Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1028-1034 (doi:10.1542/10.1542/peds.2006-0416)
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Use and Efficacy of Endotracheal Versus Intravenous Epinephrine During Neonatal Cardiopulmonary Resuscitation in the Delivery Room

Chad A. Barber, MD and Myra H. Wyckoff, MD

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Given the paucity of information regarding endotracheal epinephrine for newborn resuscitation, the objectives of this study were: (1) to determine the frequency of endotracheal epinephrine use in newborns in the delivery room, and (2) to determine whether the previously recommended dose of 0.01 to 0.03 mg/kg of endotracheal epinephrine is effective in establishing a return of spontaneous circulation.

PATIENTS AND METHODS. A retrospective review was conducted for all neonates who received ≥1 dose of epinephrine in the delivery room between January 1999 and December 2004. Infants who received ≥1 dose of endotracheal epinephrine in the delivery room during resuscitation were included in the study population whether or not they survived to be admitted to the NICU. Exclusion criteria included lethal congenital anomalies, delivery outside the hospital, and missing medical charts.

RESULTS. Of 93656 infants, 52 neonates (0.06%) received epinephrine in the delivery room, 5 of whom met exclusion criteria. Of the remaining 47 infants, 44 (94%) received the first dose via the endotracheal tube. Only 14 (32%) of 44 achieved return of spontaneous circulation after endotracheal tube administration of epinephrine. Of the 30 remaining infants, 23 (77%) had return of spontaneous circulation with intravenous epinephrine after initially failing endotracheal tube epinephrine. There were no differences in clinical characteristics between newborns who responded to endotracheal tube versus intravenous epinephrine except for a lower blood glucose on NICU admission (52 vs 113 mg%).

CONCLUSIONS. Endotracheal epinephrine is frequently used when intensive resuscitation is required in the delivery room. The previously recommended endotracheal epinephrine dose of 0.01 to 0.03 mg/kg is often ineffective. Higher endotracheal doses will likely be needed to improve efficacy. A prospective study is needed to determine the best endotracheal epinephrine dosing regimen. Until such information is available, intravenous administration should be the preferred route of delivery.

Key Words: newborn • cardiopulmonary resuscitation • epinephrine • asphyxia • endotracheal

Abbreviations: CPR—cardiopulmonary resuscitation • ILCOR—International Liaison Committee on Resuscitation • NRP—Neonatal Resuscitation Program • ETT—endotracheal tube

The vast majority of newborns need little assistance to successfully transition from intrauterine to extrauterine life. For those that do need help, effective ventilation is typically all that is required for stabilization in the delivery room. Thus, the need for cardiopulmonary resuscitation (CPR) and/or epinephrine to support circulation is rare (1.2 per 1000 live births).1 Infants who require intensive resuscitation (CPR ± medications) despite effective ventilation typically suffer from severe asphyxia.1,2 This often results in injury to the brain and other organ systems. Prolonged intensive resuscitation is strongly associated with increased mortality and poor neurologic outcomes,3–6 emphasizing the need to optimize the neonatal resuscitation regimen.

Unfortunately, because the use of medications during neonatal resuscitation is an uncommon event, clinical investigations to determine the most effective dosing regimens for epinephrine do not exist. Previous International Liaison Committee on Resuscitation (ILCOR) guidelines from 19997 (which served as the basis for previous American Academy of Pediatrics/American Heart Association Neonatal Resuscitation Program [NRP] guidelines8) recommended administration of 0.1 to 0.3 mL/kg of a 1:10 000 epinephrine solution (0.01–0.03 mg/kg) either via the endotracheal tube (ETT) or intravenously for an inadequate heart rate (<60 beats per minute) despite adequate ventilation and chest compressions. Although adult and animal data suggest that epinephrine delivery via the endotracheal tube is less efficacious than intravenous,9–12 the endotracheal route was included as an option because intravenous access is rarely available immediately at the time of delivery. New ILCOR guidelines emphasize that administration of epinephrine via the umbilical vein is preferable to endotracheal administration and allow that if no intravenous access is available, higher ETT epinephrine doses (≤0.1 mg/kg) may be used.13 However, there is no information regarding the efficacy of the previous ETT epinephrine dosing regimen at 0.01 to 0.03 mg/kg in newborns or neonatal animal models requiring CPR. Because of concerns from the existing adult and animal literature regarding the efficacy of endotracheal epinephrine, as well as the lack of clinical data, a retrospective clinical review of epinephrine use in neonates in the delivery room was performed. Each case was reviewed to determine how often endotracheal epinephrine is used and whether the previously recommended endotracheal epinephrine dosing achieved return of spontaneous circulation.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population and Data Collection
Parkland Memorial Hospital in Dallas, TX, is a large, urban hospital with >15 000 deliveries and ~1100 NICU admissions per year. As described previously,2 high-risk deliveries and those with unanticipated difficulties in neonatal transition are attended by a resuscitation team. The resuscitation team is composed of a senior pediatric resident or neonatal nurse practitioner, a neonatal nurse with special training in resuscitation, and a neonatal respiratory therapist. A neonatal fellow and/or attending physician is also present for selected high-risk patients and cases requiring CPR. For infants requiring active resuscitation in the delivery room (ie, bag/mask ventilation ± additional therapy), an obstetrica circulating nurse records interventions and heart rate every 30 seconds on a standardized form. The resuscitation team is trained to communicate out loud with one another so that all involved (including the obstetrical nurse recording the resuscitation interventions) can hear the assessments, responses, and next steps to be taken. If any clarifications are needed, the obstetrical nurse will obtain the information before transport of the infant to the NICU. The resuscitation nurse and physician must concur with the resuscitation record before leaving the delivery room. The resuscitation team is specifically trained to focus on effective ventilation and is instructed to confirm endotracheal tube placement and adequate ventilation using best clinical judgment before initiating CPR and/or administering medications in accordance with ILCOR and NRP recommendations.7,8 All of the infants that require CPR and medications in the delivery room are triaged to the NICU.

A resuscitation registry was created in 1990 to prospectively gather information about resuscitation and delivery room stabilization for all of the infants admitted to the NICU. This registry includes data such as date of birth, race, gender, birth weight, gestational age, maternal complications, mode of delivery, details of the resuscitation measures, Apgar scores, cord blood gas values, admission diagnoses, ventilatory support, vital signs, rectal temperature, and admission laboratory values. All of the information is recorded within the first 4 hours of life by the resuscitation nurse. The resuscitation registry is compliant with the Health Insurance Portability and Accountability Act and has been approved for use by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas. A review of this resuscitation registry was conducted to identify all of the neonates that received epinephrine in the delivery room between January 1999 and December 2004. After identification, a comprehensive retrospective review of the medical charts of these infants was performed. All of the infants who received ≥1 dose of epinephrine in the delivery room during resuscitation were included in the study population. Exclusion criteria included lethal congenital anomalies, delivery outside the hospital, and missing medical charts. The study focused on the subset of neonates who received ≥1 dose of endotracheal epinephrine in the delivery room. Endotracheal epinephrine was delivered undiluted by direct injection into the hub of the endotracheal tube and followed by 1 mL of normal saline flush before positive pressure breaths to deliver it to the lungs. Return of spontaneous circulation was defined as return of an audible heart rate >60 beats per minute. Mortality was defined as death before hospital discharge. Approval for this specific study was obtained from the Institutional Review Board of the University of Texas Southwestern Medical Center.

Statistical Analysis
Student's t test was used to compare continuous variables. Categorical data were compared using Fisher's exact test and {chi}2 testing, where appropriate. Statistical significance was defined as a P < .05. All of the statistical analysis was performed using Sigma Stat 3.1 (SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the 6-year study period, 93 656 infants were delivered at Parkland Memorial Hospital. A total of 52 neonates (0.06%) received epinephrine in the delivery room (Fig 1). Five infants were excluded, including 3 with severe congenital anomalies, 1 born at home, and 1 with a missing medical chart. Thus, 47 infants comprised the study population. Three of the 47 (6%) received only intravenous epinephrine, and all 3 (100%) achieved return of spontaneous circulation. As might be expected, for infants who received the first dose of epinephrine intravenously, there was sufficient time to anticipate that intravenous access would be needed (early recognized abruption, maternal motor vehicle accident, and prolonged shoulder dystocia). In each case, there was time to mobilize appropriate personnel and equipment. The remaining 44 infants (94%) received the first dose of epinephrine via ETT (Fig 1), with only 14 of 44 (32%) achieving return of spontaneous circulation within the first 20 minutes of life. The 14 infants who responded to ETT epinephrine are referred to as the ETT epinephrine group. Ten of these infants responded after a single dose of ETT epinephrine, and 4 reestablished perfusion after a second dose of ETT epinephrine. The remaining 30 infants (68%) who did not respond to ETT epinephrine subsequently received intravenous epinephrine. In contrast to the ETT epinephrine group, 23 of 30 (77%) of the infants had return of spontaneous circulation with intravenous epinephrine after failing to respond to ETT epinephrine (P < .001). The 23 infants who responded to intravenous epinephrine after failing ETT epinephrine are referred to as the intravenous epinephrine group. The ETT epinephrine and intravenous epinephrine groups were similar with respect to birth weight, gestational age, gender, breech presentation, meconium staining of amniotic fluid, need for cesarean section, and emergent cesarean section rate (Table 1). The intravenous epinephrine group required intensive resuscitation for a longer time (reflected in the lower 10-minute Apgar score) but did ultimately achieve return of spontaneous circulation (Table 2). There was no difference in the initial dosage of epinephrine used or the time of administration of the first dose of epinephrine between groups. Intravenous epinephrine responders received more total epinephrine doses before return of spontaneous circulation compared with ETT epinephrine responders, reflecting the initial failed endotracheal doses before intravenous administration for the intravenous epinephrine group. Intravenous epinephrine responders received 2 endotracheal epinephrine doses before receiving their first intravenous epinephrine dose and subsequently responded after one 0.01-mg/kg intravenous dose (comparing medians, because data were nonparametric). The time to return of spontaneous circulation after the last dose of epinephrine was shorter for the intravenous epinephrine responders compared with the ETT epinephrine responders. The frequency of asystole, hypovolemia, and severity of asphyxia (as reflected by arterial cord blood gas pH, PCO2, and base excess) was similar for both groups. There were no instances in either group where concerns for inadequate ventilation were subsequently raised.


Figure 1
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  		FIGURE 1 Infants who received epinephrine in the delivery room (1999–2004).

 

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  		TABLE 1 Characteristics of the Study Population

 

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  		TABLE 2 Clinical Features in the Delivery Room for ETT Epinephrine Responders Versus ETT Failures That Subsequently Responded to Intravenous Epinephrine

 
On admission to the NICU, the ETT epinephrine and intravenous epinephrine groups were similar with respect to heart rate, blood pressure, hematocrit, and blood gas values (Table 3). The ETT epinephrine group had significantly lower blood glucose levels on NICU admission. There was a trend for the ETT epinephrine responders to have more hypoglycemia, although the sample size was too small to be statistically significant. The mortality rate for the infants who survived the delivery room and were admitted to the NICU was similar among both groups.


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  		TABLE 3 Clinical Features on Admission to the NICU for ETT Responders Versus ETT Failures That Responded to Intravenous Epinephrine

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Epinephrine is the preferred adrenergic agonist for the treatment of neonatal cardiac arrest that does not respond to effective ventilation. During CPR, the most important action of epinephrine is to stimulate {alpha}-adrenergic receptor-mediated vasoconstriction to elevate the aortic to right atrial pressure gradient during the relaxation phase of CPR (coronary perfusion pressure).14,15 Thus, effective administration of epinephrine leads to increased coronary perfusion pressure, thereby increasing myocardial blood flow that is vital to reestablishing return of spontaneous circulation.16 Consequently, during neonatal cardiac arrest, if effective ventilation and cardiac compressions have failed to reestablish perfusion, epinephrine should be given rapidly by the most accessible route.

This report calls attention to the fact that in the rare but critical situation where a newborn requires CPR and epinephrine in the delivery room, the first dose of epinephrine is almost always delivered via the ETT. Indeed, the only 3 cases where intravenous epinephrine was used for the initial dose were all situations where there was quick recognition that epinephrine might be required before birth, and there was ample time to prepare personnel and equipment for line placement before delivery. It is important to note that initial intravenous epinephrine resulted in successful return of spontaneous circulation of all 3 of the infants. The high frequency of initial use of ETT epinephrine compared with intravenous makes it critical that the recommended dose for endotracheal epinephrine be as effective as possible. This report is the first to describe response rates for the previously recommended endotracheal epinephrine dosing regimen of 0.01 to 0.03 mg/kg from the past ILCOR and NRP guidelines. Disappointingly, this endotracheal dosing regimen failed to establish adequate circulation in more than two thirds of cases, and yet the same dose given intravenously worked the majority (77%) of the time. These findings support the new ILCOR guidelines recommending a higher dose of endotracheal epinephrine.13 In addition, the data raise the possibility that the longer time from birth to establish return of spontaneous circulation for the intravenous epinephrine group was because of time spent waiting to see if there would be a response to endotracheal epinephrine in addition to the time it took to get the umbilical venous catheter in place for intravenous delivery of medication.

One might presume that the response to ETT epinephrine would be contingent on the severity of the insult, such that those who responded to ETT epinephrine were less asphyxiated and, thus, easier to resuscitate. Surprisingly, however, the umbilical artery cord gas, admission vital signs, and arterial blood gas information were equivalent between the ETT epinephrine and intravenous epinephrine groups. There seems to be no obvious way to differentiate who will or will not respond to ETT epinephrine. The poor response to ETT epinephrine and lower blood glucose levels after ETT administration could be because of inadequate absorption. The shorter time to return of spontaneous circulation from the time of intravenous dose for intravenous responders compared with the time from last endotracheal epinephrine dose for ETT epinephrine responders may also point to poorer absorption. Several factors could contribute to insufficient drug absorption in the alveoli, some of which are unique to newborns: (1) insufficient pulmonary blood flow during CPR to transport drugs from the alveoli to the central circulation; (2) pulmonary vasoconstriction from acidosis during cardiac arrest and/or the epinephrine itself, which could impede drug absorption; (3) persistent alveolar fluid that might dilute the epinephrine; and (4) potential right-to-left intracardiac shunts that could bypass the pulmonary circulation altogether via the patent foramen ovale or patent ductus arteriosus, which may persist with ineffective neonatal transition.15 It is possible that other factors, including improper positioning of the endotracheal tube and mechanical obstruction, could contribute to the failure of endotracheal epinephrine.

The fact that using an endotracheal epinephrine dose that is equivalent to the intravenous dosage results in less successful delivery room resuscitation is not surprising, given the aforementioned explanations for limited alveolar drug absorption. Although early experimental work by Redding et al17 suggested that a ETT epinephrine dose (0.1 mg/kg) would be as effective as intravenous epinephrine in achieving return of spontaneous circulation from asphyxia-induced cardiac arrest, most subsequent studies demonstrated that ETT epinephrine is poorly or slowly absorbed and takes longer to work.9–12 Many investigators report that even in adult animal models10,12,18–20 and human patients with intact circulation21–23 (and thus likely sufficient pulmonary perfusion), ≥10 times the currently recommended dose of ETT epinephrine is required to achieve equivalent increases in plasma epinephrine concentrations or to elicit any physiologic effect, such as a rise in blood pressure, when compared with intravenous epinephrine. Manisterski et al24 compared different doses of ETT epinephrine, ranging from 0.02 to 0.3 mg/kg, in healthy anesthetized dogs, but only 10 to 30 times the currently recommended dose (0.3 mg/kg) led to a sustained increase in blood pressure.

Similar to the findings in nonarrest models and patients, most investigators using the ventricular fibrillation (the most common cause of adult cardiac arrest) model of cardiac arrest also report that much higher doses of ETT epinephrine are required to achieve return of spontaneous circulation.10,12,18,25,26 In fact, every single study that has examined the currently recommended ETT epinephrine dose range of 0.01 to 0.03 mg/kg has shown no increase in plasma epinephrine concentrations, blood pressure response, or return of spontaneous circulation when compared with placebo.10,12,25 Although confined to a few small retrospective reviews, even studies of higher dose ETT epinephrine in adult cardiac arrest patients demonstrate little or no benefit.27–29

Asphyxia-induced cardiopulmonary collapse is the most frequent etiology of neonatal cardiopulmonary arrest. Jasani et al30 was only able to successfully resuscitate a third of asphyxiated, asystolic pigs with 0.05 mg/kg of ETT epinephrine (a slightly higher dose than currently recommended). This response rate is similar to that described in the current clinical report. In other studies using asphyxia as the cause for arrest, the rates of return of spontaneous circulation and elevation of mean arterial pressure were significantly lower with ETT epinephrine.17,31

Previous data supporting the use of ETT epinephrine in newborns requiring resuscitation are limited to 3 small, nonrandomized reports. Two of these used significantly higher doses than currently recommended by the NRP.32,33 The third is a case series describing administration of 0.015 to 0.040 mg/kg ETT epinephrine in 10 bradycardic, but not asystolic, newborn infants.34 The reported rapid response in heart rate (within 5–10 seconds) after ETT epinephrine administration calls into question whether these infants truly required and responded to ETT epinephrine.

The limitations of the current study include its retrospective nature and the possibility of type 2 errors given the rarity of the need for epinephrine in the delivery room. In addition, the data are from a single tertiary care center and may not be identical to the findings at other institutions. Whereas the overall number of deliveries during the study period was large, only a small proportion (0.06%) actually received epinephrine in the delivery room and is likely influenced by the presence of a highly trained and experienced resuscitation team that emphasizes effective ventilation. In addition, because all of the infants in the intravenous epinephrine group had failed previously to respond to endotracheal epinephrine, a direct, controlled comparison of ETT versus intravenous epinephrine was not possible. The study focused only on short-term outcomes with particular emphasis on return of spontaneous circulation rather than longer-term neurologic outcomes. Studies of high-dose intravenous epinephrine in adults and children have shown increases in the return of spontaneous circulation compared with low-dose but without long-term neurologic benefit.35,36 A particular strength of the study is that the sequence of delivery room interventions and responses was recorded during the resuscitation by an NRP-trained observer (obstetrical nurse) who was not on the resuscitation team, and these data were prospectively entered in a resuscitation registry.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The vast majority of studies in adults, older children, and animal models have demonstrated that 0.01 to 0.03 mg/kg of endotracheal epinephrine is not capable of achieving return of spontaneous circulation. The findings from this retrospective analysis of newborn infants also suggest that the previously recommended dose of endotracheal epinephrine, although frequently used when intensive resuscitation is required in the delivery room, is not reliable in establishing return of spontaneous circulation. Higher endotracheal doses will likely be needed to improve efficacy, as suggested in the new ILCOR guidelines.13 A prospective study will be needed to determine the best endotracheal epinephrine dosing regimen. Given the difficulties obtaining consent under such unpredictable emergency circumstances, animal studies may be a more realistic alternative. Until such information is available, adequate anticipation and rapidly obtaining intravenous access should be a top priority in the delivery room. Until intravenous access is obtained, endotracheal administration of epinephrine (0.03–0.1 mg/kg) should be considered for bradycardia or asystole that is not responsive to adequate ventilation and chest compressions.13


   FOOTNOTES
 
Accepted Mar 28, 2006.

Address correspondence to Myra H. Wyckoff, MD, University of Texas Southwestern Medical Center, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-9063. E-mail: myra.wyckoff{at}utsouthwestern.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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