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 epinephrine have a high incidence of mortality. Those who survive frequently suffer from poor long-term neurodevelopmental outcomes (4–7).

The 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. The 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 difficult 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 fibrillation arrest, which is not the pathophysiology of a newborn in the delivery room who suffers from an asphyxial arrest. Another major limitation of extrapolation from these studies is that newborns in the delivery room have unique transitional physiology including fluid-filled alveoli, an open ductus arteriosus, and high pulmonary pressures with limited pulmonary blood flow. Newly born infants must transition from fetal to newborn circulation. In the era of evidence-based medicine, due to lack of rigorous scientific evidence, proper use of epinephrine including dose and route of administration remains controversial. Even though epinephrine is not commonly needed in neonatal resuscitation, its association with death and poor prognosis raises questions as to whether optimization of epinephrine use and dosing, specifically tailored to the unique circumstances of the newly born infant, could improve outcomes.

This review aims to describe current recommendations for epinephrine use in neonatal resuscitation, the evidence behind such recommendations, and the critical knowledge gaps.

Epinephrine is the only medication recommended during neonatal 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 after the early 1950s with the evolution of modern neonatology (13, 14). George Oliver and Edward Schaffer in 1893 first showed that adrenal glands contained a substance with distinct pharmacological properties (14, 15). It is a naturally occurring catecholamine produced by chromaffin cells at the adrenal medulla and stored in chromaffin granules. In 1897, John Abel in the United States prepared crude adrenal extracts and called them epinephrine (16). Epinephrine was used first 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).

Epinephrine stimulates all four adrenergic receptors (α₁, α₂, β₁, and ß₂) in vivo. When looked at in isolation, stimulation of the different adrenergic receptors by epinephrine results in different and sometimes opposing effects. It causes peripheral vasoconstriction 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 contractility), 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. Through β₂ receptor stimulation, it causes vascular smooth muscle relaxation and increased myocardial contractility, but these effects are usually minor. In vivo effects of epinephrine depend on the dose of epinephrine, number of receptors available on target tissues, the affinity of these receptors, and local target tissue environments (23).

Initially it was believed that epinephrine causes return of spontaneous circulation (ROSC) in cardiac arrest via its myocardial stimulant effects (β adrenergic effects: chronotropic and inotropic) (10). In the 1960s, Redding demonstrated in dogs that the pure α-agonist, methoxamine, was as effective as epinephrine in achieving ROSC during CPR, whereas the pure β-agonist, isoproterenol, was no more effective than CPR alone (19). Otto et al. who used pretreatment with α-adrenergic blockade (phenoxybenzamine) and β-adrenergic blockade (propranolol) before infusing epinephrine confirmed 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 determining the effectiveness of CPR is to measure aortic diastolic blood pressure or coronary perfusion pressure (25). When heart muscles do not receive adequate blood flow 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 flows through aorta and into peripheral circulation rather than into narrow more constricted coronary arteries that have high resistance (Figure 1). The use of epinephrine in this situation results in intense peripheral vasoconstriction. This elevates the aortic to right atrial pressure gradient during the relaxation phase of CPR (26–29). Due to this pressure gradient, blood during chest compressions enters the coronary arteries and myocardial blood flow increases. Hence, this pressure gradient is called the coronary perfusion pressure. As oxygenated blood enters the coronary circulation, 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 flow, which is a good predictor of ROSC.

Although minor, β2 receptor-mediated coronary vasodilation may contribute to improved coronary perfusion following epinephrine administration (10, 21, 30). Cerebral electrographic activity and cerebral oxygen uptake improves following epinephrine administration during CPR as cerebral blood flow increases due to epinephrine-induced peripheral vasoconstriction (28, 29). Through its α receptor stimulation, epinephrine may counteract carotid artery collapse induced by elevated intrathoracic pressures due to CPR and further optimize blood flow (28).

Studies utilizing posttransition asphyxia animal model have demonstrated the importance of epinephrine, where after asphyxia cardiac arrest, chest compressions alone were ineffective, but majority of animals reached the critical diastolic blood pressure (rising aortic to right atrial pressure gradient) and ROSC after 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 compressions during CPR (31–33).

The 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. The distribution and maturation of α and β receptors in term and preterm newborns remain unknown (23).

Bradycardia in newly born infants is usually the result of inadequate aeration of lungs and ventilation or profound hypoxemia and acidosis from prior poor placental perfusion. Hence, effective 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 after 30 s of what appears to be effective ventilation with chest rise, followed by 30 s of coordinated chest compressions and ventilations (1, 8, 9).

Epinephrine during neonatal CPR in the delivery room can be given by three routes: intravenous, endotracheal (ET), and intraosseous (Table 1).

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).

Given the limitations of epinephrine in neonatal CPR, there is a great interest in finding other vasoconstrictors that have fewer detrimental side effects. 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 effect on the myocardium, and at low doses, it can vasodilate coronary, pulmonary, and cerebral vessels. Even though it has these theoretical benefits over epinephrine, in randomized control trials in adults, vasopressin has not found to be more effective than epinephrine (67). A cohort study on pediatric in-hospital cardiac arrest vasopressin was found to be less effective and associated with higher mortality (68). In neonatal piglet posttransition asphyxia model, McNamara et al. showed that vasopressin resulted in improved survival, lower postresuscitation 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.

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 different centers. Severe fetal acidemia, malpositioned ET tubes, and ineffective ventilator support contribute to the higher use of delivery room epinephrine (72, 73). Thus, 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 responding to initial positive-pressure ventilation. Provision of effective 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 suffer 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 effects of epinephrine especially postresuscitation hypertension, outcome data become even more important. Multiple retrospective observational studies have noted that preterm neonates requiring CPR and epinephrine have significantly lower survival, higher incidence of early onset sepsis, NEC, grade 3–4 intraventricular hemorrhage, cystic periventricular leukomalacia, bronchopulmonary dysplasia, and neurodevelopmental impairment (7, 74–76). These studies frequently suffer 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. These data suggest that optimization of CPR and epinephrine use in delivery room has potential to impact outcomes significantly.

Epinephrine use in delivery room remains uncommon especially when neonatal providers focus on effective 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 fibrillation cardiac arrest models and posttransition models that have little in common with newborns in the delivery room. There 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, timing, dose, route, and alternatives to epinephrine in neonatal CPR.

VK performed the literature review, created first draft of the article, revised the draft, and created and approved the final draft of the article. MW critically reviewed the first draft, revised the draft, approved the final draft of the article, and contributed substantially to this manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.