What is the optimal initial dose of epinephrine during neonatal resuscitation in the delivery room?

Abstract

The neonatal resuscitation program recommends a wide dose range of epinephrine for newborns who receive chest compressions (endotracheal tube [ET] dose of 0.05–0.1 mg/kg or intravenous [IV] dose of 0.01–0.03 mg/kg), which presents a challenge to neonatal care providers when attempting to determine the optimal initial dose. Dosing errors are common when preparing epinephrine for neonatal resuscitation. Based on animal data, we suggest preparing 0.1 mg/kg or 1 ml/kg of 1 mg/10 ml epinephrine in a 5 ml syringe for ET administration. For IV epinephrine, we suggest preparing an initial dose of 0.02 mg/kg or 0.2 ml/kg of 1 mg/10 ml epinephrine in a 1 ml syringe. A dose of 0.02 mg/kg enables use of a 1 ml syringe for a wide range of birth weights from 500 g to 5 kg. The use of a color-coded syringe may decrease errors in dose preparation.

Half a century ago, research by Redding et al. showed a significant improvement in rates of return of spontaneous circulation (ROSC) following administration of intravenous (IV) epinephrine in a canine model of asphyxia-induced cardiac arrest [1]. Currently, epinephrine is the only vasoactive drug recommended by the International Liaison Committee on Resuscitation (ILCOR) for neonates who remain severely bradycardic (heart rate < 60/min) or in cardiac arrest after effective ventilation has been established. The recommended dose is 0.01–0.03 mg/kg IV followed by a 0.5–1 ml saline flush or 0.05–0.1 mg/kg administered by the endotracheal tube (ET) route pending intravascular access placement [2].

The need for epinephrine during neonatal resuscitation in the delivery room (DR) is exceedingly rare, estimated to be <0.1% of births [3, 4]. As pointed out in a recent commentary, this low rate of use is one of the main reasons we lack strong evidence from clinical trials on the optimal dose, timing and route of epinephrine [5]. The lack of high certainty evidence was demonstrated in a recent systematic review [6], where only four single-center retrospective cohort studies met eligibility criteria for analysis. Only one study (n = 50 patients) provided data that addressed the primary outcome (death before hospital discharge). There was no difference in death before hospital discharge between initial ET vs. IV epinephrine. For the secondary outcome of failure to achieve ROSC, meta-analysis of two studies (n = 97) showed no difference between initial ET and initial IV epinephrine [6]. A retrospective review from the American Heart Association Get with the Guidelines Registry of 1153 neonates receiving chest compressions in the DR between 2001 and 2014 revealed that 561 (49%) of these infants received epinephrine. Shorter time to first epinephrine dose [4 min (IQR 1,8) vs. 7 min (IQR 1,11)] was associated with increased odds of ROSC [7]. As early ROSC may be associated with better outcomes, the incidence of ROSC with the initial dose of epinephrine or the time to achieve ROSC after epinephrine should be considered as important secondary outcomes in future studies. Pediatric studies have shown improved survival with epinephrine administered at <5 min into cardiopulmonary arrest [8-11]. The revised 2020 pediatric life support guidelines suggest that the initial dose of epinephrine in pediatric patients with non-shockable in-hospital or out-of-hospital cardiac arrest should be administered as early during resuscitation as possible [12].

The ongoing lack of strong evidence from clinical studies and the wide recommended dose ranges (ET 0.05–0.1 mg/ kg or IV 0.01–0.03 mg/kg) present a challenge to neonatal care providers when attempting to determine the optimal route and initial dose of epinephrine. More than 100 years ago, translational research played an instrumental role in laying the groundwork for the clinical use of epinephrine [13]. The important contributions that translational animal research can provide to better understand the role of epinephrine in neonatal resuscitation should not be understated. In addition, practical and logistic aspects of preparing the optimal dose of intravascular epinephrine should be taken into consideration.

Animal studies

Studies in a perinatal asphyxiated cardiac arrest lamb model with a transitioning circulation and fluid-filled lungs that closely mimic the newborn in the DR offer valuable knowledge on the use of epinephrine. The fetal lamb has a relatively large size that allows for easy instrumentation to accurately measure important physiologic parameters including blood pressure and blood flow. Frequent blood sampling enables pharmacokinetic and pharmacodynamic (PK/PD) analysis. In lamb models, epinephrine is essential to increase carotid arterial blood flow and blood pressure during chest compressions [14]. In lambs with cardiac arrest from umbilical cord occlusion, ET epinephrine at the higher range of the Neonatal Resuscitation Program (NRP)-recommended dose (0.1 mg/kg) had a significantly lower success in achieving ROSC compared to IV administration of epinephrine at 0.03 mg/kg (30% vs. 83%, respectively; p < 0.05) [15-17]. Also, the peak plasma epinephrine concentrations were significantly lower and delayed following ET epinephrine (umbilical vein 450 ± 190 ng/ml at 1 min vs. ET 130 ± 60 ng/ml at 5 min after epinephrine administration, p < 0.05) [15]. These results provide compelling evidence to support what we clinicians “know from experience” [5] about the effectiveness of epinephrine and the benefits of early IV dosing while resuscitating newborns in the DR. A summary of the effectiveness of epinephrine at different doses and routes of administration from lamb studies is shown in Table 1.

Table 1.

Summary of studies performed in perinatal lambs with cardiac arrest receiving epinephrine [15-17, 26].

Medication	n	Dose (mg/kg)	Route	Administration time from PPV onset (min)	ROSC with first dose	ROSC with multiple doses	No ROSC	p value (cf. 0.01 mg/kg IV)	p value (cf. saline)
Epinephrine	59	0.03	UVC/JV	1–6	49 (83%)	5	5 (8.5%)	0.02b	<0.01b
Epinephrine	4	0.02	UVC	5	3 (75%)	0	1 (25%)	0.61	0.048b
Epinephrine	22	~0.01	UVC/JV	1–6	12 (55%)	3	7 (32%)	N/A	0.047b
Epinephrine	27	~0.1	ET	0.5–1.5	8 (30%)	15a	4 (15%)	0.09	0.30
Epinephrine	6	~0.13	Nasal	1.5	1 (17%)	5a	0	0.17	1
Salinec	5	5 ml	JV	1.5	0	0	5 (100%	0.047b	N/A

ET endotracheal, JV jugular vein, PPV positive-pressure ventilation, ROSC return of spontaneous circulation, UVC umbilical vein catheter.

^aIncludes IV epinephrine.

^bp value by chi-square test.

^c27% of lambs with cardiac arrest (no pulses, no audible heart rate but with minimal electrical activity on EKG) achieve ROSC with 1–5 min of chest compressions before administration of epinephrine in our lab (data based on n = 82 lambs).

The preferred route of epinephrine administration is through a low-lying umbilical venous catheter (UVC), which is followed by a normal saline flush of 0.5–1 ml per the current NRP guidelines. This flush volume may clear a 5 Fr single lumen UVC (internal volume of 0.55 ml) and deposit epinephrine in the umbilical vein [18]. In the absence of spontaneous cardiac activity, this flush volume may not be adequate to propel epinephrine into the right atrium and general circulation during chest compressions. The comparison of plasma epinephrine concentrations and efficacy of different flush volumes (1 ml, 2.5 ml and 3 ml/kg or ~10 ml at term gestation) following epinephrine administration of 0.03 mg/kg through a low-lying UVC in a perinatal asphyxiated lamb model are presented in Table 2. A larger flush volume increases the probability of ROSC with the 1st dose of epinephrine but may be associated with a relatively high plasma epinephrine concentration. There was no difference in post-ROSC heart rate or blood pressure between the three groups. However, the safety of a 3 ml/kg flush in preterm models is not known. For these reasons, we suggest a 2.5–3 ml flush to clear the UVC catheter and propel epinephrine into the ductus venosus. This flush volume was associated with 73% ROSC with the first dose [18].

Table 2.

Comparison of plasma epinephrine concentrations and incidence of return of spontaneous circulation with 1st dose of epinephrine with different flush volumes following low UVC epinephrine [15, 17].

Parameter	1 ml flush volume (n = 7)	2.5 ml flush volume (n = 11)	3 ml/kg (~10 ml in term lambs) flush volume (n = 9)
Plasma epinephrine concentrations (ng/ml)	494 ± 171	450 ± 190	1195 ± 1311
ROSC with 1st dose of epinephrine n (%)	3 (43%)	8 (73%)	8 (89%)a
Heart rate 10 min after ROSC (/min)	198 ± 14	192 ± 14	189 ± 27
Mean blood pressure 10 min after ROSC (mm Hg)	64 ± 25	68 ± 12	63 ± 16

Data are mean (standard deviation).

UVC Umbilical venous catheter, ROSC Return of spontaneous circulation.

^ap < 0.05 compared to 1 ml flush.

Species differences and pharmacokinetic differences between lambs and human babies may influence the applicability of these results to humans. The exact time of insult and arrest are known in animal studies. However, in a clinical setting, the time of insult might be intermittent, prolonged and the time gap between insult and delivery is not known. Other important limitations of current animal studies include the lack of data on long-term and neurological outcomes. However, in the absence of human trials, physiological data from translational animal research has the potential for generating recommendations that could reasonably inform clinical guidelines. These findings support the preference to use IV epinephrine recommended by the American Academy of Pediatrics (AAP) NRP. Given the higher incidence of chest compressions and epinephrine need among preterm infants ≤33 weeks’ gestation (accounting for nearly half of all births receiving chest compressions, although they constitute only 3–4% of all births in the US), studies evaluating optimal dose, pharmacokinetics, and adverse effects of epinephrine among preterm are warranted.

Practical challenges

Logistic and practical challenges play a role in determining the initial dose of epinephrine. Medication errors count among the greatest sources of adverse events in hospitals and weight-adjusted dosing in newborns puts this group at increased risk of drug errors [19]. Data by the Vermont Oxford Network’s voluntary reporting system has revealed that about half of reported errors are drug errors [20]. Simulation studies have shown that dosing errors are common when preparing epinephrine for neonatal resuscitation whether the dose is ordered using a mass (mg/kg) or volume (ml/kg) expression [21]. Selecting the wrong concentration of epinephrine is an important source of potential errors. Because epinephrine is available in two concentrations (1 mg/1 ml and 1 mg/10 ml), selecting the wrong concentration can result in a tenfold dosing error, and use of a printed cognitive aid only partially decreases the risk [22]. To prevent errors, we recommend stocking only the dilute solution of epinephrine (1 mg/10 mL) in the DR and preparing the dose in a 5 ml syringe for endotracheal administration or a 1 ml syringe for intravascular (including low UVC) and intraosseous administration.

Currently, preparation of epinephrine requires weight-based calculations and use of an unfamiliar transfer device during the time-pressure and emotional stress of a neonatal resuscitation. This increases cognitive load and the likelihood of dosing errors [21, 23]. Based on animal data, and to simplify the required calculations [15, 24], we suggest using 0.1 mg/kg or 1 ml/kg of 1 mg/10 ml epinephrine for endotracheal administration to newborns with fluid-filled lungs in the DR. For intravascular (including low UVC) and intraosseous epinephrine, we suggest an initial dose of 0.02 mg/kg or 0.2 ml/kg of 1 mg/10 ml epinephrine. The advantages and disadvantages of 0.01, 0.02 and 0.03 mg/kg are shown in Fig. 1. A dose of 0.02 mg/kg enables use of a 1 ml syringe for a wide range of birth weights from 500 g to 5 kg. At this dose, 0.1 ml of epinephrine can be reliably prepared in a 1 ml syringe for an extremely premature infant weighing 500 g [23]. The NRP has released the practice changes for the upcoming 8th edition textbook (https://downloads.aap.org/AAP/PDF/NRP%208th%20Edition%20Busy%20People%20Update%20(1).pdf). To further decrease the risk, we suggest development and testing of a purpose-built, color-coded 5 ml syringe for neonatal endotracheal administration and a different color-coded 1 ml syringe for neonatal IV epinephrine administration as shown in Fig. 1 [25]. The color-coded syringes will be subcategorized into four zones by weight, for example: (purple) <1 kg, (yellow) 1–2 kg, (green) 2–3 kg and (pink) 3–5 kg. The color-coding will add a layer of safety when drawing up the medication. When the exact weight is known, the volume of epinephrine drawn should fall within the corresponding color zone. When the infant’s weight is estimated, the color-coded syringe facilitates drawing the medication within the limits of the zone corresponding to the estimated weight without the need to calculate an exact dose. The estimated weight will be rounded up to the nearest kg.

Fig. 1. Suggested initial endotracheal and intravenous (IV) epinephrine doses using 5 ml and 1 ml syringes, respectively.

The use of color-coded syringes may decrease errors in dose preparation. The advantages and disadvantages of the current recommended IV epinephrine dose range of 0.01–0.03 mg/kg used during neonatal resuscitation.

We recognize the ongoing need for randomized clinical trials, observational studies in term and preterm infants from registries and large delivery services, and animal data evaluating the optimal dose of epinephrine. These studies will provide much needed evidence on the optimal dosing and route of administration that results in the best long-term outcomes.