Characteristics and outcomes of very low birth weight infants receiving epinephrine during delivery room resuscitation

Accepted Manuscript Title: Characteristics and outcomes of very low birth weight infants receiving epinephrine during delivery room resuscitation Author: Malvi Savani Kirtikumar Upadhyay Ajay J. Talati PII: DOI: Reference:

S0300-9572(17)30109-0 http://dx.doi.org/doi:10.1016/j.resuscitation.2017.03.009 RESUS 7101

To appear in:

Resuscitation

Received date: Revised date: Accepted date:

5-12-2016 2-3-2017 7-3-2017

Please cite this article as: http://dx.doi.org/10.1016/j.resuscitation.2017.03.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Characteristics and outcomes of very low birth weight infants receiving epinephrine during delivery room resuscitation

3 Malvi Savani1, Kirtikumar Upadhyay1, Ajay J. Talati1,2

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1Division

of Neonatal-Perinatal Medicine, Department of Pediatrics and 2OB/GYN, University of Tennessee Health Science Center,

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Memphis, TN, USA

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Correspondence:

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Ajay Talati, MD

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Division of Neonatal-Perinatal Medicine

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853 Jefferson Ave #201

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Memphis, TN 38163

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E-mail: [email protected]

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Phone #: 901-448-4751

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Scientific Section: Neonatal Resuscitation, original article

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Running Title: VLBW and epinephrine

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Key Words: preterm, survival, resuscitation, epinephrine

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Pages: 18

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Word Count: abstract-239; manuscript-2097; references- 18; figures- 1; tables- 4

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31 32 33 34

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37 38 ABSTRACT

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Background: Delivery room resuscitation of very low birth weight infants can involve use

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of endotracheal or intravenous epinephrine. Data of the past 19 years were reviewed to

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identify the usage of epinephrine in delivery room and identify characteristics of these

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babies. Methods: Neonates with ≤1500gm birthweight from January 1996 to August 2014

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were reviewed. Infants born alive and admitted to NICU were eligible. Characteristics such

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as demographics, survival and outcomes were recorded. Variables significant at p≤0.1

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among neonates receiving epinephrine were further analyzed via multiple logistic

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regressions. Results: Out of 5868 eligible neonates, 416 (7%) received epinephrine in the

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delivery room. The infants who received epinephrine were of lower estimated gestational

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age (25 vs 28 wk) and lower birth weight (746 vs 980g). Gender, race and mode of delivery

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were comparable between the two cohorts. Survival was higher in non-epinephrine group

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(89.4 vs 61.1%). Bacterial infection (24.3 vs 18.4%) and combined grade 3 and 4

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intraventricular hemorrhage (18.4 vs 8.4%) were higher in epinephrine group. Use of

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epinephrine in the delivery room was associated with decreased survival even after

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controlling for birth weight, gestational age and low Apgar scores [Odd ratio- 0.48 with 95%

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CI (0.37-0.62), p <0.001). Conclusion: Neonates with lower birth weight and younger

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gestational age were more likely to receive epinephrine during resuscitation at birth. Use of

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epinephrine in delivery room was associated with lower survival and severe

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intraventricular hemorrhage among very low birth weight infants.

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67 INTRODUCTION

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Of the approximately 4 million annual births in the United States, 10 percent fail to initiate

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effectual breathing; most of these neonates start breathing after initial stimulation by the

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health personnel while about 3-5% need basic resuscitation, and <1% require advanced

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resuscitative effort to achieve efficient circulation to the vital organs.1 Approximately 6-

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10% of very low birth weight (VLBW) and extremely low birth weight (ELBW) infants are

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reported to receive extensive CPR measures.2 In addition, a proportion of infants receive

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extensive resuscitative measures during their stay in the neonatal intensive care unit

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(NICU).3

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Extensive delivery room (DR) resuscitation constitutes initiation of CPR with or without the

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use of EPI during the first few minutes of birth when respiratory support alone fails to

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restore cardiopulmonary circulation.1,4,5 American Academy of Pediatrics (AAP) guidelines

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for neonatal resuscitation, CPR is initiated in infants with a persistently decreased heart

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rate (HR) of less than 60 beats per minute (bpm) despite positive pressure ventilation. And

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if adequate ventilation and oxygenation, preferably through an endotracheal tube, coupled

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with chest compressions fails to increase HR to greater than 60 bpm, administration of 0.01

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to 0.03 mg/kg EPI or volume, or both, is indicated.4,6 The guidelines regarding use of IV EPI

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remained unchanged while the use of endotracheal route for EPI was deemed suboptimal.

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The evidence of these recommendations is based on consensus of experts’ opinion and

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based on very limited population studies mainly in adults and animals.4 This leads to

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evolving controversies regarding neonatal resuscitation, especially in extremely preterm

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infants.

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While EPI does pose the risk of vasoconstriction and an increase in myocardial oxygen

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consumption, it is optimal in providing adequate cerebral perfusion while simultaneously

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increasing coronary blood flow to restore cardiopulmonary circulation.7 However, the use

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of DR-CPR still remains controversial as multiple institutions present suboptimal outcomes

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of VLBW and EBLW infants who underwent DR-CPR.8

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Reports of outcomes of infants who have received extensive CPR efforts have yielded

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varying results.9,10 The data regarding outcomes of neonates, including VLBW infants in

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particular that receive EPI during DR resuscitation is sparse.8 The objective of our study

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was to identify the characteristics and outcomes of VLBW infants who received extensive

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CPR with use of EPI in delivery room at our institution over the last 2 decades.

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100 METHODS

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In this cross-sectional retrospective study, medical records of all deliveries and the

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newborns ≤1500g birth weight during a period from January 1996 to August 2014 were

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selected. All live newborn infants who were admitted to the NICU of Regional One Health

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were included in the study. The NICU staff attends deliveries for all VLBW infants at

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Regional One Health and admits infants directly to NICU from the DR. Exclusion criteria for

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the purposes of our study include infants that died in the delivery room and could not be

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admitted directly to the NICU. In addition, infants weighing less than 250 g were also

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excluded from the study. The groups in our study were stratified into those infants who

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received EPI and those who did not receive EPI in the DR. All health care providers in DR

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including neonatal nurse practitioners, pediatric residents, neonatology fellows are trained

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in the Neonatal Resuscitation Program (NRP) and follow NRP guidelines for resuscitation of

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newborn, under the supervision of a neonatologist. The study was approved by the

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University of Tennessee Health Science Center Institutional Review Board.

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Data

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All data were obtained from a perinatal database of the infants’ medical records. Neonatal

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characteristics including gender, race, gestational age (GA), birth weight (BW), mode of

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delivery, antenatal steroids, Apgar scores, bronchopulmonary dysplasia (BPD), necrotizing

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enterocolitis (NEC) stage 2 or 3, bacterial infection, patent ductus arteriosus (PDA),

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intraventricular hemorrhage (IVH) grade 3 or 4 along with other delivery room course,

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admission, and discharge information of neonates were recorded by investigators. IVH was

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defined by Papile’s classification of blood in germinal matrix or ventricular system with or

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without ventricular dilatation and parenchymal extension.11 Our study focused on severe

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IVH defined by grade 3-4.11 NEC stages were defined by clinical criteria developed by Bell in

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1978.12,13 Survival was defined as discharge home from NICU. Infants receiving EPI were

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compared to the rest of VLBW infants.

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Statistical analysis

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Differences between the two groups were analyzed using t-test and chi-square tests. A p-

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value of <0.05 was considered statistically significant. Multiple logistic regression was

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performed to adjust for the impact of some of the clinically significant univariates on

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mortality among neonates receiving EPI in DR.

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RESULTS

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Out of 5868 eligible neonates admitted to the NICU, EPI was administered during delivery

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room resuscitation to 416 (7.08%). Figure 1 shows the distribution of EPI use in DR over

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the past 18 years and was similar over the years. The median GA was 28 weeks (IQR 26-30

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weeks) for the group of infants that did not receive DR EPI and 25 weeks (IQR 24-27 weeks)

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for the group that did receive DR EPI. Table 1 outlines the demographics of infants between

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the two cohorts in our study. Mean BW was lower among VLBW infants who received

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epinephrine in delivery room compared to those who did not receive epinephrine with a

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mean BW 746 g ± 251 vs 980 g ± 319, respectively. Approximately half of the neonates in

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both groups were males with a greater proportion of neonates that were identified as

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African-Americans in both cohorts as well. Mode of delivery was comparable between both

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cohorts while Apgar scores at 1 and 5 minutes were lower in the group receiving DR EPI.

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Survival to hospital discharge among those that did not receive DR EPI was 89.4%

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compared to 61.1% among those that did receive DR EPI (Table 2). BPD was noted in 22.7%

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of neonates that did not receive DR EPI and in 52.1% of neonates that did receive DR EPI.

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Table 2 shows the differences in other outcomes such as hemodynamically significant PDA,

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bacterial infections and grade III/IV IVH. Table 3 outlines mortality during hospital stay

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stratified by birth weight and epinephrine utilization with unadjusted odds ratios.

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Multivariate logistic regression showed that use of epinephrine in delivery room was

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associated with decreased survival even after controlling for BW and low Apgar scores (<2)

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at both 1 and 5 min [Odds ratio 0.48 with 95% CI (0.37-0.62)], p <0.001) as outlined in

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Table 4.

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154 DISCUSSION

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Timely identification and prompt resuscitation of newborns in the delivery room (DR) may

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cause a decline in neonatal morbidity and mortality. Due to recent advances in neonatal

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medicine, there has been an improvement in the outcomes of VLBW infants.14 This trend

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can be partly explained by advances in initial resuscitation efforts during “the golden hour”

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after delivery. Recent NRP guidelines recommend use of IV route over endotracheal

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administration of epinephrine.15 Endotracheal route results in unpredictable absorption of

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EPI, requiring a much higher dose of EPI than the IV route. The guidelines, however, do not

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address the use of EPI specifically for VLBW infants and the effect of EPI on morbidity and

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survival. Our institutional experience with DR EPI in VLBW infants reveals a decreased

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survival in the group receiving EPI versus those that did not receive EPI despite correction

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for BW and Apgar scores. Moreover, infants with a lower BW were in general more likely to

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receive DR EPI.

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Our study revealed 10.5% mortality within 24 hours among infants receiving EPI versus

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3.3% mortality within 24 hours among infants that did not receive EPI. In concordance with

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our study, a similar study conducted by Cho et al in Korea analyzing outcomes among VLBW

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showed a greater early mortality of less than 7 days along with an increased IVH ≥ grade 3,

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periventricular leukomalacia and NEC in the group receiving DR-CPR compared to those

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only receiving positive pressure ventilation.16 Our study showed an 18.4% incidence of IVH

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≥ grade 3 among infants receiving EPI versus 8.4% among those that did not receive EPI.

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Both outcomes necessitate the importance of meticulous monitoring of infants receiving

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epinephrine during DR-CPR to reduce the early deaths in susceptible VLBW infants.

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Wyckoff et al examined 1333 out of 8685 ELBW infants that underwent DR-CPR defined as

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chest compressions, medications or both.4 The study noted higher rates of mortality and

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neurodevelopmental impairments in infants who received DR-CPR, raising the question of

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the risks versus long term survival benefits of DR-CPR.5 In contrast, our study specifically

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evaluated the use of EPI in infant outcomes due to its effect on the cardiovascular system

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while the Wyckoff et al noted a worse outcome with the use of both chest compressions and

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medications.

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A study conducted by Frontanes et al reviewed the outcomes of 1,604 VLBW infants out of

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which 100 received EPI in the DR.8 Their study excluded infants with BW of less than 500 g

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while we reviewed all NICU admissions over 250 g BW. Moreover, while Frontanes et al

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included demographics and results with matched controls, our study incorporated all 5,868

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VLBW infants to avoid the possibility of selection bias. Similar to our study, they noticed

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those infants who received EPI were generally smaller in terms of BW and GA. However,

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overall survival was lower in the EPI group (26% vs. 43%, p<0.01). Of note, the overall

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survival was remarkably lower for both groups in their study compared to our cohorts

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(61.1% vs. 89.4%, p<0.0001). In terms of the incidence of grade 3 and 4 IVH, Frontanes et al

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noted a higher rate of grade 3 and 4 IVH in the cohort of infants that received EPI versus

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those that did not (42% vs. 29%) that was not statistically significant. Our study noted a

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statistically significant increase in the rate of grade 3 and 4 IVH in the group of infants that

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received DR EPI (8.4% vs. 18.4%, p<0.0001). However, the difference in the magnitude of

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survival could be attributed to the overall difference in neonatal mortality and NICU

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management in the United States and Puerto Rico, which poses a challenge to the

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generalizability of their results.8

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A retrospective study was led by DeMauro et al that evaluated the relationships between

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intensity of DR resuscitation and outcomes at a corrected age of 18 months in a large

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international cohort of 2006 VLBW infants enrolled in Caffeine for Apnea of Prematurity

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Trial.17 The study revealed that the risk of death or neurodevelopmental disability at 18

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months did not increase substantially with increasing intensity of DR resuscitation.17

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We have several limitations to our study including the fact that our data could not be

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stratified between those infants that received endotracheal versus IV EPI. Animal studies

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have shown that administration of EPI through the endotracheal route at the recommended

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dose of 10 μg/kg is found to be ineffective. Since the change in AAP guidelines, it has been

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shown that a much higher dose of EPI is required to be effective if administered via the

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endotracheal route in place of IV administration.5 Another limitation of our study includes

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the fact that the number of doses of epinephrine that each infant received in addition to any

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possible dosing errors could not be obtained in our collection of data. Epinephrine doses

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given under resuscitation can possibly be out of the recommended range of dose and such

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errors could be life-threatening.18 However, we cannot address it due to unavailability of

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such information in our database.

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Practical nonpharmacological alternatives to address prolonged bradycardia and/or

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asystole included preventative measures and treating the underlying etiology of the cardiac

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arrest. Delayed cord clamping in preterm infants can help maintain an adequate circulating

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volume after the expansion of pulmonary circuit, thus avoiding a stimulus for bradycardia

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and the subsequent sequelae from immediate clamping.15 Accurate identification of specific

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risk factors and anticipation at birth of a high-risk neonate should prompt adequate

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preparation and resuscitation of neonates that might require a higher level of care.

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223 CONCLUSION

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Neonates of a smaller birth weight and lower GA were noted to be more likely to receive DR

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EPI. A greater proportion of neonates that received DR EPI also had lower Apgar scores at 1

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and 5 minutes compared to those that did not receive DR EPI. Moreover, the incidence of

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grade III and IV IVH along with BPD was significantly higher in neonates that received DR

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EPI than those that did not. A significant proportion of neonates that did not receive DR EPI

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had an improved survival. More preterm and lower birth weight neonates required

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epinephrine during neonatal resuscitation and its use was associated with higher mortality.

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Longer-term neurodevelopmental assessment of surviving infants could identify the

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potential impact of EPI on the developing brain.

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CONFLICT OF INTEREST STATEMENT

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The authors declare no conflict of interest.

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CONFLICT OF INTEREST STATEMENT

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All the authors have made substantial contributions to the conception and design of the study, data acquisition, analysis and interpretation of data, and drafting the manuscript. All authors have also reviewed the final versions of the manuscript and have no conflict of interest to disclose.

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cardiopulmonary resuscitation in the delivery room for infants born at less than 33

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weeks gestational age. Resuscitation. 2014;85(2):238–43.

2. Fanaroff AA, Hack M, Walsh MC. The NICHD neonatal research network: changes in

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practice and outcomes during the first 15 years. Semin Perinatol. 2003;27(4):281-

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3. Finer NN, Horbar JD, Carpenter JH, Network FTVO. Cardiopulmonary Resuscitation

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in the Very Low Birth Weight Infant: The Vermont Oxford Network Experience.

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Pediatrics. 1999;104(3):428-434.

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4. The International Liaison Committee on Resuscitation. The international liaison

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6. Kattwinkel J, Perlman JM, Aziz K, et al. Part 15: Neonatal Resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18_suppl_3).

7. Caen ARD, Maconochie IK, Aickin R, et al. Part 6: Pediatric Basic Life Support and Pediatric

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8. Frontanes A, García-Fragoso L, García I, Rivera J, Valcárcel M. Outcome of very-low-

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birth-weight infants who received epinephrine in the delivery room. Resuscitation.

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2011;82(4):427–430.

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9. Lantos JD, Miles SH, Silverstein MD, Stocking CB. Survival after Cardiopulmonary Resuscitation in Babies of Very Low Birth Weight. N Engl J Med. 1988;318(2):91-95.

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11. Papile LA, Burstein J, Burstein R et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500

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Table 1. Demographics of Very Low Birth Weight Infants No Epinephrine (n=5452)

Epinephrine (n=416)

p value

Maternal Age

24.93 (13-46)

24.03 (14-43)

p=0.006

Gestational Age (OB/US)

28 (27-30)

25 (24-27)

p<0.001

p=0.472

54.6%

51.6%

C-section

45.3%

48.3%

Male Gender

49.8%

51.4%

Birth Weight (grams)

980.33 (±319)

746.34 (±251)

African-American

81.2%

Apgar <5 at 1 min

47.8%

Apgar <2 at 1 min

12%

Apgar <5 at 5 min

14.9%

Apgar <2 at 5 min

5.2%

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Vaginal

p<0.001

82.4%

p=0.096

96.5%

p<0.001

59.8%

P<0.001

66.5%

p<0.001

22.4%

P<0.001

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p=0.514

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Mode of Delivery

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Table 2. Clinical Outcomes of Very Low Birth Weight Infants Epinephrine (n=416)

p value

18.4%

24.3%

p=0.004

Hemodynamically 13.4% significant PDA

31.2%

p<0.001 p<0.001

Grade III/IV IVH

8.4%

18.4%

Death <24 hours

3.3%

10.5%

Survival to discharge

89.4%

61.1%

307

p<0.001

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p<0.001

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Bacterial Infection

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No Epinephrine (n=5452)

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Table 3. Infant mortality by birth weight and epinephrine utilization Unadjusted Odds ratio ( 95% CI)

72% (41/57)

p<0.001

0.27 (0.14-0.5)

20% (221/1093)

45% (89/199)

p<0.001

0.33 (0.24-0.46)

751-999 g

7.7% (95/1229)

24.4% (23/94)

p<0.001

1001-1250 g

3.82% (51/1334)

10.8% (5/46)

p=0.017

1251-1500 g

2.67% (37/1381)

20% (4/20)

p<0.001

N= 416

250-500 g

41% (172/415)

501-750 g

311

0.26 (0.15-0.45)

0.31 (0.11-0.83)

0.15 (0.04-0.56)

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EPI administration

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p value

No EPI administration

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Table 4. Infant

Odds Ratio Estimate

Birth weight

95% Confidence Interval

1.003

1.002- 1.003

1 min apgar ≤2

2.219

1.748- 2.816

5 min apgar ≤2

5.157

3.813- 6.975

Use of epinephrine

0.481

0.370- 0.625

320 321 322 323 324

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Table 4. Multivariate logistic regression show decreased survival with use of epinephrine when adjusted for birthweight and Apgar scores

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(continuous)

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Point estimate

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Characteristics

Figure 1. Use of DR-EPI in NICU from 1996-2013

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