Article pharmacology

Inotrope and Vasopressor Support in

Neonates
J. Lauren Ruoss, MD,* Educational Gaps
Christopher McPherson,
1. There is limited knowledge regarding the optimal management of neonates with
PharmD,†‡
hemodynamic instability.
James DiNardo, MDx
2. One approach to hemodynamic instability may not be efficacious for all neonates.

Author Disclosure Abstract

Dr Ruoss, Hemodynamic instability is a common problem in neonates and has important implica-
tions for long-term outcomes. Inotropes and vasopressors are commonly used to treat
Dr McPherson, and
low blood pressure or poor perfusion in neonatal intensive care, despite limited evidence
Dr DiNardo have
to guide optimal management in specific clinical situations. Dopamine is the most com-
disclosed no financial monly used agent in clinical practice, increasing blood pressure with limited adverse ef-
relationships relevant fects compared with epinephrine. Dobutamine is less commonly used but may be the
to this article. This optimal agent for premature neonates with poor perfusion due to immature myocardial
commentary does contractility. New evidence is emerging to guide the treatment of hypotension in the set-
ting of sepsis and persistent pulmonary hypertension. Norepinephrine and vasopressin
contain a discussion of
may have utility in the setting of refractory hypotension due to sepsis. Increasing evidence
an unapproved/
supports use of norepinephrine, milrinone, and vasopressin in the setting of persistent
investigative use of pulmonary hypertension. Hydrocortisone should be reserved for vasopressor-resistant hy-
a commercial product/ potension in preterm neonates; however, this agent may also prove useful in the treat-
device. ment of persistent pulmonary hypertension in term neonates. Further clinical trials are
necessary to determine the optimal treatment algorithm for neonates with hemodynamic
instability. Future trials should include physiologically relevant end points and long-term
follow-up. However, one approach may not be efficacious for all neonates even with
a similar diagnosis. Therefore, bedside assessment techniques should continue to be ex-
plored to allow tailored therapy based on real-time assessment of underlying physiology.

Objectives After completing this article, readers should be able to:

1. Characterize the mechanism of action, pharmacokinetic properties, and cardiovascular

effects of different inotropes.
2. Describe additional medications that can provide cardiovascular support.
3. Determine clinical factors that affect medication selection.

Introduction
Hemodynamic instability represents an ongoing challenge in the management of critically
ill neonates. (1) Neonatal hypotension has been associated with brain injury, (2) necrotiz-
ing enterocolitis, (2) retinopathy of prematurity, (2) and death. (1) Unfortunately, recog-
nition (2)(3) and management of hypotension in the neonate can be exceedingly difficult
(4)(5) partly because normative blood pressure parameters are not standardized in neo-
nates and hypotension alone does not predict negative outcomes. (6)
There are multiple accepted definitions of hypotension in neonates; however having hy-
potension does not necessarily equal inadequate end-organ perfusion. (7) Recently, the focus
of clinicians and researchers has shifted from blood pressure to end-organ perfusion. (8) For

*Department of Newborn Medicine, Boston Children’s Hospital, Boston, MA.

†
Department of Pharmacy, Brigham and Women’s Hospital, Boston, MA.
‡
Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA.
x
Department of Cardiac Anesthesia, Boston Children’s Hospital, Boston, MA.

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pharmacology / inotrope and vasopressor support
the purpose of this article, the term hypotension is used to
reflect an inadequate blood pressure to maintain end-organ
perfusion. Importantly, poor cerebral perfusion has been as-
sociated with brain injury, death, and neurodevelopmental
impairment in early childhood. (9) There are emerging
technologies, such as functional echocardiography and
near-infrared spectroscopy, that allow real-time assessment
of cardiac output and cerebral blood flow. (10)
In addition to a change in evaluation strategies, the ap-
propriate goals of cardiovascular support in neonates have
also been questioned. Historically, trials of medications
for the treatment of hemodynamic instability in neonates
focused primarily on the correction of hypotension.
However, attention is increasingly directed toward assess-
ment of perfusion and the effect of various interventions
on long-term outcomes. (5) The aims of this article are to
review the inotropes most commonly used in neonatol-
ogy, discuss other pharmacologic management strategies
for hypotension and hypoperfusion in neonates, and dis-
cuss clinical factors that affect medication selection.
Catecholamines
Dopamine
Dopamine is an endogenous sympathomimetic amine that
potentiates the release of norepinephrine in addition to di-
rect action on a-, b-, and dopaminergic receptors. (1)(4)
(11)(12) a1-receptor stimulation produces systemic vaso-
constriction, and b1- receptor stimulation increases cardiac
output through positive inotropy (ie, myocardial con-
tractility) and chronotropy (ie, heart rate). Dopaminer-
gic receptor stimulation increases renal blood flow
through renal vasodilation, change in tubular absorp-
tion, and positive inotropy. (6) Stimulation of dopami-
nergic receptors is also responsible for the endocrine
effects of dopamine, including decreased thyrotropin,
prolactin, and thyroxine. (13) Potential negative effects
of dopamine include abnormalities of the endocrine sys-
tem, arrhythmias, and an increase in pulmonary vascular
resistance. (11)(12)
The receptor effects of dopamine are dose dependent
in children and adults, with a low dose (0.5–2 mg/kg/min)
acting on dopaminergic receptors, a medium dose (2–
6 mg/kg/min) acting on cardiac b1-receptors, and a higher
dose of greater than 6–10 mg/kg/min acting on a1-receptors
(Table 1). (11) However, the effective dose to stimulate
each receptor subtype varies substantially among neonates.
Premature neonates may be affected by dopamine at lower
doses secondary to decreased metabolism of the drug. (6)
Conversely, premature neonates may be relatively resistant
to dopamine secondary to blunted norepinephrine release as
a result of immature sympathetic innervation.
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Dopamine is the most commonly used drug for the
management of hypotension by neonatologists. (4)(14)
It is more effective at increasing mean arterial pressure
(MAP) than dobutamine. (15)(16) When compared with
epinephrine for treatment of hypotension in low-birth-
weight neonates, it has a comparable effect on MAP and
urine output. (17) Although the use of epinephrine is as-
sociated with a higher incidence of transitory metabolic ef-
fects, such as hyperglycemia, increased plasma lactate level,
and lower bicarbonate level, there is no difference in the
incidence of gastrointestinal complications and mortal-
ity. (14)(17) Dopamine also increases peripheral perfu-
sion in normotensive very low-birth-weight (VLBW)
neonates (18) and increases cerebral blood flow and tis-
sue oxygenation in hypotensive VLBW neonates. (14)
It is plausible that the abrupt increases in MAP found
in these trials may place VLBW neonates at risk for
brain injury. Further research is needed to evaluate
the effect of dopamine on brain injury and long-term
neurodevelopmental outcomes.
Dopamine is also the most commonly used therapy for
treatment of hypotension associated with persistent pul-
monary hypertension of the newborn (PPHN). Although
dopamine is highly effective at increasing MAP in these
patients, it may also increase pulmonary vascular resis-
tance, compromising oxygenation. (3) Literature regard-
ing the outcomes of neonates with PPHN treated with
dopamine is lacking, and trials demonstrating its benefit
are needed.
Table 2 summarizes the clinical effects on neonates of
dopamine and other inotropes and vasopressors discussed
in this review.
Dobutamine
Dobutamine is a synthetic sympathomimetic amine that
acts directly on a- and b-receptors without the release of
norepinephrine. (19)(20) This synthetic catecholamine has
a relative affinity for b1-cardioreceptors, leading to in-
creased myocardial contractility, (21) and b2-receptors,
leading to vasodilation of the peripheral vasculature (Table 1).
(20) Peripheral vasoconstriction via a-receptor stimulation
is counterbalanced by b2-receptor stimulation, producing
a net systemic vasodilation. (12) The possible negative ef-
fects of dobutamine include arrhythmias and peripheral va-
sodilation with associated hypotension. (22)
Dobutamine is used in the neonatal period primarily
for the treatment of decreased myocardial contractility
and low cardiac output. (20)(22) Dobutamine may be
the drug of choice during the transition period in premature
neonates secondary to its ability to improve contractility of
the immature myocardium and decrease afterload. (5)
 pharmacology / inotrope and vasopressor support

Table 1. Mechanism of Action and Dosages of Inotropesa

Vascular Cardiac
Peripheral
Peripheral Vasoconstriction Vasodilation Contractility Rate Contractility
Drug Dosage a1 a2 b2 a1 b1 b2
Dopamine, mg/kg/min
0.5–2 0 0 0 0 D 0
2-6 0/D 0 DD 0/D DDDD DD
>6–10 DDDD 0 D DDD DDDD D
Dobutamine, mg/kg/min
2–10 D 0 DD D DDDD DDDD
1–20 DD 0 DDDD DDD DDDD DDDD
Epinephrine, mg/kg/min
0.01–0.1 DD DD DDD D DDDD DDDD
>0.1 DDDD DDDD D DDD DD DD
Norepinephrine, mg/kg/min
0.05–0.5 DDDD DDDD 0/D DD DDD DD
a
Specific dose responses are based on data in children and adults.

Dobutamine significantly increases cardiac output but does
not have a significant effect on endogenous catecholamine
levels, MAP, or heart rate in preterm neonates. (19)
Dobutamine increases renal perfusion, likely because of de-
creased systemic vascular resistance rather than a direct ef-
fect on the kidneys. (20) Although dopamine more
effectively increases blood pressure, dobutamine more ef-
fectively increases systemic blood flow in preterm neonates.
(15) A comparative trial of dobutamine vs dopamine in pre-
term neonates with low cerebral blood flow found no dif-
ference in mortality but a reduction in late grade III or
IV intraventricular hemorrhage. (23) The follow-up for
this trial revealed that neonates treated with dobutamine
incurred significantly less disability (eg, cerebral palsy,
blindness, deafness, and severe developmental delay)
in early childhood. (9) However, the trial found no dif-
ference in the overall incidence of intraventricular hem-
orrhage or the combined rates of death or disability at 3
years of age. There was a significant crossover between
the treatment groups and a high rate of treatment fail-
ure despite crossover, which limits the possible conclu-
sions from this trial. Further studies are necessary to
define the outcomes of preterm neonates treated with
dobutamine.
Dobutamine has also been described for the treatment
of myocardial dysfunction secondary to PPHN. In animal
models, dobutamine improves myocardial function, de-
creases pulmonary vascular resistance, and improves oxy-
gen delivery. (4) However, dobutamine has not been
formally studied for this indication in clinical trials in
human neonates and needs further investigation before
routine use.
Epinephrine
Epinephrine is an endogenous catecholamine that stimu-
lates a1,2- and b1,2-receptors. (3)(12) The b-receptor effect
is seen at low doses (0.01–0.1 mg/kg/min) and causes
an increase in myocardial contractility with associated
peripheral vasodilation. (12)(14) High-dose epinephrine
(>0.1 mg/kg/min) is associated with increased systemic
vascular resistance due to a-receptor–mediated peripheral
vasoconstriction (Table 1). (3)(22) Notably, dose thresholds
have not been established in neonates. The possible negative
effects of epinephrine include tachycardia, arrhythmias, pe-
ripheral ischemia, lactic acidosis, and hyperglycemia. (17)
(21) Importantly, tachycardia is most likely attributable
to b2-receptor stimulation in the heart, while lactic acido-
sis and hyperglycemia are most likely attributable to b2-
receptor stimulation in the liver. Excessive vasoconstriction
leading to peripheral ischemia occurs predominantly at
high doses and does not represent the most likely cause
of these adverse effects in routine clinical practice.
Epinephrine is primarily used in neonates with hypoten-
sion refractory to first-line therapies. As primary therapy, epi-
nephrine increases blood pressure with an efficacy similar to
dopamine, although producing increases in heart rate,
plasma lactate level, and blood glucose level. (17) Impor-
tantly, these adverse effects do not appear to produce a dif-
ference in short-term clinical outcomes between therapies.
(22) Similar effects occur when epinephrine is used to treat
hypotension unresponsive to dopamine in VLBW infants. In

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pharmacology / inotrope and vasopressor support

Benefits and Limitations of Inotropes and Vasopressors in

Table 2.

Neonates
Drugs Benefits Limitations
a
Transition Period
Dopamine Increased Increase in systemic vascular resistance
Myocardial contractility may impair cardiac contractility
Mean arterial pressure (high dose) (high dose)
Systemic vascular resistance (high dose)
Cerebral blood flow
Tissue oxygenation
Epinephrine Increased Increased
Myocardial contractility Heart rate
Mean arterial pressure (high dose) Plasma lactate
Systemic vascular resistance Blood glucose
(high dose)
Cerebral blood flow
Dobutamine Increased Decreased
Myocardial contractility Peripheral vascular tone
(cardiac output)
Renal perfusion No change
Cerebral blood flow Mean arterial pressure
PPHNb
Dopamine Increased Increased
Myocardial contractility Pulmonary artery pressure (all doses)
Mean arterial pressure (high dose) Pulmonary vascular resistance (high doses)
Systemic vascular resistance
(high dose)
Decreased No change
Mesenteric vascular resistance Oxygen extraction: systemic or splanchnic
(high doses)
Norepinephrine Increased Increased
Mean arterial pressure Peripheral ischemia
Systemic vascular resistance Dose >3.3 mg/kg/min
Left ventricular output Acidosis
Decreased Dose >3.3 mg/kg/min
FiO2 requirement
Pulmonary to systemic
pressure ratio
Epinephrine Increased No change
Myocardial contractility Pulmonary artery pressure (high dose)
Mean arterial pressure (high dose) Pulmonary vascular resistance (high dose)
Systemic vascular resistance
(high dose)
Milrinone Increased Decreased
Myocardial contractility Mean arterial pressure
Oxygenation
Decreased
Ductal shunting
iNO requirement
Lactic acid
Vasopressin Increased
Mean arterial pressure
Systemic vascular resistance
Decreased
Pulmonary vascular resistance
Oxygenation index
iNO requirement
Continued

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 pharmacology / inotrope and vasopressor support

Table 2. (Continued)

Drugs Benefits Limitations

c
Septic Shock
Dopamine Increased
Myocardial contractility
Mean arterial pressure (high dose)
Systemic vascular resistance (high dose)
Epinephrine Increased Increased
Myocardial contractility Lactic acidosis
Mean arterial pressure (high dose) Peripheral ischemia (high dose)
Systemic vascular resistance (high dose) Mesenteric ischemia (high dose)
Norepinephrine Increased Increased
Myocardial contractility Myocardial oxygen consumption
Mean arterial pressure Increase in systemic vascular
Systemic vascular resistance resistance may impair cardiac
Tissue perfusion contractility (high dose)

Hydrocortisone Increased
(catecholamine-resistant Mean arterial pressure
septic shock) Systemic vascular resistance
Decrease
Vasopressor requirement
Vasopressin Increased Increase in systemic vascular
Mean arterial pressure resistance may impair cardiac
Systemic vascular resistance contractility (high dose)
Decreased
Catecholamine requirement (low dose)
Dobutamine (only use Increased Decreased
in conjunction with Myocardial contractility Systemic vascular resistance
another inotrope
in warm shock)
FiO2¼fraction of inspired oxygen; iNO¼inhaled nitric oxide; PPHN¼pulmonary hypertension of the newborn.
a
Pathophysiologic factors include immature peripheral vascular tone and decreased myocardial contractility.
b
Pathophysiologic factors include increased pulmonary pressures and decreased right-sided cardiac function; if prolonged, leads to decreased bilateral cardiac
function.
c
Pathophysiologic factors include systemic inflammatory response, multiple organ dysfunction; warm shock: peripheral vasodilation, decreased cardiac output,
decreased preload and afterload; and cold shock: peripheral vasoconstriction, increased afterload, decreased cardiac output.

this setting, improvements in blood pressure occur in the
context of a worsening base deficit. (24) Of interest, epi-
nephrine increases cerebral blood flow in extremely preterm
neonates, potentially to a greater degree than dopamine.
(14) As with dopamine, the effect of epinephrine on brain
injury and subsequent outcome has not been adequately
described.
Epinephrine has also been evaluated for the treatment
of systemic hypotension associated with PPHN in pre-
clinical models. (25) In this setting, epinephrine produces
similar increases in cardiac output to dopamine; however,
epinephrine increases systemic vascular resistance prefer-
entially over pulmonary vascular resistance. (25) These
findings are most likely secondary to a2-mediated nitric
oxide production, resulting in relative pulmonary vasodi-
lation. (26)(27) However, the role of epinephrine in
human neonates with PPHN has not been evaluated.
The utility of epinephrine is likely limited by the occur-
rence of tachycardia and lactic acidosis, which may neg-
atively affect the pathophysiology of PPHN. Until further
studies are performed evaluating long-term outcomes, it
is difficult to recommend epinephrine over other ino-
tropes for treatment of PPHN.
Norepinephrine
Norepinephrine is an endogenous catecholamine that in-
creases systemic vascular resistance and cardiac output by
activation of a1,2- and b1-receptors (Table 1). (22)(27) As
with epinephrine, norepinephrine constricts systemic vas-
culature to a greater degree than pulmonary vasculature.
(26)(27) Norepinephrine also increases cardiac output
by increasing contractility via b1-receptors, although this

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pharmacology / inotrope and vasopressor support
effect is less pronounced in the setting of potent a-receptor–
mediated vasoconstriction. The potential negative effects of
norepinephrine include excessive peripheral vasoconstric-
tion, leading to tissue ischemia. (6)
Norepinephrine is widely used for the management
of hypotension secondary to septic shock in adult and
pediatric patients. In adult patients with septic shock,
norepinephrine improves survival when compared with
dopamine. (28) In 2012, the Surviving Sepsis Campaign’s
International Guidelines recommended norepinephrine as
the first-line agent for treatment of adult patients and the
second-line treatment of pediatric patients with hypoten-
sion secondary to septic shock. (29) At this time, dopa-
mine remains the first agent for treatment of septic
shock in pediatric patients. Although norepinephrine has
become the standard of care for treatment of vasodilatory
septic shock in adults and children, it is not commonly
used in neonates. (7) Clinical experience in the setting
of sepsis is limited to an observational report of term neo-
nates with refractory hypotension, defined as persisting de-
spite fluid resuscitation plus dopamine or dobutamine with
or without hydrocortisone. In this setting, norepinephrine
increases MAP, decreases oxygen requirement, and im-
proves tissue perfusion. (1) A high rate of mortality
(18%) makes the results of this observational study difficult
to interpret given the acuity of illness before initiation of
treatment with norepinephrine. Given the benefits of nor-
epinephrine in pediatric and adult patients with septic
shock, further investigation in neonates is warranted.
Norepinephrine has also been evaluated in neonates
with PPHN. Preclinical data suggest that norepinephrine
produces pulmonary vasodilation during fetal life via
a2-receptor stimulation. (26) Although preclinical data
are promising, published experience in human neonates
is limited to observational reports. (26)(27) In term neo-
nates with PPHN treated with inhaled nitric oxide, nor-
epinephrine decreases oxygen requirement, increases
cardiac output, and improves blood flow into the lungs,
without evidence of peripheral ischemia. (30) Further in-
vestigation, potentially including trials comparing norepi-
nephrine to current standards of care, appears warranted.
Adjuncts and Alternatives to Catecholamines
Milrinone
Milrinone is a phosphodiesterase type 3 inhibitor with ino-
tropic, inodilator (promotes myocardial contractility and
produces vasodilation), and lusitropic (promotes myocar-
dial relaxation) properties. (5)(31)(32) The inotropic effect
results from decreased breakdown of cyclic adenosine
monophosphate by phosphodiesterase type 3, perpetuating
calcium influx into myocardial cells and resulting in
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myocardial contraction. (32)(33)(34) The inodilator effect
results from a similarly derived influx of calcium into
smooth muscle cells, increasing relaxation and leading to
peripheral vasodilation. (35) Finally, the lusitropic effect is
caused by myocyte relaxation due to actin-myosin complex
breakdown. (35) Cumulatively, milrinone increases cardiac
output without an increase in myocardial oxygen demand
while decreasing afterload by decreasing systemic vascular
resistance. (32) The possible negative effects of milrinone
include systemic hypotension, tachycardia, tachyarrhyth-
mias, and thrombocytopenia. (31)
Milrinone has primarily been investigated in infants for
the prevention and treatment of low cardiac output after
cardiac surgery. (19) In this setting, milrinone decreases
systemic and pulmonary vascular resistance while increasing
cardiac index. Despite these physiologic benefits, milrinone
does not appear to alter early postoperative outcomes. (36)
Dose optimization studies that incorporate age, disease,
and type of surgery as covariates are being undertaken in
an effort to link milrinone’s favorable hemodynamic profile
to improved patient outcomes. (37)
Theoretically, milrinone could be ideal to treat low cere-
bral blood flow commonly seen in conjunction with reduced
myocardial contractility in extremely preterm neonates. (38)
Unfortunately, a randomized clinical trial that used
milrinone to ameliorate low cerebral blood flow in extremely
preterm neonates did not find a benefit with regard to sys-
temic blood flow, brain injury, or mortality. (34) The limi-
tations of this trial included the low incidence of low cerebral
blood flow in both the treatment and control groups, ad-
ministration of a normal saline bolus to all neonates, and
administration of prophylactic indomethacin to more than
half of the enrolled neonates. Pending further investigation,
milrinone cannot be recommended as the primary inotrope
for preterm infants in the early neonatal period.
Milrinone has also been evaluated for the treatment of
PPHN. Through phosphodiesterase inhibition, milrinone
augments the pulmonary vasodilation induced by nitric
oxide. (39) In observational clinical trials, milrinone de-
creases pulmonary artery pressures and oxygenation index
without a significant effect on blood pressure. (33)(40)
These findings are promising and require further investiga-
tion, including trials focusing on the effect of milrinone
therapy on outcome in neonates with PPHN. However,
in these trials, milrinone was used in the setting of PPHN
unresponsive to inhaled nitric oxide and in neonates who
were hemodynamically stable. Milrinone should be used
with caution in PPHN with associated hypotension be-
cause of the potential for decreased coronary perfusion.
Milrinone has unique pharmacokinetic properties
compared with the other inotropes discussed in this

review. A relatively large volume of distribution necessi-
tates that a loading dose be used before continuous infu-
sion to achieve therapeutic concentrations in the acute
care setting. There are age-related differences in clear-
ance, but generally speaking, the half-life of milrinone
is 1.5 to 3.5 hours compared with 1 to 2 minutes for
the other inotropes. (41) Practically speaking, this means
that the physiologic effects of milrinone persist long after
the drug is weaned. In addition, administration of the
loading dose can produce profound hypotension, leading
many practitioners to forgo the loading dose in favor of
a higher initial infusion rate and delayed drug onset.
Vasopressin
Endogenous arginine-vasopressin (AVP) is a neuropeptide
that increases vascular tone and regulates fluid homeostasis
by binding to vasopressin 1 (V1) and vasopressin 2 (V2)
receptors in smooth muscle. (42) AVP is normally secreted
by the posterior pituitary gland in response to decreased
circulating volume or increased osmolality. (42) V1 recep-
tors mediate vascular tone, platelet function, and release of
aldosterone and cortisol, (43) whereas V2 receptors influ-
ence fluid balance and vascular tone. The effectiveness of
endogenous AVP is decreased in vasodilatory shock and
after cardiac bypass. (44) Potential negative effects of
AVP include cutaneous ischemia and necrosis, liver ische-
mia, and hyponatremia.
The role of AVP as a rescue therapy for refractory hy-
potension in patients with vasodilatory shock has been
extensively studied in adults and children. In this setting,
AVP increases vascular tone and produces coronary and
pulmonary vasodilation. (43) Clinical effects include in-
creased blood pressure and cardiac output with a de-
creased catecholamine requirement. (44) There have
been several small neonatal studies evaluating the use
of AVP in catecholamine refractory hypotension due to
sepsis and after cardiac bypass. (45)(46) Low-dose AVP
(0.00017–0.0007 U/kg/min) appears to decrease cate-
cholamine requirement without associated hyponatremia.
(46) In neonates, high-dose AVP (0.001–0.02 U/kg/min)
also appears to be effective but is associated with adverse
effects, including transient hyponatremia and transaminitis.
(45) Trials evaluating the outcomes of neonates treated with
AVP may further define the role of this emerging therapy in
clinical practice.
The selective pulmonary vasodilatory effects of low-
dose AVP make this agent appealing for the treatment
of PPHN. Benefits in neonates were first observed in
the setting of severe pulmonary hypertension after repair
of obstructive total anomalous pulmonary venous return.
(47) Subsequently, a case series in neonates with PPHN
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pharmacology / inotrope and vasopressor support
found that low-dose AVP improved blood pressure, urine
output, and oxygenation index while reducing the re-
quirement for inhaled nitric oxide. (48) Adverse effects
were not observed. The role of AVP as a primary systemic
vasopressor and pulmonary vasodilator for the treatment
of neonates with PPHN requires further evaluation.
Hydrocortisone
Hydrocortisone is inferior to dopamine as a first-line agent
for the treatment of neonatal hypotension, with a delayed
onset followed by significant hypertension after 24 to 48
hours of therapy. Relative or absolute adrenal insufficiency
may be present in neonates with refractory hypotension
secondary to decreased cortisol stores and decreased ability
to increase cortisol in response to stress. (49) Diagnosing
adrenal insufficiency in neonates is challenging, with normal
cortisol levels varying with gestational age, weight, and se-
verity of illness. Importantly, a normal cortisol level in the
setting of stress may indicate relative adrenal insufficiency
in a neonate that will respond to hydrocortisone supple-
mentation. Corticosteroids aid in the management of
hypotension by decreasing the breakdown of catechol-
amines, increasing calcium levels in myocardial cells,
and upregulating adrenergic receptors. (6) Adverse ef-
fects of corticosteroids include hyperglycemia, gastric
irritation, and fluid retention. Long-term exposure in-
creases the risk of osteopenia and inhibits immune func-
tion and somatic growth.
The optimal timing of hydrocortisone therapy for the
prevention and treatment of hypotension in preterm neo-
nates has been extensively explored. Hydrocortisone pro-
phylaxis in preterm neonates has been suggested to
prevent adrenal insufficiency and subsequent complications
of uninhibited inflammation. (2) In a randomized clinical
trial, neonates exposed to histologic chorioamnionitis had
lower mortality when treated with prophylactic hydrocorti-
sone soon after birth. Importantly, this trial was halted early
because of the high incidence of spontaneous intestinal per-
forations in the treatment group. Subsequent analysis re-
vealed that this complication occurred predominantly in
the setting of concurrent indomethacin therapy. (50)
As discussed previously, hydrocortisone is inferior to
dopamine as a first-line agent for the treatment of neona-
tal hypotension. (16) Multiple studies have evaluated
hydrocortisone in preterm neonates with refractory hypo-
tension. Hydrocortisone effectively increases blood pres-
sure and reduces catecholamine requirement without
serious adverse events. (49) The long-term effect of hy-
drocortisone as an adjunctive therapy in the setting of
catecholamine-resistant hypotension has not been evaluated.
Whether improvements in blood pressure and reduction in
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pharmacology / inotrope and vasopressor support
catecholamine use are associated with improved survival and
neurodevelopmental outcome remains to be seen.
Hydrocortisone has been less extensively evaluated for
the treatment of PPHN in term neonates. In neonatal
lambs, hydrocortisone treatment at clinically relevant
doses improves oxygenation and decreases hyperoxia-
induced changes in soluble guanylate cyclase and phos-
phodiesterase type 5 activity, increasing cyclic guanosine
monophosphate levels. (51) Additional potential benefits
include reduced ventilation-perfusion mismatch due to de-
creased pulmonary inflammation and reduced right-to-left
patent ductus arteriosus shunting due to increased sys-
temic blood pressure. It remains to be determined whether
these physiologic benefits will be verified in human neo-
nates and whether these effects improve clinical outcomes.
Conclusion
Current standard of care dictates the use of dopamine as
the first-line agent for the management of hypotension
and hypoperfusion in the neonate regardless of the clinical
scenario (ie, transition period, sepsis, or PPHN). This is pri-
marily based on historical data and the comfort level of
clinicians. However, there is emerging evidence that chal-
lenges the routine use of dopamine as the first-line therapy
in every clinical situation. Data support the use of dobutamine
during the transition period, epinephrine for sepsis, nor-
epinephrine and vasopressin for sepsis and/or PPHN,
and milrinone for PPHN. Although dopamine has
proven to be an effective drug at increasing MAP, it
has not been found to improve long-term outcomes in
neonates. Randomized clinical trials are needed to evalu-
ate the use of dopamine and other inotropes and vaso-
pressors in specific clinical situations, such as sepsis and
PPHN. Careful analysis of data from smaller clinical trials
evaluating the efficacy and safety of the available agents in
neonates must guide construction of these trials. In addi-
tion, future trials should focus on defining and measuring
physiologically relevant end points, such as systemic and
cerebral oxygen delivery, and on tailoring drug selection
and dose titration to the underlying pathophysiologic
findings of the neonate.
American Board of Pediatrics Neonatal-Perinatal
Content Specification
• Know the management of an infant with
systemic hypotension and the adverse
effects of such management.
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NeoReviews Vol.16 No.6 June 2015 e359
pharmacology / inotrope and vasopressor support

NeoReviews Quiz Requirements

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60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. If you score less than
60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.
NOTE: Learners can take NeoReviews quizzes and claim credit online only at: http://neoreviews.org.

1. A 3-day-old 25-week gestational age neonate has low blood pressure and is given a continuous infusion of dopamine.
The infant is suspected of having sepsis. Which of the following statements regarding dopamine is correct?
A. Dopamine is an endogenous inhibitor of norepinephrine.
B. Dopamine generally lowers the mean arterial pressure in neonates.
C. Dopaminergic receptor stimulation in the kidney leads to renal vasoconstriction.
D. Dopamine at low doses (0.5–2 mg/kg/min) acts on dopaminergic receptors.
E. Dopamine has no chronotropic effect at any dose.

2. The patient continues to have low blood pressure despite increasing dopamine infusion rate, several fluid
boluses, and a packed red blood cell transfusion. Which of the following statements regarding medical
treatment of hypotension is correct?
A. Dopamine tends to cause hypertension at low doses (<2 mg/kg/min) and hypotension when the infusion
rate is increased higher than 5 mg/kg/min.
B. Dobutamine is a synthetic sympathomimetic amine that acts directly on a- and b-receptors without the
release of norepinephrine.
C. Dobutamine causes decreased myocardial contractility but increased chronotropy and net systemic
vasoconstriction.
D. Epinephrine at low doses (0.01–0.1 mg/kg/min) increases peripheral vasoconstriction and decreases
myocardial contractility.
E. Common adverse effects of epinephrine infusion are hypoglycemia and bradycardia.

3. A newborn term male infant is born to a mother with prolonged rupture of membranes and is depressed at birth
with low Apgar scores and poor respiratory effort. He is admitted to the neonatal intensive care unit and given
intravenous antibiotics. During his first hospital day, he is treated for hypotension with fluid boluses, but he
continues to have persistently low blood pressure. Which of the following treatments for neonatal hypotension
is described correctly?
A. Norepinephrine inhibits the activation of a1,2- and b1-receptors, leading to decreased vascular resistance.
B. Norepinephrine is contraindicated in persistent pulmonary hypertension of the newborn because it can
lead to pulmonary vasoconstriction, exacerbating the primary disease.
C. Milrinone has an inotropic effect by causing decreased breakdown of cyclic adenosine monophosphate.
D. Milrinone tends to have an effect of increasing cardiac output but also causes a corresponding increase in
myocardial oxygen demand because of increased systemic vascular resistance.
E. The mechanism of action of dobutamine primarily involves the inhibition of phosphodiesterase type 3.

4. A 5-day-old term female infant underwent cardiac surgery for several congenital abnormalities, including
aortic arch abnormality. She has low cardiac output and is being treated with milrinone. Which of the
following statements regarding milrinone is correct?
A. Possible negative effects of milrinone include systemic hypotension, tachycardia, tachyarrhythmias, and
thrombocytopenia.
B. The primary action of milrinone in this setting is to cause peripheral vasoconstriction, thereby increasing
blood pressure.
C. Milrinone has a relatively quick action at small initial doses and should not be used as a continuous
infusion.
D. The half-life of milrinone is 18 to 24 hours and requires close monitoring of drug levels during treatment.
E. Milrinone should be avoided when pulmonary hypertension is present because it increases pulmonary
arterial pressures and oxygenation index.

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 pharmacology / inotrope and vasopressor support

5. A 28-week gestational age male infant is now 10 days old and has hypotension associated with a new-onset
infection. The team considers the use of hydrocortisone for his condition. Which of the following statements
regarding hydrocortisone for the treatment of neonatal hypotension is correct?
A. If there is a normal age-specific cortisol level obtained, there is no indication of absolute or relative adrenal
insufficiency; therefore, corticosteroids will have no effect.
B. A potential side benefit of hydrocortisone therapy is increased growth and improved bone maturation.
C. Corticosteroids address hypotension by acting on calcium channel receptors in smooth muscle, leading to
decreased calcium levels in myocardial and endothelial cells.
D. Prophylactic hydrocortisone and concurrent indomethacin therapy has been associated with spontaneous
intestinal perforation.
E. Low-dose hydrocortisone given prophylactically or in the setting of hypotension leads to improved survival
and neurodevelopmental outcomes.

NeoReviews Vol.16 No.6 June 2015 e361

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 Inotrope and Vasopressor Support in Neonates
J. Lauren Ruoss, Christopher McPherson and James DiNardo
NeoReviews 2015;16;e351
DOI: 10.1542/neo.16-6-e351

Updated Information & including high resolution figures, can be found at:
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http://neoreviews.aappublications.org/content/16/6/e351#BIBL
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 Inotrope and Vasopressor Support in Neonates
J. Lauren Ruoss, Christopher McPherson and James DiNardo
NeoReviews 2015;16;e351
DOI: 10.1542/neo.16-6-e351

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/16/6/e351

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