Physiology of neonatal resuscitation: Giant strides with small breaths

Abstract

The transition of a fetus to a newborn involves a sequence of well-orchestrated physiological events. Most neonates go through this transition without assistance but 5—10% may require varying degrees of resuscitative interventions at birth. The most crucial event during this transition is lung inflation with optimal concentrations of oxygen. Rarely, extensive resuscitation including chest compressions and medication may be required. In the past few decades, significant strides have been made in our understanding of the cardiorespiratory transition at birth from a fetus to a newborn and the subsequent resuscitation. This article reviews the physiology behind neonatal transition at birth and various interventions during neonatal resuscitation.

Introduction

Among the 140 million live births globally in a year, about 5—10% of newborns require some intervention to initiate breathing at birth and 1% require extensive resuscitation.¹ Neonates constitute 33% of the infants dying every year in the United States (U.S.), one-quarter of which are secondary to birth asphyxia.^2,3 In the past three decades, phenomenal strides have been made in the field of neonatal resuscitation with improvement in neonatal outcomes. These include deferred cord clamping (DCC), an emphasis on early establishment of ventilation, provision of positive end expiratory pressure (PEEP) in the delivery room (DR), judicious use of oxygen (O₂) during resuscitation, approach to meconium-stained amniotic fluid (MSAF), optimizing depth of chest compressions (CC) and dose and flush volume with epinephrine. Temperature regulation by providing warmth is a key initial step in newborn resuscitation and can be accomplished by kangaroo mother care.⁴ This article is a narrative review of fetal to neonatal transition and the physiologic basis of neonatal resuscitation.

Fetal to neonatal transition (Fig. 1)

Fig. 1 –

Changes in PaO₂ (A), mean systemic arterial pressure and mean pulmonary arterial pressure (all in mmHg) and pulmonary blood flow (in ml/kg/min) in near-term lambs (B). The cord was clamped at birth. Pooled data from Lakshminrusimha et al (Copyright Satyan Lakshminrusimha (2021)).^70,71 The role of ductal flow in increasing blood flow to the lung after birth is shown in C and D. During fetal life, pulmonary arterial pressure is higher than systemic arterial pressure and ductus arteriosus shunts right-to-left. After clamping the umbilical cord, systemic vascular resistance increases and with aeration of the lungs, pulmonary vascular resistance decreases, leading to a left-to-right shunt across the ductus further contributing to oxygenated blood flowing through the pulmonary artery leading to further vasodilation. Copyright Satyan Lakshminrusimha (2021).

In the fetus, 85—90% of the right ventricular output bypasses the lungs and enters the descending aorta through the ductus arteriosus.⁵ After oxygenation in the placenta, at least 50% of the umbilical venous blood passes through the ductus venosus to the inferior vena cava without significant mixing, and enters the left atrium through the foramen ovale. Thus, the umbilical venous return is the primary source of left ventricular preload in the fetus (Figs. 1C and 2A), although fetal breathing movements may lead to increase in fetal pulmonary blood flow and decrease in pulmonary vascular resistance (PVR).

Fig. 2 –

Fetal circulation (A) and oxygenation changes associated with immediate cord clamping (ICC) before establishment of ventilation (B) and deferred cord clamping (DCC) after establishment of ventilation (C). During fetal life, the main source of left ventricular (LV) preload is the umbilical venous (UV) return with oxygen saturation (SO₂) of 80—85%. Pulmonary venous (PV) return contributes to a small portion of LV preload with an SO₂ of 55% from a fluid-filled lung. With ICC, there is abrupt loss of UV return, and PV return, as it slowly increases with aeration of a partially fluid filled lung, is the sole source of LV preload. Thus, the cardiac output is low and there is higher risk of severe intraventricular hemorrhage (sIVH). With DCC on the other hand, there is “dual-site” gas exchange as both the UV and the PV bring oxygenated blood to the heart, thus improving cardiac output and decreasing risk of sIVH. Copyright Satyan Lakshminrusimha (2021).

At birth, the fetal lung fluid is absorbed into the pulmonary interstitial space and lymphatics and is replaced by air with the first few breaths (the predominant mechanism being Na⁺ uptake across the airway epithelium leading to lung liquid reabsorption, stimulated by stress induced epinephrine release, and to a lesser extent, squeeze by the birth canal).^6,7 In term infants, the crying breaths⁸ with expiratory braking distribute air uniformly to more alveoli establishing functional residual capacity (FRC).⁹ Inflation of the alveoli with air containing 21% O₂ increases alveolar oxygen tension (PAO₂) and arterial oxygen tension (PaO₂) leading to a decrease in PVR (Fig. 1A and B). Cord clamping detaches the low resistance placental circulation and raises the systemic vascular resistance (SVR) reversing the ductal shunt from right-to-left to left-to-right (Fig. 1D). All these changes result in a dramatic increase in pulmonary blood flow which along with lung aeration enables the lungs to take over as the primary organ of gas exchange.¹⁰ However, in extremely preterm infants, 21% oxygen may not be adequate to mediate pulmonary vasodilation and a higher inspired oxygen of ~ 30% may be needed.¹¹

Deferred cord clamping (DCC)

Immediate or early cord clamping prior to onset of ventilation can deprive the left ventricle of its preload that is derived mainly from the umbilical venous return (and shunting via foramen ovale), in the absence of adequate pulmonary venous return (Fig. 2B).^12,13 On the other hand, physiological or deferred cord clamping (DCC) after lung aeration with adequate FiO₂ facilitates adequate preload to the left ventricle from both of these sources, until pulmonary venous return is sufficient to take over the role (Fig. 2C). Additionally, both the placenta and the lungs can serve as sites of gas exchange (Fig. 2C),¹⁴ until ventilation and pulmonary blood flow are well established. Initial breaths of the newborn facilitate this placental transfusion, that appears to be independent of the cessation of cord pulsations.^13,15 In a clinical retrospective cohort study by Lodha et al. comparing DCC and immediate cord clamping, infants born between 22 and 28 weeks gestation were included from tertiary neonatal intensive care units (NICUs) in the Canadian Neonatal Network. In this study, DCC was associated with significantly reduced odds of the primary composite outcome of neurological injury or mortality (Adjusted odds ratio, AOR 0.80; 95% confidence interval CI, 0.67—0.96), mortality (AOR 0.74; 95% CI, 0.59—0.93), and severe neurological injury (AOR 0.80; 95% CI, 0.84—1.19).¹⁶ During brief ventilation or CPAP with high inspired O₂ in extremely preterm infants¹⁷ and lambs,¹⁴ DCC “dilutes” systemic PaO₂ by diluting pulmonary venous return (with SO₂ of ≥95%) with umbilical venous return (SO₂~85%) thereby limiting systemic oxygen toxicity (Fig. 2C).

DCC of 1 and 5 min increases blood volume, RBC mass and hematocrit at birth (thus improving iron stores, decreasing iron deficiency anemia and need for transfusions), reduces risk of necrotizing enterocolitis and intraventricular hemorrhage (IVH) in premature infants, and improves developmental outcomes.^18,19 However, polycythemia and hyperbilirubinemia are known complications of DCC.²⁰ The American College of Obstetrics and Gynecology (ACOG) recommends delaying cord clamping by 30—60 s after birth in vigorous term and preterm infants, whereas the recent Consensus on Science and Treatment Recommendations (CoSTR) from the International Liaison Committee on Resuscitation (ILCOR) recommends delaying by ≥60 s (weak recommendation, very low certainty evidence) for term and late preterm infants born at ≥ 34 weeks and at least 30 s for infants born at < 34 weeks gestation not requiring immediate resuscitation (weak recommendation, low certainty of evidence).²¹ Although DCC is feasible in dichorionic twins as demonstrated by a retrospective study, pregnancies with multiple gestation have not been included in most clinical trials.²² Keeping in mind potential benefits of DCC and theoretical risks with hemodynamic compromise in monochorionic placentation, the ACOG states that there is not enough evidence to recommend for or against DCC in the setting of multiple gestation.²¹ Umbilical cord milking is not recommended due to association with death/ severe IVH in extremely premature infants.²³ This association between severe IVH and umbilical cord milking is more common in extremely preterm infants following vaginal delivery in the presence of chorioamnionitis and lack of spontaneous respiration. We speculate that an abrupt increase in systemic vascular resistance in the descending aorta induced by milking leads to a surge of blood to the brain leading to IVH. In the absence of spontaneous breathing, PVR remains high preventing a pop-off across the ductus (Fig. 3). A clinical trial is currently ongoing to evaluate cord milking in non-vigorous term neonates (NCT03631940).

Fig. 3 –

Umbilical cord milking (UCM) and association with severe intraventricular hemorrhage (IVH) in extremely preterm infants. We speculate that following vaginal delivery, with uterine contractions, there is high placental vascular resistance. With milking of the umbilical cord, the reverse pull of blood in the umbilical arteries leads to high pressure in the descending aorta. In extremely preterm infants, high pulmonary vascular resistance secondary to poor spontaneous breathing prevents left-to-right ductal shunt. The net effect is a huge surge in blood to the brain resulting in severe IVH. Based on Katheria et al.⁷² Copyright Satyan Lakshminrusimha (2021).

Ventilation

During fetal life, the larynx offers resistance to efflux of lung liquid resulting in lung distension to approximately functional residual capacity (FRC). This distending pressure generated by the fetal lung fluid (~100 ml at term gestation) is essential for lung development. The first cry after birth generates a large negative pressure breath (with forceful exhalation against a partially closed glottis). This in turn generates FRC with air that inflates the lung with an increase in hydrostatic pressure in the alveoli, leading to expulsion of the lung fluid out of the alveoli and into the interstitial space. Within 3—5 breaths with large inhalations and slow exhalations, the lung fluid is cleared and the compliant neonatal chest wall allows for adequate lung expansion.¹⁰ Lung aeration (even regional) in turn decreases PVR leading to global increase in pulmonary blood flow that will eventually serve as the sole source of left ventricular preload (Fig. 1).¹⁰

Most newborns take their first breath with no or minimal interventions such as drying and stimulation. A fetus in primary apnea can recover following birth with stimulation. However, in the presence of secondary apnea, stimulation is not adequate. About 56% of newborns require positive pressure ventilation (PPV) to establish respiration due to secondary apnea, while ~2% require an advanced airway (i.e. endotracheal intubation).²⁴ A bag and mask or a T-piece resuscitator with an appropriate sized mask is used to provide PPV. The American Academy of Pediatric-Neonatal Resuscitation Program (NRP) guidelines recommend the use of 2-person technique with one person performing two-hand hold to ensure adequate seal around the mask and the second person providing breaths, to improve effectiveness of PPV (Fig. 4). Effective PPV that moves the chest is promptly followed by a rise in heart rate and a subsequent rise in arterial blood pressure.²⁵ Laryngeal mask airways (LMAs) may be used as an alternate interface for ventilation, and may be especially advantageous in low-resource settings. When PPV is not effective, troubleshooting using “MR.SO.PA” (mask adjustment, reposition of head, suctioning of mouth then the nose, opening of mouth, pressure increase and alternate airway, in that sequence) should be performed.²⁶ The use of respiratory function monitors in DR has been suggested to measure the exhaled tidal volume and exhaled CO₂ to optimize PPV, but their use does not increase the percentage of lung inflations within a predetermined range of exhaled tidal volume.^27,28

Fig. 4 –

Proper technique for holding the face mask during PPV in the delivery room (two-person technique or two-hand hold for mask ventilation).

On the other hand, spontaneously breathing term infants can experience respiratory distress at birth (most likely due to retained fetal lung fluid) and may require face mask CPAP delivered using either a flow-inflating bag or a T-piece resuscitator (but not a self-inflating bag without a PEEP-valve, which is commonly used in resource-limited settings). Vyas et al., measured pulmonary pressures in spontaneously breathing neonates in the first postnatal minutes and reported median pressures of 40 cm H₂O (range 12—80) and 72 (12—120) cm H₂O during inspiration and expiration respectively.²⁹ Although adding another 5–6 cm H₂O through CPAP to the existing airway pressures in order to maintain the FRC may not cause additional harm, air leaks such as pneumothoraces are potential complications.³⁰ Evidence is lacking on the risks and benefits of DR CPAP in term infants. If CPAP is required, attempts should be made to wean off CPAP as lung compliance improves.

Newborns delivered through MSAF may have respiratory distress due to mechanical obstruction (and ball-valve effect causing hyperinflation and air leaks), chemical pneumonitis (surfactant inactivation), hypoxemia, acidosis and pulmonary vasoconstriction leading to pulmonary hypertension.³¹ Withholding drying and stimulation, and performing intratracheal suctioning are no longer recommended due to resultant delay in initiation of PPV and lack of favorable outcomes.^6,32

Oxygen use during neonatal resuscitation (Fig. 5)

Fig. 5 –

Oxygenation during resuscitation. Twenty-one percent inspired oxygen (O₂) is recommended at initiation of resuscitation in term and near-term infants. The optimal initial concentration of inspired O₂ in preterm infants is controversial but current guidelines suggest use of 21—30% followed by titration based on preductal SpO₂. Currently recommended preductal SpO₂ target ranges during the first 10 min are shown in the figure. If chest compressions are needed, inspired O₂ is increased to 100%. Following return of spontaneous circulation (ROSC), it is important to wean inspired O₂ to 21% in term infants without lung disease⁷³ and 30—40% in preterm or with lung disease. Copyright Satyan Lakshminrusimha (2021).

The end of the 20th century and beginning of the 21st century saw a paradigm shift towards use of room air in resuscitation of term newborns after centuries of using 100% O₂.^33,34 Within minutes after birth, there is an increase in PaO₂ from 25 to 30 mmHg in the fetus to 45—80 mmHg in the newborn breathing room air (21% O₂) which is sufficient to cause pulmonary vasodilation (Fig. 1A) and possibly even some free radical production. A systematic review of 10 clinical studies comparing 21% and 100% O₂ in asphyxiated newborns showed reduced mortality with 21% O₂.³⁵ During resuscitation, supplemental O₂ can be subsequently titrated to target preductal saturations (SpO₂) ranges per NRP guidelines.⁶ However, these ranges are derived from infants receiving early cord clamping. Ongoing studies are investigating whether recommended SpO₂ target ranges should be revised for term and preterm infants following DCC, with lower inspired O₂ requirement (Fig. 6).^36,37

Fig. 6 –

Differences in oxygenation during the first few minutes after birth with immediate cord clamping (ICC) and deferred cord clamping (DCC). Preductal SpO₂ medians are in the 60—65% range with ICC (Dawson curve — dark black line in the central graph).⁷⁴ With DCC for ≥ 60 s, there is dual sources of preload to left ventricle (LV) from the umbilical vein (UV) and pulmonary veins (PV), and higher SO₂ in PV leads to better preductal SpO₂ as evidenced by the Vento curves (dark blue line in the graph).⁷⁵ By 5—10 min after birth, lungs are better aerated, and PV return increases contributing to preductal SpO₂ of 85—95%. UV, umbilical vein; PV, pulmonary veins; SO₂, oxygen saturation; SpO₂, pulse-oximetry saturation. Copyright Satyan Lakshminrusimha (2021).

During cardiac arrest, should CC be carried out with 21% or 100% O₂?³⁸ In a severely asphyxiated animal model with cardiac arrest, PaO₂ concentrations are very low (23.9 ± 6.8 mmHg) even when ventilated with 100% O₂ during CC.³⁹ This supports the current recommendation of using 100% O₂ when CC are needed. However, immediately after return of spontaneous circulation (ROSC), there is a rapid increase in cerebral O₂ delivery.^40,41 Cerebral oxidative stress in addition to reperfusion injury (due to hypercapnia and increase in cerebral blood flow) status post ROSC can be deleterious. Hence, rapid weaning to 21% O₂ immediately after ROSC, followed by judicious titration of O₂ is warranted to avoid the complications of hypoxia and hyperoxia.^42,43

Chest compressions

In asphyxiated neonates, the priority is effective ventilation that allows removal of lung liquid and enables lung aeration leading to increase in pulmonary blood flow. Asphyxiated neonates with persistent bradycardia tend to develop hypoxia, hypercarbia and severe acidosis causing myocardial dysfunction, peripheral vasodilation, and low diastolic blood pressures. In this scenario when the heart is unable to effectively pump blood to the lungs to allow gas exchange during PPV, CC may pump blood from the heart to the lungs to enable adequate oxygenation during PPV until the myocardium recovers.²⁶ There is preferential perfusion of the heart and brain during CC, achieving approximately 50% of the normal circulation to these vital organs.^44,45 The heart rate at which CC should be initiated is currently being investigated; it is possible that CC asynchronous with inherent heart beats may be harmful due to abnormal retrograde coronary blood flow during the decompression phase of CC.⁴⁶

In the presence of severe bradycardia (heart rate < 60 beats per min) in a neonate despite at least 30 s of effective ventilation, CC are indicated during neonatal resuscitation (CC: PPV= 3:1).⁶ In a newborn piglet model of asystolic arrest, initiating CC at 30, 60 and 90 s after onset of ventilation was studied by Dannevig et al.⁴⁷ The authors found that continuing ventilation beyond 30 s (for another 30 s) to ensure effective ventilation did not affect success of ROSC and delaying onset of CC to 90 s decreased the incidence of and delayed ROSC, and required more doses of epinephrine to achieve ROSC.⁴⁷

Interruption of CC for ventilation may adversely affect myocardial perfusion.⁴⁵ Adult animal models have shown improved outcomes after uninterrupted CC in ventricular fibrillation induced cardiac arrest,⁴⁸ but a clinical randomized controlled trial (RCT) did not demonstrate improved survival or neurological outcomes.⁴⁹ Additionally, the presence of ductus arteriosus in newborns may not allow sustained building-up of sufficient diastolic pressure and coronary perfusion pressure during CC. In a neonatal model of asphyxial arrest, CC with asynchronous ventilation led to higher carotid arterial blood flow and cerebral O₂ delivery.^50,51 The 2020 Neonatal Life Support guidelines suggest a 3:1 compression: ventilation ratio (weak recommendation, very low quality evidence).^52,53 The 2 thumb-fingers encircling technique is the preferred method of delivery of CC, when compared to 2 finger (index and middle) technique.⁵²

Medications in neonatal resuscitation

Epinephrine (adrenaline) is the only medication recommended by the ILCOR in neonates and is required in ~0.05—0.06% of all births.⁵⁴ The primary mechanism of action of epinephrine in neonatal resuscitation is α1-receptor mediated vasoconstriction that increases the SVR. Epinephrine is indicated when the heart rate remains <60 bpm despite 30 s of effective PPV and another 60 s of CC coordinated with PPV. Intravenous (IV) epinephrine (0.01—0.03 mg/kg, 0.02 mg/kg preferred) can be administered either via a low umbilical venous catheter (UVC, preferred) placed 2—4 cm from skin followed by a 3 ml flush of normal saline, or via intraosseous route.⁵⁵ Endotracheal (ET) epinephrine, although less effective, can be administered at 0.1 mg/kg while awaiting UVC placement, followed by IV epinephrine administration immediately upon UVC placement.^56,57 Low UVC epinephrine at 0.03 mg/kg dose followed by a larger flush volume of 3 ml/kg resulted in earlier and higher incidence of ROSC in a term ovine model of asphyxial arrest, when compared to 0.01 mg/kg- 1 ml flush, 0.01 mg/kg- 3 ml/kg flush and 0.03 mg/kg-1ml flush (Fig. 7).^58,59 Due to infrequent need for epinephrine, it is difficult to conduct rigorous RCTs to compare and evaluate the safety and efficacy of different doses in a clinical setting. In an elegant retrospective study by Halling et al., use of 0.01 mg/kg IV as initial dose of epinephrine necessitated escalating, repeated doses and higher cumulative dose of epinephrine to achieve ROSC.⁵⁴ A recent retrospective review of 1153 neonates receiving CC in the DR between 2001 and 2014 reported that about half of the neonates received epinephrine.⁶⁰ Furthermore, an earlier time of epinephrine administration increased the odds of ROSC.⁶⁰ NRP has suggested the use of 0.02 mg/kg epinephrine as the initial dose until further evidence is available.⁵⁵

Fig. 7 –

Optimal flush volume following epinephrine (adrenaline) administration from the umbilical venous catheter (UVC). Use of larger flush volume of 2.5 ml and 10-ml following a 0.03 mg/kg dose of UVC epinephrine resulted in 80% and 89% incidence of return of spontaneous circulation (ROSC) with the first dose of epinephrine when compared to 40% with 1 ml flush.^58,59 Copyright Satyan Lakshminrusimha (2021).

Volume resuscitation with fresh whole blood or normal saline bolus may be indicated in newborns with hypovolemic or hemorrhagic shock (e.g. fetomaternal hemorrhage or occult blood loss) with hemodynamic compromise, not responding to resuscitative interventions.⁶¹

Resuscitation of preterm infants

Preterm infants are vulnerable to hypothermia at birth. Hypothermia is an individual factor that increases morbidity and mortality.⁶² Providing warmth by placing a newborn infant under a radiant warmer is a key initial step in resuscitation. Additionally, an ambient DR temperature of 23—25 °C, warming blankets, plastic wrapping without drying, chemical warming mattress and using a cap (with or without a plastic wrap) can help to prevent hypothermia. Furthermore, the plastic wrap also helps minimize fluid losses in the DR.⁶¹ A recent multicenter, international study demonstrated the effectiveness of early kangaroo mother care in reducing neonatal mortality and hypothermia in low birth weight infants <1.8 kg in Africa and India (Fig. 8). Early kangaroo care with skin-to-skin contact with the mother might promote bonding, transmission of beneficial maternal microbiota, enhance breastmilk production and breastfeeding in addition to providing warmth and was associated with lower incidence of sepsis in this study.⁴

Fig. 8 –

Graphic abstract of WHO Immediate Kangaroo Mother Care (KMC) study.⁴ The benefits of early KMC compared to conventional therapy under the radiant warmer/incubator for infants < 1.8 kg birth weight. Benefits of early KMC initiated immediately after birth included lower incidence of hypothermia, neonatal mortality, and sepsis. Please see Ref.⁴ for more details. Copyright Satyan Lakshminrusimha (2021).

Unlike term infants in whom large negative and positive pressures are generated in the airways with the first few breaths, the preterm infants are unable to generate enough pressure to achieve their FRC.⁶³ Additional factors that predisposes premature infants to respiratory distress at birth include immature, surfactant deficient and insufficient alveoli that are prone to atelectasis, slow clearance of lung fluid, collapse of extrathoracic airway causing obstruction, very compliant chest wall but noncompliant lungs and inherent ventilation-perfusion mismatch.⁶³ Early initiation of CPAP in the DR allows premature infants to achieve adequate FRC, decreases incidence of respiratory failure, reduces need for mechanical ventilation and lowers mortality.⁶⁴ Achieving preductal SpO₂ >80% by 5 min after birth along with a heart rate >100/min by 2 min after birth, is crucial to decrease odds of intraventricular hemorrhage and optimize cognitive outcome.^65–67 Hence starting with higher inspired O₂ and titrating faster may be necessary in preterm infants born at < 32 weeks gestation compared to term infants (Fig. 2C).

Gentle handling, minimal stimulation, and lung protective (to limit volutrauma) and neuro-centric (to avoid hypo and hypercapnia) strategies for ventilation may decrease the morbidity and mortality in premature infants.^68,69

Conclusions

In the last decade, we have made giant strides in our understanding of the physiology of fetal to neonatal transition and neonatal resuscitation. Despite such rapid progress, there are several gaps in our knowledge in this field (Table 1). Funding and research, especially randomized controlled trials are needed to fill these knowledge gaps and hence improve neonatal outcomes.

Table 1 –

Gaps in our knowledge on neonatal resuscitation.

Event	Current gaps in our knowledge
Umbilical cord management	Can deferred cord clamping (DCC) improve outcomes in asphyxiated newborns? Is it feasible? Is umbilical cord milking (UCM) beneficial in term infants requiring resuscitation? Is UCM safe/beneficial for late preterm infants? Can it improve neurodevelopmental outcomes? Should DCC be performed routinely until after lung inflation/ ventilation?
Ventilation	What are the optimal initial pressures (PIP and PEEP) to achieve optimal lung inflation in an apneic neonate? Is there a role for sustained inflation in neonatal resuscitation? Is LMA advantageous over bag and mask ventilation? Do LMAs increase success of airway management compared to ETT? Should respiratory monitors be used in the DR in neonatal resuscitation? What is the optimal PaCO2 during PPV? Should non-invasive monitoring be used as a feedback device for optimal PPV in the DR? Could this be a surrogate marker for cerebral blood flow during resuscitation?
Oxygen use	What is the optimal initial inspired O2 for preterm neonates? Should we adopt “Vento” target ranges for preductal SpO2 with DCC? What is the optimal inspired O2 during CC? How quickly should inspired O2 be titrated?
Chest compressions	What is the ideal depth of CC and how to quantify them? Should CC and PPV be coordinated? What is the heart rate below which CC should be initiated? Can CC be harmful in bradycardia?
Medication	What is the ideal timing and frequency of epinephrine administration? What is the optimal route of epinephrine administration? Is there any utility for other medications such as caffeine and vasopressin in neonatal resuscitation? Is there a role for NO in neonatal resuscitation?
Volume resuscitation	Does volume resuscitation have a role in neonatal resuscitation? How should volume resuscitation be performed in hypovolemic/ hemorrhagic shock causing severe asphyxia?

DCC: deferred cord clamping. UCM: umbilical cord milking. PIP: peak inspiratory pressure. PEEP: positive end expiratory pressure. DR: delivery room. LMA: laryngeal mask airway. ETT: endotracheal tube. SpO₂: oxygen saturation. CC: chest compressions. PPV: positive pressure ventilation. NO: nitric oxide.

Practice bullet points.

• Ventilation with adequate lung inflation is the key step that remains the basis for neonatal resuscitation.

• Deferred (delayed) cord clamping allows improved hemodynamics and oxygenation in the neonate with placenta serving as a source of left ventricular preload and gas exchange prior to establishment of the lungs as the primary site of gas exchange.

• Initiating ventilation of premature infants with higher FiO₂ (compared to term infants) and titrating up faster may be needed to achieve heart rate >100 bpm by 2 min after birth and preductal SpO₂> 80% by 5 min after birth, to ultimately improve neonatal outcomes.

• Target preductal SpO₂ ranges may need to be higher with delayed cord clamping compared to the current standard practice, and needs more evidence.