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Neonatal resuscitation: foetal physiology and pathophysiological aspects

Berger, Thomas M.

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European Journal of Anaesthesiology: August 2012 - Volume 29 - Issue 8 - p 362-370
doi: 10.1097/EJA.0b013e328354a4e7
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The respiratory and cardiovascular changes that occur at birth are considerable and unparalleled by any other physiological event of extrauterine life. Transition from intrauterine to extrauterine life is a dangerous time point in the life of a human being. Although neonatal mortality has decreased dramatically in industrialised countries over the past 50 years, deaths in the first week and in the first month of life account for the largest proportion of childhood mortality.1 The most common causes of death are related to prematurity, congenital malformations and perinatal asphyxia.2,3 Immediate and adequate support of newborn infants who fail to adapt normally in the delivery room is critically important for their prognosis.

In many institutions, in unexpected emergency situations, paediatricians or neonatologists are not immediately available and midwives, obstetricians or anaesthesiologists must initiate resuscitation of newborn infants. All parties who are involved in neonatal resuscitation should be acquainted with the finer points of neonatal resuscitation in order to make appropriate decisions in emergency situations. Knowledge of foetal physiology, normal adaptation and the most common causes of adaptation failure form the best basis for understanding the essential elements of neonatal resuscitation.

Neonatal resuscitation guidelines were recently revised and published by the International Liaison Committee on Resuscitation (ILCOR)4,5 and adapted by the European Resuscitation Council (ERC)6 and the American Heart Association (AHA).7 This review will focus on foetal physiology and normal neonatal adaptation to provide a solid basis for understanding neonatal resuscitation guidelines.

Foetal physiology

Secretion and absorption of foetal lung liquid

The spaces that will contain air, once air breathing starts, are filled with lung liquid while the foetus is in utero. Its production is mediated by chloride (Cl) secretion by alveolar type II cells. Sodium (Na+) follows passively and water flows down the osmotic gradient.8 In foetal sheep, lung liquid secretion increases from 1.6 ml kg−1 h−1 at midgestation to 3.5–5.5 ml kg−1 h−1 in the third trimester. In the days prior to delivery, it falls to less than 3 ml kg−1 h−1.9 With the vocal cords acting as a one-way valve, the foetal lung liquid stretches the lung tissue and stimulates its growth. An intraluminal pressure of 2–3 mmHg above the intra-amniotic pressure is generated and, given a compliance of 15–20 ml mmHg−1 of the fluid-filled lung, a volume of at least 30 ml kg−1 is maintained during the third trimester which is equivalent to or even above the functional residual capacity of the human neonatal lung.9,10 Through intermittent foetal breathing movements, lung liquid, and with advancing gestational age surfactant, can pass through the vocal cords and are either swallowed or added to the amniotic fluid. Prior to the availability of exogenous surfactant, detection and quantification of surfactant components in the amniotic fluid (lecithin/sphingomyelin ratio, phosphatidylgylcerol and/or phosphatidylinositol) were used to determine lung maturity.11,12

Continuously draining lung liquid (e.g., after premature and prolonged rupture of membranes) prevents the development of a fluid filled functional residual capacity and can result in hypoplastic lungs, whereas obstructing outflow of lung liquid leads to hyperplastic lungs. The latter observation formed the basis for foetal surgery for congenital diaphragmatic hernia using the ‘Plug the Lung Until it Grows’ concept.13

Around the time of birth, however, the lung liquid must be removed to allow the newborn infant to breathe air. In the postneonatal lung, the air spaces contain only 0.35 ml kg−1 of liquid.8 Two mechanisms involved in this process have been described, both of which are at least in part linked to the process of labour. The first one involves surges of foetal hormones (epinephrine, cortisol, T3) during labour and delivery. Thyroid and glucocorticoid hormones act synergistically to prime the lung to allow epinephrine to enhance transepithelial Na+ absorption through an epithelial Na+ channel (consisting of α, β, and γ-ENaC subunits). Interestingly, α-ENaC(−/−) knock-out mice develop respiratory distress and die within 40 h of birth from failure to clear their lungs of liquid,14 supporting the hypothesis that ENaC plays a critical role in the adaptation of the newborn lung to extrauterine life. However, this conclusion and its relevance for human babies has recently been challenged by Huppmann et al.15 who described a preterm infant with a homozygous loss-of-function mutation of the gene encoding for the α-ENaC subunit who had an unimpaired postnatal respiratory adaptation. This infant presented on the 9th day of life with hyperthermia, lethargy and severe hyponatraemia (126 mmol l−1), hyperkalaemia (8.9 mmol l−1) coupled with high renin and aldosterone plasma concentrations, consistent with pseudohypoaldosteronism type I. The authors concluded that clearance of alveolar fluid after birth in humans may not be critically dependent on ENaC. The second mechanism, so far only seen in sheep, is characterised by rhythmic foetal trunk muscle contractions, which frequently occur in synchrony with uterine contractions during active labour and lead to the expulsion of lung liquid.16 The larynx acts as a one-way valve that allows liquid to leave the lung but not enter from the outside.17

More recently, researchers have been able to visualise lung aeration after birth using phase contrast X-ray imaging in newborn rabbits.18 They have shown that residual lung liquid clearance from the airways is closely associated with inspiratory activity, but there was no significant distal movement of the air–liquid interface between breaths. They speculated that transpulmonary hydrostatic pressure generated by inspiration provides the predominant driving force for residual lung liquid clearance. Lung aeration over the first 2 h of life was highly variable with some animals achieving 70% of total lung aeration within 30 s, whereas others achieved only 25–50% at 15–30 min after birth. In addition, the spatial pattern of lung aeration was not uniform and depended on body position. When placed on their sides, dependent regions of the lung aerated more slowly than nondependent regions and airway refilling occurred more often in the dependent lung18 (see supplemental videos at:, accessed 14 December 2011).

When delivery occurs before the onset of labour (e.g. by elective caesarean section), there are no surges of foetal stress hormones and lung liquid absorption is impaired. This may be coupled with a lack of lung liquid expulsion because of the absence of uterine contractions. These phenomena are likely explanations for the increased respiratory morbidity seen after prelabour caesarean deliveries.19–21

From foetal to neonatal circulation

In utero, the placenta is responsible for foetal gas exchange. The foetal cotyledons are bathed in the maternal blood of the intervillous space and CO2 is removed from and O2 taken up by the foetal blood. Foetal oxygen loading is facilitated by a higher oxygen affinity of foetal haemoglobin [HbF: P50 of 2.5 kPa (19 mmHg)] compared with adult haemoglobin [HbA: P50 of 3.6 kPa (27 mmHg)]. This is due to the fact that 2,3-diphosphoglycerate binds to β-chains of HbA (α2β2) and cannot interact with HbF (α2γ2). Oxygen transfer is further supported by the double Bohr effect, wherein the oxygen dissociation curves for maternal HbA and foetal HbF move in opposite directions when PCO2 increases in maternal blood and decreases in foetal blood. The partial pressure of oxygen (PuvO2) in the umbilical vein only reaches 4 kPa (30 mmHg), but because of the properties of HbF still results in an oxygen saturation of 65–70%. This is the highest oxygen saturation in the foetus. The foetal blood is then collected in the umbilical vein, bypasses the liver through the ductus venosus Arantii and enters the inferior vena cava just below the right atrium. Mixed with blood from the lower body of the foetus, the umbilical venous blood is preferentially directed from the right atrium across the foramen ovale into the left atrium (intracardiac streaming).22 It is then ejected from the left ventricle into the ascending aorta. As a result, better oxygenated foetal blood is directed to the myocardium and the foetal brain. In contrast, deoxygenated blood from the superior vena cava is directed across the right atrium into the right ventricle and pumped into the pulmonary artery. Because pulmonary vascular resistance is very high in utero, more than 85–90% of the right ventricular cardiac output bypasses the lung and flows through the ductus arteriosus Botalli into the descending aorta. Through admixture of this poorly oxygenated blood, the lower part of the body is perfused with blood that only has an oxygen saturation of 45%. Vascular resistance of the placenta is low and approximately 50% of the combined right and left ventricular cardiac output flows through the internal iliac arteries into the umbilical arteries and eventually reaches the placenta via the umbilical cord (Fig. 1).22

Fig. 1
Fig. 1:
No captions available.

After birth, dramatic changes in the circulatory system occur that are vital for normal adaptation. When the umbilical cord is cut, the low resistance placental vascular bed is excluded from the circulation and the systemic vascular resistance increases suddenly. Cessation of blood flow through the umbilical vein facilitates collapse of the ductus venosus Arantii. At the same time, with the onset of air breathing, high concentrations of oxygen reach the pulmonary blood vessels [alveolar PO2 of 14.2 kPa (107 mmHg) when breathing room air] leading to vasodilatation via an NO-mediated mechanism.23 With the fall in pulmonary vascular resistance, pulmonary perfusion increases and pulmonary gas exchange can occur. Pulmonary venous return increases and, when left atrial pressure rises above right atrial pressure, the foramen ovale closes. As pressure in the pulmonary artery falls and pressure in the aorta increases, shunt across the ductus arteriosus Botalli changes from right-to-left to bidirectional and finally left-to-right. The smooth muscle cells of the ductus arteriosus Botalli respond to the increase in PaO2 with constriction,24 ultimately leading to functional and later anatomical closure of this shunt (Fig. 2).

Fig. 2
Fig. 2:
No captions available.

Foetal response to intrauterine hypoxia

In utero, foetal hypoxia stimulates chemoreceptors of the ascending aorta leading to bradycardia. At the same time, intracardiac streaming increases22 and cardiac output is redistributed to protect the perfusion of the myocardium, the central nervous system and the adrenal glands.25,26 In parallel, a typical sequence of respiratory patterns can be observed. Following a period of rapid shallow breathing, a first period of apnoea occurs (i.e., primary apnoea). If intrauterine hypoxia is not corrected, the foetus will then develop gasping respirations followed by a second period of apnoea (secondary apnoea). When delivery occurs during primary apnoea, a newborn infant can be stimulated to restart breathing. In contrast, tactile stimulation alone will be insufficient to correct secondary apnoea and without adequate intervention (i.e. bag-mask ventilation) circulatory collapse will ensue (Fig. 3).27

Fig. 3
Fig. 3:
No captions available.

Normal adaptation

The prerequisite for normal adaptation is the initiation of breathing. With the first breaths, the remaining foetal lung liquid is replaced by air.18 The forces required to establish an air–liquid interface are surprisingly high (during the first breaths, animals generate intrapleural pressures between −40 and −60 cmH2O). Subsequently, compliance normalises to values around 3–5 ml cmH2O−1,28 so that a pressure gradient of 5–8 cmH2O will result in a normal tidal volume of 6 ml kg−1 in a term infant with a birth weight of 4 kg.

Lung aeration and maintenance of a stable functional residual capacity are essential for pulmonary vasodilatation after delivery. Apart from changes in pulmonary vascular geometry,10,29 oxygen plays a major role because the increase in alveolar PO2 stimulates endothelial NO synthetase leading to vasodilatation.29

Normally, a healthy newborn starts to breathe or cry within 30–60 s after delivery. Preductal oxygen saturation increases from a foetal value of 65% to more than 90% within the first 10 min of life.30–32 During transition from foetal to neonatal circulation, venous admixture through a patent ductus arteriosus into the descending aorta can occur and postductal oxygen saturations can be significantly lower than values measured in preductal positions.33,34 Therefore, during resuscitation in the delivery room, oxygen saturation should be measured in the right hand in a preductal position to monitor the infant's heart rate and document the expected increase in oxygen saturation over the first minutes of life.

Impaired adaptation

There are numerous maternal and foetal conditions that are associated with an increased risk of impaired adaptation (Table 1). Many of these conditions can be recognised antenatally and the need for resuscitative measures can be anticipated. However, some complications occur unexpectedly (e.g., placental abruption, cord prolapse, uterine rupture, and so on) and can affect individual or all aspects of neonatal adaptation.

Table 1
Table 1:
Risk factors associated with impaired neonatal adaptation

Impairment of lung liquid clearance

Delayed or insufficient clearance of lung liquid can occur after elective caesarean section, following rapid delivery or in the premature.35 As long as the newborn infant has an adequate respiratory drive, impairment of lung liquid clearance will manifest as respiratory distress with tachypnoea (respiratory rate above 60 breaths min−1), retractions, flaring, grunting and possibly cyanosis. The degree of respiratory support required by infants with transient tachypnoea of the newborn (TTN or wet lung) will depend on the severity of the respiratory distress, ranging from the provision of supplemental oxygen to the use of continuous positive airway pressure or even intubation and mechanical ventilation.

Impairment of respiratory drive

The two most common scenarios in which respiratory drive is impaired after delivery are perinatal asphyxia and prematurity. In rare cases, drugs that have been administered to the mother during labour can affect the infant's respiratory centre (e.g. opioids) or weaken its muscular strength (e.g. magnesium sulphate for pre-eclampsia).

Impairment of circulatory adaptation

Impaired circulatory adaptation and, thus, persistence of foetal circulation can occur after perinatal asphyxia and meconium aspiration, following prolonged rupture of membranes with oligohydramnios and consequent pulmonary hypoplasia, or in the setting of severe sepsis. Even after successful initial transition, a newborn infant can fall back into a foetal circulatory state, particularly when there is hypoxaemia and/or severe acidosis (i.e. conditions that induce pulmonary vasoconstriction).

Neonatal resuscitation algorithm

Approximately, 10% of all newborn infants require some minor intervention such as tactile stimulation, proper positioning and suctioning of mouth and nose and supplemental oxygen after delivery. More advanced resuscitative measures are necessary in about 1% of all deliveries and 80% of these neonates will respond to bag–mask ventilation.36 In term infants, extensive resuscitation with intubation, chest compressions and administration of resuscitation drugs is very rarely required, in about 1 : 1000 deliveries.

It is important that midwives, obstetricians, neonatologists and anaesthesiologists communicate well to facilitate anticipation of potential problems that present in the newborn (Table 1). A well organised resuscitation team with clearly defined roles for each team member, including the designation of an experienced team leader, as well as the preparation of proper resuscitation equipment are prerequisites for successful resuscitation.

Once it has been recognised that an infant might be compromised, as soon as the cord has been cut the infant should be placed on a resuscitation unit without delay. Initial measures include drying of the infant to prevent heat loss and to provide tactile stimulation, correct positioning of the head (i.e. in a sniffing position) and clearing the airway by suctioning of mouth and nose if necessary. This is followed by the assessment of both breathing effort and heart rate, and less importantly tone (note that colour is no longer assessed at this point). If the infant is gasping or not breathing at all, or his/her heart rate is less than 100 beats min−1, positive pressure ventilation must be provided. Because secondary apnoea cannot be distinguished from primary (see above), the more serious condition must be assumed. No further time should be wasted with stimulation of the infant, and instead positive pressure ventilation with room air should be initiated (see below).

In the delivery room, a self-inflating or flow-inflating bag or T-piece resuscitator can be used for respiratory support.37 Positive end-expiratory pressure may be useful to stabilise the infant's labile functional residual capacity, particularly in preterm infants. Successful ventilation requires a proper fit of the mask, an open airway and adequate inflation pressure. Intubation should be considered when resuscitation is likely to be prolonged or more advanced life support measures are required (see below). Expansion of the chest should be visible but not excessive to avoid volutrauma. The heart rate should readily increase above 100 beats min−1 and preductal oxygen saturation should reach values above 90% by the age of 10 min (Fig. 4, insert). In neonatal resuscitation, successful ventilation is the most important intervention and will suffice in the majority of patients.

Fig. 4
Fig. 4:
No captions available.

If the heart rate falls to less than 60 beats min−1 despite adequate ventilation, more advanced life support measures are indicated. In this situation, chest compressions at a rate of 90 min−1 must be coordinated with positive pressure ventilation at a rate of 30 min−1 with a compression to ventilation ratio of 3 : 1. Chest compressions are applied over the lower third of the sternum and should compress the chest one third of its anterior–posterior diameter. It is important that chest inflations only briefly interrupt compressions. The so-called two thumb-encircling hands method is the preferred mode; however, the two-finger method can be used transiently to facilitate the insertion of an umbilical venous catheter.

Whenever advanced methods of life support are provided, it is important to achieve rapid vascular access to administer drugs and isotonic crystalloid solutions (i.e., normal saline, Ringer's lactate) for volume expansion. In depressed neonates, cannulation of peripheral veins is difficult and it is easiest to gain access through the umbilical vein. In most cases, blood can be aspirated from an umbilical venous line and blood gas analyses and glucose measurements can be performed. In rare cases, when umbilical access cannot be established, an intraosseous needle can be placed. If positive pressure ventilation and chest compressions do not restore spontaneous circulation after 30 s, intravenous epinephrine should be given at a dose of 10–30 μg kg−1. If no venous or intraosseous access is available but the infant is intubated, epinephrine can be given intratracheally at a dose of 50–100 μg kg−1; however, the efficacy of this route is likely to be inferior to intravenous.4–7

If these interventions are unsuccessful or if a once-stable infant deteriorates again, a pneumothorax must be excluded. Its diagnosis can be challenging; unilaterally decreased breath sounds and lateralisation of the heart sounds to the opposite side are the best clinical signs. If the resuscitation area can be darkened, transillumination of the chest with a high intensity light source can identify a pneumothorax.

The essential steps of neonatal resuscitation are summarised in Fig. 4. Information on endotracheal tube sizes and insertion depths, as well as drug dilutions and doses should readily be available in the resuscitation area (Table 2).

Table 2
Table 2:
Endotracheal tube sizes (including insertion depths), epinephrine dilutions and doses, as well as fluids used in neonatal resuscitation

Oxygen supplementation in the delivery room

The most important aspects of the 2010 revision of the neonatal resuscitation guidelines4–7 have been discussed elsewhere38,39 and are summarised in Table 3. This review will now focus on the recommendations for the use of supplemental oxygen in the delivery room, as this is probably the most remarkable change that has occurred since 2005.

Table 3
Table 3:
Major changes in international resuscitation guidelines between 200544–46 and 20104–7

Recommended fraction of inspired oxygen at start of resuscitation

For more than 200 years, 100% oxygen has been used in neonatal resuscitation40 and this has remained undisputed until very recently. Although concerns about the ability of newborn infants to cope with oxidative stress41,42 and epidemiological reports of potential long-term consequences of perinatal exposure to high oxygen concentrations (i.e., increased risk of developing childhood cancer) have been discussed for many years,43–45 the 2005 recommendations for neonatal resuscitation published by the ILCOR, the ERC and AHA still maintained that resuscitation should in general be started with 100% oxygen. They conceded, however, that lower oxygen concentrations and even room air could be chosen as well.46–48

The guidelines were reviewed following several meta-analyses49–53 of prospective randomised controlled trials54–64 that found that resuscitation with 100% oxygen was not superior to air and could increase mortality, with a number needed to harm of 2053 to 3651 (Table 4). The revised ILCOR and ERC guidelines of 2010 now uniformly recommend the use of room air rather than 100% oxygen in the resuscitation of term infants.4,5 In contrast, the more conservative 2010 recommendations from the AHA state that room air or blended oxygen can be used to achieve oxygen saturation in the interquartile range of preductal saturations measured in healthy term infants (Fig. 4, insert). If blended oxygen is not available, resuscitation should begin with room air.4,5

Table 4
Table 4:
Meta-analyses of studies reporting resuscitation of newborn infants with 21 or 100% oxygen

As outlined above, even room air increases the oxygen exposure of the newborn infant from an umbilical venous PuvO2 of 4 kPa (30 mmHg) to an alveolar PaO2 of more than 14 kPa (100 mmHg). This may well be sufficient to support the circulatory changes that occur after birth in the majority, and the risk–benefit ratio of increasing the FiO2 to much higher values may be unfavourable. However, there may be a subgroup of infants that might benefit from higher oxygen concentrations for example, newborns with persistent pulmonary hypertension.

In infants who do not respond to resuscitation with room air, the FiO2 should be increased. The ILCOR and ERC recommendations fail to provide details but simply state:4–6 ‘if despite effective ventilation there is no increase in heart rate or if oxygenation (guided by oximetry) remains unacceptable, use of a higher concentration of oxygen should be considered.’ The AHA recommendations are more specific and suggest:7 ‘if the baby is bradycardic (heart rate <60 beats min−1) after 90 s of resuscitation with a lower concentration of oxygen, oxygen concentration should be increased to 100% until recovery of a normal heart rate.’

Pulse oximetry

As discussed previously, changes in oxygen saturation in the first minutes of life are gradual and it takes several minutes before healthy term infants achieve oxygen saturations above 90%.30–32 Pulse oximetry is the best method to follow this trend. During transition, a preductal location of the oxygen sensor is important because preductal SaO2 values may be 10–15% higher than postductal SaO2 values.31 Pulse oximetry also provides continuous information on heart rate and so helps to guide resuscitation.

Key learning points

  1. Up to 10% of all newborn infants require some form of assistance after birth, but only 1% of all neonates require more advanced measures of life support.
  2. Normal adaptation requires timely clearance (absorption, expulsion) of lung liquid, adequate respiratory drive and successful transition from foetal to neonatal circulation.
  3. Effective ventilation, indicated by chest movement and an increasing heart rate, is the most important intervention in neonatal resuscitation.
  4. According to recent international guidelines, resuscitation of term neonates should be started with room air.
  5. Supplemental oxygen should only be used if, despite effective ventilation with room air, there is no increase in heart rate or oxygenation remains unacceptably low.


I would like to thank my colleagues Martina Steurer, Martin Jöhr, Martin Stocker and Thomas Neuhaus for their critical review of the manuscript and their valuable suggestions.

Financial support and sponsorship: none.

Conflicts of interest and sources of funding: none declared. This is an invited review article requested in association with a Refresher Course at the 2012 Euroanaesthesia meeting in Paris. The author has previously published two review articles on neonatal resuscitation in German (Der Anaesthesist 2009;58 : 39–50, Pädiatrie up2date 2009;2 : 123–140). Inevitably, there is some overlap of the current EJA review article and those two articles. However, the present EJA review article takes into account the most recent international recommendations published in 2010 by the ILCOR, the ERC and the AHA. It also puts more emphasis on physiology and pathophysiology and discusses the oxygen paradigm shift in detail.


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foetal circulation; lung liquid clearance; neonatal adaptation; neonatal resuscitation; oxygen toxicity

© 2012 European Society of Anaesthesiology