Epinephrine Use during Newborn Resuscitation

Abstract

Epinephrine use in the delivery room for resuscitation of the newborn is associated with significant morbidity and mortality. Evidence for optimal dose, timing, and route of administration of epinephrine during neonatal resuscitation comes largely from extrapolated adult or animal literature. In this review, we provide the current recommendations for use of epinephrine during neonatal resuscitation and also the evidence behind these recommendations. In addition, we review the current proposed mechanism of action of epinephrine during neonatal resuscitation, review its adverse effects, and identify gaps in knowledge requiring urgent research.

Full text

May 2017 | Volume 5 | Article 971
REVIEW
published: 01 May 2017
doi: 10.3389/fped.2017.00097
Frontiers in Pediatrics | www.frontiersin.org
Edited by:
Graeme R. Polglase,
Monash University, Australia
Reviewed by:
Elizabeth Foglia,
Children’s Hospital of
Philadelphia, USA
Georg Schmolzer,
University of Alberta, Canada
*Correspondence:
Vishal S. Kapadia
vishal.kapadia@utsouthwestern.edu
Specialty section:
This article was submitted
to Neonatology,
a section of the journal
Frontiers in Pediatrics
Received: 10January2017
Accepted: 13April2017
Published: 01May2017
Citation:
KapadiaVS and WyckoffMH
(2017) Epinephrine Use during
Newborn Resuscitation.
Front. Pediatr. 5:97.
doi: 10.3389/fped.2017.00097
Epinephrine Use during Newborn
Resuscitation
Vishal S. Kapadia* and Myra H. Wyckoff
Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Epinephrine use in the delivery room for resuscitation of the newborn is associated
with signicant morbidity and mortality. Evidence for optimal dose, timing, and route of
administration of epinephrine during neonatal resuscitation comes largely from extrapo-
lated adult or animal literature. In this review, we provide the current recommendations
for use of epinephrine during neonatal resuscitation and also the evidence behind these
recommendations. In addition, we review the current proposed mechanism of action of
epinephrine during neonatal resuscitation, review its adverse effects, and identify gaps in
knowledge requiring urgent research.
Keywords: epinephrine, neonatal resuscitation, asphyxia, newborn, delivery room, infants
INTRODUCTION
Approximately 10% of newborns require some assistance to begin breathing at birth (1). Majority
of these newborns improve without the need for cardiac compression or epinephrine if skillful
positive-pressure ventilation is initiated in a timely manner. Less than 0.1% of all newborns require
epinephrine, making epinephrine use in delivery room neonatal resuscitation an uncommon event
(2, 3). Newborns who do require extensive cardiopulmonary resuscitation (CPR) including epi-
nephrine have a high incidence of mortality. ose who survive frequently suer from poor long-
term neurodevelopmental outcomes (4–7).
e majority of recommendations regarding indication, dose, and route of administration of
epinephrine in the delivery room are based on extrapolations from adult and animal studies. e
infrequent use of epinephrine in the delivery room and ethical dilemmas in designing a clinical
trial for examining the role of epinephrine during neonatal resuscitations make it very dicult to
obtain high levels of evidence for recommendations regarding epinephrine use during neonatal
resuscitation. Many of the animal and adult data come from a non-perfusion ventricular brillation
arrest, which is not the pathophysiology of a newborn in the delivery room who suers from an
asphyxial arrest. Another major limitation of extrapolation from these studies is that newborns in
the delivery room have unique transitional physiology including uid-lled alveoli, an open ductus
arteriosus, and high pulmonary pressures with limited pulmonary blood ow. Newly born infants
must transition from fetal to newborn circulation. In the era of evidence-based medicine, due to lack
of rigorous scientic evidence, proper use of epinephrine including dose and route of administration
remains controversial. Even though epinephrine is not commonly needed in neonatal resuscita-
tion, its association with death and poor prognosis raises questions as to whether optimization of
epinephrine use and dosing, specically tailored to the unique circumstances of the newly born
infant, could improve outcomes.
is review aims to describe current recommendations for epinephrine use in neonatal resuscita-
tion, the evidence behind such recommendations, and the critical knowledge gaps.

FIGURE 1 | Epinephrine and coronary perfusion pressure.
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HISTORY OF EPINEPHRINE USE IN
NEONATAL RESUSCITATION
Epinephrine is the only medication recommended during neo-
natal resuscitation in the delivery room (8, 9). Naloxone, sodium
bicarbonate, and other vasopressors are currently not considered
a part of acute resuscitation but can be used postresuscitation
for special circumstances (9–11).
Management of the airway and assisted ventilation of the
newborn baby can be found in ancient texts dating back to the
Old Testament of the Bible, the Talmud, and Hippocrates (12, 13).
However, reports of medication use in neonatal resuscitation can
only be found aer the early 1950s with the evolution of modern
neonatology (13, 14). George Oliver and Edward Schaer in
1893 rst showed that adrenal glands contained a substance with
distinct pharmacological properties (14, 15). It is a naturally
occurring catecholamine produced by chroman cells at the
adrenal medulla and stored in chroman granules. In 1897, John
Abel in the United States prepared crude adrenal extracts and
called them epinephrine (16). Epinephrine was used rst time
in pulseless patients in around 1906 by Crile and Dolley (17). Its
resuscitative properties were further investigated by Wiggers in
the 1930s and Redding and Pearson in the 1960s (18, 19).
HEMODYNAMIC EFFECTS OF
EPINEPHRINE
Epinephrine stimulates all four adrenergic receptors (α1, α2, β1,
and ß2) invivo. When looked at in isolation, stimulation of the
dierent adrenergic receptors by epinephrine results in dierent
and sometimes opposing eects. It causes peripheral vasocon-
striction via stimulation of α1 receptors in vascular smooth muscle
cells. By stimulating β1 receptors in the myocardium, it causes
chronotropy (increased heart rate), inotropy (increased contrac-
tility), dromotropy (increase conduction velocity), and lusitropy
(increased rate of myocardial relaxation) (10, 20–22). Stimulation
of α2 receptors leads to presynaptic inhibition of nor-epinephrine
release in the central nervous system and vasoconstriction of
coronary arteries. rough β2 receptor stimulation, it causes
vascular smooth muscle relaxation and increased myocardial
contractility, but these eects are usually minor. In vivo eects
of epinephrine depend on the dose of epinephrine, number of
receptors available on target tissues, the anity of these receptors,
and local target tissue environments (23).
MECHANISM OF ACTION DURING CPR
Initially it was believed that epinephrine causes return of
spontaneous circulation (ROSC) in cardiac arrest via its myo-
cardial stimulant eects (β adrenergic eects: chronotropic and
inotropic) (10). In the 1960s, Redding demonstrated in dogs that
the pure α-agonist, methoxamine, was as eective as epinephrine
in achieving ROSC during CPR, whereas the pure β-agonist, iso-
proterenol, was no more eective than CPR alone (19). Otto etal.
who used pretreatment with α-adrenergic blockade (phenoxy-
benzamine) and β-adrenergic blockade (propranolol) before
infusing epinephrine conrmed that α-adrenergic stimulation is
the most important action of epinephrine for ROSC in CPR (24).
It is now established that the most reliable method for deter-
mining the eectiveness of CPR is to measure aortic diastolic
blood pressure or coronary perfusion pressure (25). When heart
muscles do not receive adequate blood ow and/or oxygen,
their energy substrate is depleted. In turn, heart muscles stop
contracting and the heart stops pumping. To restart the cardiac
pump, it is critical that myocardial perfusion with oxygenated
blood is reestablished. In acidotic asphyxiated neonates, there
is loss of peripheral vascular tone, i.e., maximum vasodilation.
When chest compressions are performed, blood from the cardiac
chambers takes the path of least resistance and thus preferentially
ows through aorta and into peripheral circulation rather than
into narrow more constricted coronary arteries that have high
resistance (Figure 1). e use of epinephrine in this situation
results in intense peripheral vasoconstriction. is elevates the
aortic to right atrial pressure gradient during the relaxation phase

TABLE 1 | Epinephrine use during newborn resuscitation: route, dose,
and summary of evidence.
Route Dose Summary of evidence
Intravenous 0.01–0.03mg/kg • Preferred route and appear to be more
efcacious than other routes
• Dose extrapolated from adult experience
• High-dose epinephrine offers no
advantage and is associated with
increased postresuscitation adverse
effects and increased mortality
• Dose escalation studies in neonatal
animal model with transition physiology
are urgently needed
Endotracheal
(ET)
0.05–1mg/kg • Less effective than IV route
• Achieved plasma concentration is less
and it peaks slower with ET epinephrine
compared to IV epinephrine
• Can be used until IV access is available
Intraosseous 0.01–0.03mg/kg • Limited evidence compared to IV route
• Providers frequently involved in newborn
resuscitation feel more comfortable with
rapid UVC insertion compared to IO route
Intramuscular Not recommended • Very limited evidence
• Signicant tissue damage at local site
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of CPR (26–29). Due to this pressure gradient, blood during chest
compressions enters the coronary arteries and myocardial blood
ow increases. Hence, this pressure gradient is called the coronary
perfusion pressure. As oxygenated blood enters the coronary cir-
culation, it facilitates resynthesis of adenosine triphosphate within
myocardial mitochondria improving myocardial contractility
and viability. In animal models and humans, coronary perfusion
pressure correlates directly with myocardial blood ow, which is
a good predictor of ROSC.
Although minor, β2 receptor-mediated coronary vasodila-
tion may contribute to improved coronary perfusion following
epinephrine administration (10, 21, 30). Cerebral electrogra phic
activity and cerebral oxygen uptake improves following epineph-
rine administration during CPR as cerebral blood ow increases
due to epinephrine-induced peripheral vasoconstriction (28, 29).
rough its α receptor stimulation, epinephrine may counteract
carotid artery collapse induced by elevated intrathoracic pres-
sures due to CPR and further optimize blood ow (28).
Studies utilizing posttransition asphyxia animal model have
demonstrated the importance of epinephrine, where aer asphyxia
cardiac arrest, chest compressions alone were ineective, but
majority of animals reached the critical diastolic blood pressure
(rising aortic to right atrial pressure gradient) and ROSC aer
epinephrine administration (31–33). It is important to note that
these studies also showed that interruptions in chest compression
lead to lowering of diastolic blood pressure, thus highlighting
the importance of minimizing interruptions in cardiac compres-
sions during CPR (31–33).
e majority of the above information was obtained from
adult animal studies, posttransitioned neonatal animal studies,
or human adult studies. No studies in term or preterm newborns
or animal models with newborn transition physiology have
investigated the mechanism of action of epinephrine during CPR.
e distribution and maturation of α and β receptors in term
and preterm newborns remain unknown (23).
CURRENT INDICATION FOR
EPINEPHRINE DURING NEONATAL CPR
Bradycardia in newly born infants is usually the result of inad-
equate aeration of lungs and ventilation or profound hypoxemia
and acidosis from prior poor placental perfusion. Hence, eective
ventilation is the top priority during delivery room resuscitation
of the bradycardic newborn. Current resuscitation guidelines
recommend that epinephrine should be used if the newborn
remains bradycardic with heart rate <60bpm aer 30s of what
appears to be eective ventilation with chest rise, followed by 30s
of coordinated chest compressions and ventilations (1, 8, 9).
OPTIMAL DOSE AND ROUTE OF
ADMINISTRATION OF EPINEPHRINE
DURING CPR
Epinephrine during neonatal CPR in the delivery room can be
given by three routes: intravenous, endotracheal (ET), and intra-
osseous (Table1).
Intravenous Epinephrine
is is the preferred route of administration during neonatal
CPR in the delivery room as it appears to be more ecacious
compared to other routes (1, 8, 9). e umbilical vein is a rap-
idly accessible, direct intravenous route. If epinephrine use is
anticipated based on risk factors and no response to optimized
positive-pressure ventilation (preferably via a secured airway),
one team member should prepare to place an umbilical venous
catheter, while the others continue to provide ventilation and chest
compression. Chest compressions should be provided from head
of the bed to allow adequate access to place the umbilical venous
catheter (1).
e optimal dose of intravenous epinephrine has been the
subject of much debate. In animal ventricular brillation models,
Redding and Pearson demonstrated that intravenous epineph-
rine of 1mg (0.1 mg/kg in 10 kg dogs) increased ROSC when
combined with ventilation and chest compressions alone (19).
Human studies following this study did not take into account the
weight dierence between the 10-kg dogs that were studied and
the average adult weight, which is 7- to 10-fold more. Surprisingly,
even with such low doses, epinephrine was reported to be eective
in achieving ROSC in adult CPR (34). As there are no neonatal
epinephrine dosing studies, the recommended dose was extrapo-
lated from the adult experience with a suggested dosing range of
0.01–0.03mg/kg. Given the overlooked weight dierence between
dogs in the study by Redding and Pearson (19) and humans, studies
were conducted to see if higher dose epinephrine would be more
ecacious. Initially, studies in ventricular brillation adult ani-
mal model showed increased ROSC and improved cerebral and
coronary blood ow with escalating doses of epinephrine (35).
Based on these data, adult and pediatric resuscitation guidelines
started recommending using 0.1mg/kg high dose of epinephrine
if no response was seen with standard dose epinephrine (36).

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Clinical studies conducted later found that high-dose epinephrine
(0.1mg/kg) is not more eective and may be harmful (35, 37, 38).
Animal Data
Berg etal. in a pediatric asphyxia swine model demonstrated that
high-dose epinephrine did not result in increased ROSC, and in
fact, there was higher postresuscitation mortality (39). Burcheld
etal. in a neonatal lamb model demonstrated that high-dose epi-
nephrine reduced stroke volume and cardiac output (40). McCaul
etal. demonstrated dose-related adverse outcomes with higher
tachycardia, hypertension, mortality, and increased troponin
with high-dose epinephrine in a rat model (41). Observation of
hypertension following hypotension with high-dose epinephrine
is especially important for preterm newborns who are vulnerable
to development of intraventricular hemorrhage with uctuations
in blood pressure (42, 43).
Adult Data
Meta-analysis of randomized control trials in adult cardiac arrest
patients demonstrated increased ROSC with high-dose epineph-
rine but no improvement in survival to hospital discharge (35).
Older Children
Perondi etal. randomized 68 children (mean age of 6years) to
either 0.1 versus 0.01mg/kg for the second dose of epinephrine
aer failure of standard rst dose (0.01mg/kg) (38). is study
demonstrated that ROSC rates were similar between both groups.
Alarmingly, no child survived in the high-dose epinephrine group
compared to 21% survival in the standard epinephrine group.
Patterson etal. conrmed these ndings that high-dose epineph-
rine did not confer any benets but reduced survival when arrest
was precipitated by asphyxia (37).
Neonatal Data
ere is a stark absence of any neonatal studies including
randomized controlled trials studying any dose of epinephrine.
Halling etal. described in an observational study of 20% success
rate with single standard dose of IV epinephrine. Multiple doses
were needed by large number of newborns (3).
In summary, these data suggest that there is no advantage with
high-dose epinephrine, and it is associated with postresuscitation
hypertension, tachycardia, and increased mortality especially
following cardiac arrest from asphyxia. Neonatal data remain
sparse, and dose escalation studies in appropriate neonatal mod-
els with transition physiology are urgently needed.
ET Epinephrine
Although the ET route is readily available and less time consum-
ing than establishing an intravenous or intraosseous access, it
appears to be less eective (36, 44, 45). However, until intravenous
access is available, some clinicians may choose to give epineph-
rine ET (1, 9). Currently, the recommended dose is 0.05–0.1mg/
kg, which is much higher than the recommended intravenous
epinephrine dose (1, 9).
Adult Animal Data
Redding etal. were the rst to suggest the use of ET epinephrine
during cardiac arrest (46). In a ventricular brillation pig model,
Crespo etal. compared 0.01 versus 0.1mg/kg ET epinephrine
doses (47). e study demonstrated that higher dose was able to
achieve higher plasma concentrations of the drug but that did not
translate to higher blood pressure. Roberts etal. also investigated
dierent ET epinephrine doses and compared them with equiva-
lent intravenous epinephrine doses (48). e study demonstrated
that the peak concentration of epinephrine was found in 15s aer
either route of administration, but with ET epinephrine, blood
concentrations were more sustained. Importantly maximum
plasma concentration achieved by ET epinephrine was one-tenth
of the plasma concentration achieved by the intravenous route.
Vali and Lakshminrusimha conducted a study of ET versus
intravenous epinephrine in a fetal lamb model of asphyxia where
animals had not yet transitioned to newborn circulation (49).
ey demonstrated that plasma epinephrine peaks much faster
and higher compared to ET epinephrine although no dierence
in rates of ROSC was observed between either group.
Human Adult Data
Many retrospective adult case series have noted ET epinephrine
to be less eective than IV epinephrine in achieving ROSC during
CPR (36, 44, 45).
Neonatal Data
Four case series in neonates noted some evidence of absorp-
tion or cardiovascular improvement following ET epinephrine
administration, but doses were 10 times higher than typical
intravenous doses, and the majority of newborns had brady-
cardia, not asystole (50–52). Barber and Wycko reported on a
retrospective review of all neonates who received epinephrine
in the delivery room during the study period (2). e study
demonstrated that the majority of infants received their rst
dose as ET epinephrine. ey found that ET epinephrine dose of
0.01–0.03mg/kg failed to re-establish HR>60bpm two-thirds
of time. In the neonates who failed to respond to ET epinephrine,
77% of them responded to subsequent intravenous epinephrine.
ET epinephrine ecacy may be limited in the newly born due
to dilution by non-mobilized lung uid. Elevated pulmonary
arterial pressure in the presence of patent ductus arteriosus
could result in right-sided cardiac output bypassing the lungs
and thus limiting epinephrine absorption from the lung (23, 25).
Based on this evidence, guidelines recommended an increase in
ET epinephrine dosing from 0.01 to 0.03 to 0.05 to 0.1mg/kg
(1, 9). Halling etal. presented a retrospective review comparing
the dosing from 0.03 to 0.05mg/kg (3). ey found no improve-
ment in rates or time of ROSC with the higher ET epinephrine
dose. It is possible that there may not be an optimal ET epineph-
rine dose. Current guidelines stress the importance of education,
practice, and preparation to rapidly establish IV access in delivery
room for newborns who need epinephrine during delivery room
resuscitation (9).
Intraosseous Epinephrine
Simulation studies have shown that for inexperienced person-
nel, establishment of an intraosseous line was faster and easier
than the placement of umbilical catheters (53). In a neonatal case
series of 27 neonates who received intraosseous epinephrine for
resuscitation, no short-term complications were demonstrated

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(54). Also many critical clinical outcomes were not described.
Given the comfort level that can be achieved by neonatal provid-
ers for rapid placement of umbilical catheters and limited evi-
dence regarding IO placement in delivery room, IV epinephrine
is preferred (1).
Intramuscular Epinephrine
Mauch et al. demonstrated that 0.1 mg/kg of IM epinephrine
resulted in similar ROSC and survival in infant piglet cardiac arrest
model (55). Case reports indicate that intramuscular epinephrine
of 0.02mg/kg causes signicant tissue damage at injection site
(56). Currently, intramuscular epinephrine is not recommended
for neonatal CPR.
ADVERSE EFFECTS OF USE OF
EPINEPHRINE DURING CPR
Epinephrine especially with repeated doses or with high doses
can cause postresuscitation hypertension and tachycardia
(39, 57). This can result in injury to various organ systems
especially in preterm neonates. Excess epinephrine due to its
vasoconstrictive properties can impair blood flow to various
organs such as kidneys and intestines. Epinephrine can also
result in elevation of pulmonary arterial pressures and increase
myocardial oxygen consumption and demand through its β
adrenergic effects (58, 59). This may be detrimental especially
in situations where hypoxia persists and oxygen delivery
is impaired. It has also been associated with imbalance of
various neurotransmitters such as gamma-aminobutyric acid,
dopamine, serotonin, acetylcholine (60–63). It can impair
blood–brain barrier and possibly decrease the threshold for
seizures (62, 64).
ALTERNATIVES TO EPINEPHRINE IN DR
Given the limitations of epinephrine in neonatal CPR, there
is a great interest in nding other vasoconstrictors that have
fewer detrimental side eects. Vasopressin has been studied in
the adult literature as an alternative. Endogenous vasopressin
levels were found to be higher in successfully resuscitated adults
compared to those who died. Vasopressin through V1 receptors
is a potent vasoconstrictor of blood vessels in the skin, skeletal
muscle, and mesenteric blood vessels (10, 65, 66). It does not
have any stimulant eect on the myocardium, and at low doses,
it can vasodilate coronary, pulmonary, and cerebral vessels. Even
though it has these theoretical benets over epinephrine, in
randomized control trials in adults, vasopressin has not found to
be more eective than epinephrine (67). A cohort study on pedi-
atric in-hospital cardiac arrest vasopressin was found to be less
eective and associated with higher mortality (68). In neonatal
piglet posttransition asphyxia model, McNamara etal. showed
that vasopressin resulted in improved survival, lower postresus-
citation troponin, and less hemodynamic compromise compared
to epinephrine (69). No human neonatal data exist regarding
vasopressin in CPR. Studies with neonatal animal models with
transition physiology are urgently needed.
OTHER CONSIDERATIONS FOR
EPINEPHRINE IN THE DELIVERY ROOM
Interval between Doses
e current recommendation is to repeat the dose of IV epineph-
rine every 3–5 min if the heart rate remains less than 60bpm
(1, 9). Vali and Lakshminrusimha in a fetal lamb asphyxia model
demonstrated an incremental increase in plasma epinephrine
concentration with repeated IV epinephrine doses every 3–5min
(49). Warren etal. performed retrospective review of in-hospital
cardiac arrest in adults and found the optimal interval to repeat
dose to be 9–10min instead of 3–5min (70). Linner etal. gave
epinephrine before chest compressions to bradycardic and
severely asphyxiated newborn piglets and demonstrated that
this strategy did not improve ROSC or cerebral circulation (71).
More studies are needed to nd out optimal interval between
doses, but current evidence would suggest that more frequent or
early epinephrine does not seem to be more benecial.
Flush Volume after IV Epinephrine
Dose through Low UVC
Currently recommended ush volume aer IV epinephrine
dose is 0.5–1ml (1). Vali and Lakshminrusimha showed higher
incidence of ROSC and faster ROSC with right atrial epinephrine
compared to low UVC epinephrine in fetal lamb asphyxia model
(49). It is possible that the currently recommended ush volume
will deposit the epinephrine in umbilical vein but might not be
enough to reach the heart. It is unclear if current ush volume is
adequate and if higher ush volume may result in faster rise and
higher epinephrine plasma concentrations. Studies are underway
to answer this question.
OUTCOMES IN NEWBORNS WHO
REQUIRE EPINEPHRINE IN THE
DELIVERY ROOM
Cohort study data suggest that epinephrine is needed in <0.1%
of all liver born deliveries (2, 3) although there is a large variation
among dierent centers. Severe fetal acidemia, malpositioned
ET tubes, and ineective ventilator support contribute to the higher
use of delivery room epinephrine (72, 73). us, it remains critical
that neonatal providers focus on optimizing positive-pressure
ventilation including placement of an alternate airway as a part of
their ventilation corrective measures if a newborn is not respond-
ing to initial positive-pressure ventilation. Provision of eective
ventilation that moves the chest should eliminate or reduce
unnecessary intensive CPR. Term infants who require intensive
CPR including multiple epinephrine doses and those whose Apgar
score remain low at 10min of life suer from high incidence of
death or poor neurodevelopmental outcomes (4, 5). In preterm
infants due to lack of good evidence for use of epinephrine and its
adverse eects of epinephrine especially postresuscitation hyper-
tension, outcome data become even more important. Multiple
retrospective observational studies have noted that preterm
neonates requiring CPR and epinephrine have signicantly lower

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Frontiers in Pediatrics | www.frontiersin.org May 2017 | Volume 5 | Article 97
survival, higher incidence of early onset sepsis, NEC, grade 3–4
intraventricular hemorrhage, cystic periventricular leukomalacia,
bronchopulmonary dysplasia, and neurodevelopmental impair-
ment (7, 74–76). ese studies frequently suer from small
numbers and selection bias as the most compromised and sicker
preterm neonates may require CPR but all studies point toward
worse outcomes associated with extensive delivery room CPR.
ese data suggest that optimization of CPR and epinephrine use
in delivery room has potential to impact outcomes signicantly.
CONCLUSION
Epinephrine use in delivery room remains uncommon especially
when neonatal providers focus on eective positive-pressure
ventilation. Epinephrine use in delivery room is associated with
high mortality and poor long-term outcomes. Recommendations
regarding epinephrine use including dose and route are based
mostly on extrapolation of data from animals or adult literature.
Even the majority of available animal data come from ventricular
brillation cardiac arrest models and posttransition models that
have little in common with newborns in the delivery room. ere
is a scarcity of human neonatal term and preterm epinephrine data
even in the form of observational studies. Based on the limited
available literature, intravenous epinephrine is preferred to ET
epinephrine. Clinical and animal studies in transition neonatal
models are urgently needed to identify optimal indication, tim-
ing, dose, route, and alternatives to epinephrine in neonatal CPR.
AUTHOR CONTRIBUTIONS
VK performed the literature review, created rst dra of the
article, revised the dra, and created and approved the nal dra
of the article. MW critically reviewed the rst dra, revised the
dra, approved the nal dra of the article, and contributed
substantially to this manuscript.
FUNDING
is work was supported by NICHD/NIH 1K23HD083511-01A1
(to VK).
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Conict of Interest Statement: e authors declare that the research was
conducted in the absence of any commercial or nancial relationships that could
be construed as a potential conict of interest.
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