critical illness are both associated with persistent fetal circulation. Under these conditions, the RV

continues to contribute a large portion of the CO and the postductal saturations will be significantly

lower than the preductal saturations. In premature infants, the transition may be much slower and the

DA may not close despite the usual changes in systemic and pulmonary vascular resistance and the

subsequent reversal of flow. Cessation of umbilical blood flow results in closure of the ductus venosus

and increase in systemic vascular resistance. This increases the left-sided heart pressures and closes the

foramen ovale. With these changes, the transition to postnatal circulation is complete and the process of

postnatal pulmonary dependence is initiated.

Figure 99-2. The oxygen dissociation curve shows the percent saturation of Hgb at various partial pressure of oxygen and

demonstrates the equilibrium between oxyhemoglobin and deoxyhemoglobin. The sigmoidal shape is a result of the cooperative

binding between the four hemoglobin polypeptide chains. An important point is the P50 which is the partial pressure of oxygen at

which erythrocytes are 50% saturated with oxygen. When oxygen partial pressure is high, such as in the lungs, hemoglobin binds

oxygen with increased affinity. When the partial pressure of oxygen decreases such as in the peripheral tissues, oxygen is

preferentially unloaded. Multiple factors including acid–base, temperature, and 2,3 DPG affect hemoglobins affinity for oxygen

shifting the curve resulting in more or less unloading of oxygen at a given partial pressure.

In order for gas exchange to occur in the developing lung, there needs to be intimate contact between

atmospheric oxygen and capillary blood flow. This requires adequate alveolar ventilation and

pulmonary blood flow. The neonate has a number of physiologic mechanisms which allow for matching

alveolar ventilation (V) and pulmonary perfusion (Q) to optimize gas exchange. To accomplish this, an

adequate alveolar gas volume and FRC must be established shortly after birth and sustained. Once the

FRC is established, this serves as an intrapulmonary pool of oxygen. However, newborns are at

increased risk for hypoxemia due to lower than adult pO2 with less intravascular reserve, FRC closer to

airway closure, and high metabolic demand in infancy resulting in quicker depletion of oxygen stores.

At birth, the oxygen demand in the infant increases in most species by 100% to 150%. Consequently,

fetal hemoglobin with its increased oxygen affinity which was adequate for a fetus does not provide

enough oxygen diffusion and delivery in the neonate. Postnatally, the infant’s affinity decreases rapidly

and reaches normal adult values by 4 to 6 months which corresponds to the amount of time necessary

for the replacement of fetal hemoglobin by adult hemoglobin.13 The amount of HgbF decreases from

around 75% to approximately 2% during the first year of life. Until this occurs, other mechanisms help

the neonate to cope with the ex utero environment. One of the most important is an increase in the

concentration of 2,3 DPG during the first few days of life. At birth, its level is near an adult’s level of

5.43 ± 1.04 and increases to 6.58 ± 1.00. This increase has a small direct effect on fetal hemoglobin,

but also lowers the intracellular pH and thus decreases hemoglobin’s affinity for oxygen.14

Surfactant

4 While many factors play a critical role in allowing for a smooth transition, one of the most clinically

relevant pieces is the role surfactant in neonatal pulmonary mechanics and gas exchange. In pulmonary

physiology, an important concept is surface tension and its effects on the pressure drop across an

interface separating two phases of matter which was defined in the early 1800s by Young and Laplace.15

The pressure drop necessary to maintain or inflate air sacs of a given size is proportional to its surface

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tension and inversely proportional to its radius. The work of breathing is consequently directly

proportional to the surface tension. During development, surfactant production increases as type II

pneumocytes mature and alveoli increase in size. Surfactant is a mixture of phospholipids, neutral lipids,

and specific proteins that, by virtue of their amphipathic nature, decrease surface tension, stabilize small

alveoli, and improve overall alveolar inflation. Surfactant reduces the hydrostatic driving force for

pulmonary edema and decreases work of breathing. When deficient, it can lead to severe respiratory

failure. Exogenous administration has been proven effective in prophylactic or rescue treatment for

respiratory distress syndrome (RDS) in premature infants with a 40% reduction in death and a 30% to

50% reduction in the odds of pulmonary air leaks.16 Additionally, vitamin A supplementation may

reduce the risk of chronic lung disease (CLD) in extremely low–birth-weight infants and was

recommended in infants under 1,000-g birth weight though further studies have failed to confirm the

finding.17,18

Fetal Interventions

Fetal surgery has emerged as an independent subspecialty at the intersection of pediatric surgery,

maternal fetal medicine, and neonatology. It is a field that has arisen from clinical necessity. Pediatric

surgeons, maternal fetal medicine specialists, and neonatologists became frustrated with the

management of a number of congenital structural anomalies in which the baby died or suffered severe

life-long disability despite all efforts at postnatal treatment. With the advent of prenatal ultrasound in

the 1970s, many conditions were diagnosed before birth. Fetuses were followed and the prenatal

natural history was elucidated. It became clear that a component of organ failure was acquired because

of ongoing alterations in fetal development caused by the anomaly. Thus, it made sense that fetal

interventions may be of benefit – to correct the pathophysiology to restore normal fetal development in

the hope of improving survival and decreasing morbidity.

Criteria that must be met to consider fetal surgery include: (a) accurate diagnosis of the condition and

any associated anomalies that may have an impact on outcome; (b) reliable prediction of which

individual fetuses will die or suffer serious long-term morbidity without fetal intervention; and (c)

demonstration of improved fetal outcome with minimal maternal risk.

Fetal imaging is a critical component of the decision making process in fetal surgery. Prenatal

detection and serial ultrasonographic evaluation of these disorders have enhanced our understanding of

their natural history and pathophysiology, and have significantly improved perinatal management. Fetal

conditions that may benefit from in utero intervention by a pediatric surgeon include

myelomeningocele, twin to twin transfusion syndrome, sacrococcygeal teratoma (SCT), congenital

diaphragmatic hernia (CDH), and congenital lung lesions (CLLs).

Sacrococcygeal Teratoma

The evolution of high-output cardiac failure before the development of placentomegaly and hydrops in a

fetus with SCT is the sole indication for fetal surgical intervention. Furthermore, SCT may lead to

maternal mirror syndrome (Ballantine syndrome).19 Fetal echocardiography and Doppler ultrasound

measurements are important in the diagnostic assessment and follow-up of fetuses with these

conditions. Increased aortic velocity, increased combined CO, increased cardiac-to-thoracic ratio, a

dilated inferior vena cava, or reversed end-diastolic umbilical blood flow appears to be sensitive early

predictors of impending hydrops and fetal demise.20,21 For fetuses under 28 weeks estimated gestational

age (EGA), open fetal surgery and resection is the treatment of choice.

Congenital Diaphragmatic Hernia

At present, the role of fetal intervention in the management of fetuses with CDH is not clear. The

pathophysiology of CDH involves both pulmonary hypoplasia and pulmonary hypertension.

Although the cause of CDH remains unknown, the consequences to pulmonary development and

function are well known. If the pleuroperitoneal canal has not closed when the midgut returns to the

abdomen by weeks 9 to 10, the abdominal viscera herniates into the chest cavity. This affects both

ipsilateral and contralateral lung development, with hypoplasia more severe on the ipsilateral side. The

herniation occurs during the period of bronchial subdivisions. This stage becomes compromised with the

major bronchial buds present but the number of bronchial branches significantly reduced in both

ipsilateral and contralateral pulmonary specimens.22 Consequently, alveolization is severely affected

with significantly fewer normal alveoli at birth.23

Pulmonary vascular beds are also distinctly abnormal with a reduction in the total number of arterial

branches in both the ipsilateral and contralateral pulmonary parenchyma with significant adventitial and

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medial wall thickening noted with a resultant increased risk for fixed and intractable pulmonary

hypertension.1 With the institution of breathing, the pulmonary vascular resistance normally decreases

allowing for increased pulmonary blood flow. If the pulmonary vascular resistance remains high after

the transition to postnatal life, right to left shunting of blood can occur with delivery of unsaturated

blood to the systemic circulation with resultant hypoxia. The hypoxia can lead to further increases in

pulmonary vascular resistance and compromises to pulmonary flow while increasing right-to-left blood

shunting leading to severe and progressive respiratory failure. Postnatally, there is also a failure of the

normal arterial remodeling maintaining an abnormally high vascular resistance that is only partially

reversible by treatment interventions.24

Based on both experimental work in the laboratory and an understanding of congenital high airway

obstruction, the technique of in utero tracheal occlusion was developed to prevent egress of lung fluid

and enhance lung growth.25 Although early results did not appear superior to postnatal management,26

Deprest and his group refined the technique and showed promising results compared to historical

controls.27 This innovative strategy is being tested in a multicenter randomized clinical trial.28

Congenital Lung Lesions

While CDH results in hypoplasia of the lung due to a disruption of early lung development, other CLLs

including congenital pulmonary airway malformations (CPAMs), congenital lobar or segmental

emphysema and pulmonary sequestrations (PS) also form space-occupying lesions during fetal

development and are often diagnosed prenatally. The exact pathophysiology of CPAM development

remains controversial with some authors postulating that it arises from arrested development of

localized portions of the bronchial tree during the sixth to seventh week of fetal development while

others believe they are hamartomatous lesions of the bronchial tree.29 CPAMs are characterized as a

multicystic lung mass resulting from a proliferation of terminal bronchiolar structures with associated

suppression of alveolar growth.30 In contrast to CDH, in cases of CPAMs and other CLL, the lung grows

and then is compressed by the mass. Consequently, alveolization and bronchial branching is largely

preserved in the other areas of the lungs. As a result, following resection or regression there can be

normal development of other areas of lung tissue and these patients do not tend to suffer the long-term

consequence of prenatal mass effect seen in patients with CDH. The postnatal morbidity and mortality is

usually related to the size of the mass.

CPAM and bronchopulmonary sequestration are the most common congenital lung malformations that

usually cause no physiologic perturbation prenatally. The natural history and clinical spectrum of these

anomalies are variable, but they appear to depend mostly on the size of the mass and the secondary

physiologic derangement. The growth of CPAMs usually plateaus between 25 to 28 weeks at which time

the fetus appears to grow around the lesion. Most small- to moderate-sized lesions represent 90% to

95% of CPAMs and remain asymptomatic during fetal life. In contrast, large lesions represent 5% to

10% of CPAMs and may produce significant mass effect, which can lead to pulmonary hypoplasia and

associated pulmonary hypertension, impaired fetal swallowing and polyhydramnios, and impaired fetal

circulation and heart failure. Congestive heart failure in the fetus, known as nonimmune fetal hydrops,

is defined by the presence of skin or scalp edema, or by fluid accumulation in two or more serous

cavities (ascites, or pericardial or pleural effusions). The risk of hydrops appears to depend on the size

and rate of growth of the mass, and results from compression of the SVC and impaired venous return.31

In the past, hydrops was considered a harbinger of fetal demise, and was associated with near 100%

mortality.32 Rarely, hydrops is due to a tension hydrothorax from extralobar sequestration. As a

prognostic factor, the CCAM volume ratio (CVR) has been developed to correlate the relative size of

these lesions with fetal and postnatal outcome.33 In one series in which 58 fetuses with a lung mass

were followed prospectively, 75% of fetuses (12 of 16) with CVR greater than 1.6 developed hydrops,

whereas only 17% (7 of 42) with CVR 1.6 or less had this complication. However, the CVR was not

predictive of hydrops if a CCAM had a dominant cyst which may enlarge at an unpredictable rate. If

signs of hydrops appear, the treatment options include percutaneous placement of a thoracoamniotic

shunt for lesions with a dominant cyst, maternal steroids, and rarely open fetal thoracotomy and mass

resection if the fetus does not respond to steroids. Although not well understood, results from a small

series of patients suggest that maternal administration of betamethasone should be first-line therapy for

all fetuses with a large lung mass (CVR >1.6), and for those with hydrops.34,35

Preterm Labor

For every fetal surgery, there is risk of preterm delivery. Chorioamniotic membrane separation and

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preterm labor remain the Achilles’ heel of fetal interventions.36,37 Surgical approaches that involve a

smaller hysterotomy and more minimally invasive techniques appear to lower these risks.38 Specifically,

fetoscopic and percutaneous approaches lessen the maternal and fetal risks. These techniques allow

vaginal delivery after fetal surgery and appear to decrease the incidence of preterm delivery.

Preterm labor is the single biggest concern during the operation and in the postoperative period. The

mother receives a 50-mg indomethacin suppository before surgery, and remains on indomethacin for 48

hours postoperatively. Daily echocardiography is essential; if there is evidence of PDA restriction, then

the indomethacin is stopped. During the operation, nitroglycerin infusion can be used to help control

uterine irritability and enhance relaxation. During closure of the hysterotomy, the mother is given a 6-g

bolus dose of magnesium sulfate followed by a continuous infusion of 2 to 4 g per hour for up to 48

hours. Postoperatively the mother is closely monitored for pulmonary edema, fluid management, and

uterine irritability. On the second to third postoperative day, usually the magnesium and indomethacin

can be weaned, and the patient is converted to oral nifedipine.

Neonatal and Pediatric Physiology

Neonatal and Pediatric Lung Mechanics

The mechanical properties of the lung play an important role in pulmonary mechanics and neonatal

respiratory physiology. The lung has physical properties which resist inflation including recoil,

resistance, and inertance with the dynamic interaction between these processes being responsible for the

effort required during normal spontaneous breathing.39 Elastic recoil is a property of the elastic lung

tissue which must be stretched for lung inflation to occur. According to Hooke’s law, the pressure

needed to inflate the lung must be proportion to the volume of inflation. This relationship of

proportionality is change in volume divided by change in pressure or lung compliance. Dynamic

compliance is the volume change divided by the peak inspiratory transthoracic pressure. Static

compliance is volume change divided by peak inspiratory pressure.40 Throughout the range of normal

tidal volumes, this relationship is linear and starts to plateau at large lung volumes. On a static

compliance curve, ventilation normally occurs in the steep portion were large changes in volume occur

for small changes in pressure. This is not true at high or low lung volumes where large changes in

pressure are necessary for smaller changes in volume.

The total compliance for the pulmonary system is made up of the compliance of the lung and the

chest wall. The relationship can be expressed by the equation: respiratory system compliance (CRS) =

1/chest wall compliance (CCW) + 1/lung compliance (CL).39 The desire for the lung to collapse is

balanced by the outward elastic recoil of the chest wall with FRC occurring at the end of expiration

when these forces are in equilibrium. In infants, the chest wall is composed primarily of cartilage and

thus the CCW is greater in the infant and the pleural pressure is less negative. As a result of the more

compliant chest wall, the neonatal lung appears more prone to collapse.41 FRC is maintained in

newborns by increasing expiratory resistance through laryngeal abduction, maintaining inspiratory

muscle activation throughout expiration, and initiating high breathing frequencies to limit expiration

time.42

Resistance to gas flow is also an important determinant of pulmonary gas movement in the neonate.

Resistance to airflow arises due to friction between gas molecules and the walls of the airway and

because of friction between the tissues of the lung and the chest wall. The airway resistance makes up a

significantly greater proportion of the resistance making up approximately 80% of the total resistance

with 50% of the airway resistance.43 During laminar flow the pressure difference necessary for gas to

flow through the airway is directly proportional to flow times a rate constant-airway resistance.39

During turbulent flow, which occurs at branch points, sites of obstruction, and high flow, this pressure

necessary to move air is directly proportional to a constant times the flow rate squared. This constant is

directly proportional to the volumetric flow rate and gas density and is inversely proportional to the

radius of the airway and gas viscosity. Airway diameter is possibly the most important clinical factor

effecting airway resistance because airway resistance varies inversely with the radius to the fourth or

fifth power. Airway resistance is decreased during inspiration as the pleural pressure becomes negative

due to expansion of the chest wall which increases airway and alveolar diameter and decreases

resistance. During expiration, the pleural pressure increases and the airways are compressed. Collapse is

prevented by cartilage and gas pressure in the lumen which can become a problem especially in small

preterm infants with poorly supported central airways.

Work of breathing is the amount of energy required to overcome the elastic and resistive elements

within the pulmonary system and move air in and out of the lungs. This is the cumulative product of

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distending pressure and the given volume displaced during inhalation or exhalation.39 In neonates, this

is approximately 10% of the energy expenditure of an adult and the majority of work is done by the

diaphragm. One-third of the inspiratory work is presumed to overcome the resistance of gas flow in the

airways.

Evaluation of Lung Function

Knowing the terminology describing static lung measurement is essential to describing pulmonary

function (Fig. 99-3). Assessing lung function in the neonates can be difficult as they are unable to

cooperate with the examination. However, assessing and understanding lung function is essential to

understanding the physiology, pathophysiology, and response to therapeutic intervention. Tidal volume,

vital capacity, inspiratory capacity, inspiratory reserve volume, and expiratory reserve volume can be

measured directly using spirometer. On the other hand, total lung volume, FRC, and residual volume

require specialized techniques. Over the last 50 years, technologic advances have allowed for

measurements of neonatal lung function to move from the bench top to the clinic with new ventilators

able to provide breath-to-breath analysis of lung function.

The respiratory cycle is determined by changes in pressure which drives air in and out of the lungs.

During normal inspiration, the respiratory muscles contract moving the diaphragm inferiorly and chest

wall outward resulting in a transient decrease in the transpulmonary pressure from 0 to subatmospheric.

This pressure gradient peaks during midinspiration with maximal airflow at that time. It subsequently

returns to 0 at the end of inspiration. As the muscles of respiration relax, the inward recoil increases the

transpulmonary pressure causing an expiration of inspired air. The airflow again reaches its maximum

during midexpiration and returns to zero at the end of respiration. This results in a cycle of pressure

within the alveoli from negative to positive pressure during normal inspiration.

Measuring these characteristics of ventilation including pressure, volume, and flows requires

specialized equipment and methodologies. Over time, the devices to measure these parameters have

continued to significantly improve. Pneumotachometers are one device which can be utilized to airflow.

These instruments use gas flow through a tube containing a fixed laminar flow element or flowresistive–type device. Gas flow across the element causes changes in pressure which can be measured by

pressure transducers. An additional means of measuring airflow is the use of hot wire anemometers.

These devices measure the amount of current which is required to keep a fine wire a constant

temperature with current increasing as airflow increases.13,44 Volume measurements can be obtained

using a flow sensor and by the integration of the flow signal over time. This is now performed digitally.

New methods to examine lung volumes have been investigated focusing on using techniques which do

not require patient cooperation or need to connect to the open airway due to difficulty with leaks and

the influence attempts at measurement can have on neonate breathing patterns. For example, one such

technique which has been examined and validated in adults is optoelectronic plethysmography which

estimates chest wall volume using several three-dimensional markers placed on thorax. This can

accurately measure lung volume changes.45 In order to obtain meaningful static lung measurements FRC

can be measured using whole body plethysmography, however, this is not a practical means for

measuring FRC.46 Other methods for measuring FRC including helium dilution, nitrogen washout, and

sulfur hexafluoride washout, have been utilized but can be challenging in an uncooperative,

nonmechanically ventilated infant.

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Figure 99-3. Lung measurements: Tidal volume (TV) is the amount of gas moved during one normal inspiration and expiration.

Functional residual capacity (FRC) represents the volume of gas left in the lung following normal expiration. Inspiratory capacity is

the maximum volume of air which can be inspired following a normal expiration. Inspiratory reserve volume is the additional

amount of air which can be inspired following normal inspiration. Expiratory reserve volume is the additional amount of air

which can be expired following normal expiration. Residual volume is the minimum lung volume possible, which is the air which

remains in the lung following maximum expiration. Vital capacity is the maximum amount of air which can be moved, maximum

inspiration following maximum expiration. Total lung capacity is the total amount of volume present in the lung.

Assisted Ventilation

While in most instances, transition from placental support to respiratory self-sufficiency occurs without

complications, pediatric surgeons encounter many clinical scenarios where patients require additional

assistance and mechanical support of the newborn has been a growing field with many advances.

Neonatal respiratory failure has been treated with mechanical ventilation since the 1960s.47 Initially,

adult ventilators were modified for neonatal use. The first devices designed for neonates were

continuous flow, time cycled, pressure limited devices to provide intermittent mandatory ventilation

(IMV).48 There were many limitations to these ventilators as physicians could only vary fraction of

inspired oxygen, peak inspiratory pressure, positive end-expiratory pressure, inspiratory time, rate, and

circuit flow. In the 1980s, high-frequency jet ventilation (HFJV) was introduced and has since been

widely used. During the 1990s, microprocessors were incorporated into neonatal ventilators greatly

expanding the scope of neonatal ventilation with clinicians able to control a greater number of variables

including target modality, mode of ventilation, minute ventilation, cycling mechanism, assist sensitivity,

and rise time with light weight transducers giving real time breath-to-breath information allowing

easier adjustment of ventilator settings depending on patient illness.49

Currently, ventilators in clinical use are classified as either those which deliver tidal ventilation

(conventional) or devices which deliver smaller gas volumes at rapid rates (high-frequency ventilators).

Conventional ventilators have significantly improved over recent years with the addition of the

microprocessor chips. They continue to have standard modes of ventilation including IMV, synchronized

intermittent mandatory ventilation (SIMV), assist control ventilation (AC), and pressure support

venation (PSV). These modalities can be further modified to deliver either target pressure or volume.

Further description of conventional ventilators is beyond the scope of this chapter, however, the clinical

utility of various modalities has been examined in recent literature. For example, a recent meta-analysis

of pressure-controlled modalities versus volume-controlled modalities demonstrated a significant

decrease in pneumothorax and duration of ventilation as well as a decrease in CLD in preterm infants

treated with volume-controlled modes of ventilation as opposed to pressure-controlled modes.50

There are two types of high-frequency ventilation: HFJV and high-frequency oscillatory ventilation

(HFOV). HFJV provides smaller volumes (1 to 3 mL/kg) more often at a much higher rate (240 to 660

breaths per minute) and expiration is passive. Oxygenation is proportional to mean airway pressure and

ventilation is proportional to amplitude (peak inspiratory pressure vs. PEEP).48 Jet pulsations produce

high-velocity laminar flow which has the ability to bypass airway disruptions. HVOF differs in that it

delivers smaller tidal volumes (1 to 2 mL/kg) and at an even faster rate (8 to 15 Hz). The lung is

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