, increased heart rate and
tachycardia did occur after NA was started. Increased
heart rate was also found in a cohort of preterm infants
with cardiovascular compromise treated with adrenaline
in a dose range of 0.05 to 2.6 mcg/kg/min [10]. The high

rate of tachycardia could potentially be due to immaturity
of the adrenoceptors in preterm infants and explain differ-
ential responses of various inotropes in preterm infants as
compared to older infants [18]. Tachycardia during the
treatment of cardiovascular compromise can be a signifi-
cant problem. Preterm infants have a high basal heart rate
and may have limited ability to increase cardiac contrac-
tility, and tachycardia can impair cardiac output by de-
creasing ventricular filling [21]. NA was often started as
third or fourth line therapy in our cohort, and it is possible
that the tachycardia was a result of a combination of
inotropes with positive chronotropic effect via interaction
at receptor level. The risk of tachycardia might be reduced
by limiting the dose and by replacing one catecholamine
for another instead of adding them all together and pre-
vent catecholamine overload from occurring [9, 13].
Tachycardia as potential side effect of NA in preterm in-
fants needs further investigation.
Besides tachycardia, no additional side effects of NA were
found. The transitory indications of renal impairment were
more likely to be caused by the underlying cardiovascular
compromise and not necessarily related to NA use. Both ex-
perimental and clinical studies have shown that NA increases
perfusion pressure and blood flow to the kidneys and gut [1, 8,
14]. None of the infants in this cohort had persistent renal
failure, isolated bowel perforations or distal ischemic lesions
during or after NA infusion.
Neurodevelopmental impairment was high in this cohort.
Although mild NDI was comparable to local ANZNN data,
the rate of moderate to severe NDI was more than double
(ANZNN 10 %, NA cohort 23 %). There is extensive debate
on when and how to treat cardiovascular compromise in pre-
term infants and the benefits of NA and other medications in
reducing long-term morbidity has not been proven [2, 5, 16].
Prospective studies are needed to establish if NA improves
outcomes.
Our study has several limitations. The relative small sample
size and the retrospective design may limit the generalisability
of our results. There was limited availability of echocardiog-
raphy data to help explore cardiac output and estimates of
vascular resistance before and after NA. Most infants received
concomitant medications that could affect the baseline cardio-
vascular status and further response to NA.
Conclusion
This retrospective study suggests that NA may be effective in
treating preterm infants with hypotension associated with sep-
sis and/or pulmonary hypertension. NA can be used in relative
low doses and as first or second line inotrope. Mortality was
high in infants selected for NA use, and whether NA improves
long-term outcomes in survivors is uncertain.
Eur J Pediatr
Authors contributions Kirsten Rowcliff was responsible for data ex-
traction, data analysis and author of the original draft of the manuscript.
Koert de Waal was responsible for protocol development, data analy-
sis and writing of the manuscript.
Abdel-Latif Mohamed was responsible for protocol development, da-
ta analysis and writing of the manuscript.
Tejasvi Chaudhari was responsible for protocol development, data
analysis and writing of the manuscript.
Compliance with ethical standards
Funding No funding was obtained for this study.
Conflict of interest All authors declare that they have no conflict of
interest.
Ethical approval All procedures performed in studies involving hu-
man participants were in accordance with the ethical standards of the
institutional and/or national research committee and with the 1964
Helsinki Declaration and its later amendments or comparable ethical
standards. Informed consent was waived for this retrospective chart
review.
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