to thin to the point where exchange is possible. Glucocorticoids are administered to mothers undergoing

preterm labor after 24 weeks in order to promote surfactant production and maturation of the fetal

lung.111,112 The exact mechanism remains unknown, however, studies have shown that anatomic

maturation, in particular thinning of the alveolar wall, and synthesis of mRNAs encoding surfactant

proteins increase with exposure and while with removal mRNAs decrease, anatomic changes

persist.113–115

Operating on newborn infants, especially premature, can be technically challenging just by size alone.

As the size of the infants can vary from a few hundred grams to several kilograms, surgeons must

consider various technical and physiologic aspects of each procedure, choosing the safest and most

effective option.

Several developmental and physiologic issues complicate surgery on premature infants. Lack of

thermoregulation, inadequate skin integrity, and incomplete immune development are ubiquitous to all

premature infants and can affect the morbidity of surgery. These aspects must be considered in all

children, but most of all in the smallest patients, when choosing the location for surgery, transportation

of the child, skin preparation, use of prophylactic antibiotics, placement of foreign bodies, postoperative

wound management, and healing potential. Furthermore, specific physiologic processes inherent to the

premature infant further complicate surgical planning.

Propensity for certain physiologic conditions in the neonate increases the risk of morbidity of

operating on these children: hypoglycemia, apnea and respiratory distress, and neurologic development.

Though patients are commonly kept nil per os (NPO) prior to surgery, to decrease the risk of aspiration

with anesthesia, surgeons need to assess the risks and benefits of this approach for neonates who are at

significant risk for hypoglycemia. As line access for neonates may tenuous and difficult to obtain, liberal

use of enteral nutrition, appropriate timing of surgery, and early resumption of feeds in this population

should be thoroughly considered. Furthermore, the use of narcotics and sedation can increase the risk of

postoperative apnea and respiratory distress. The edema in the neonatal airway from intubation can

contribute to early postoperative morbidity and need for reintubation or positive pressure ventilation;

therefore, a conservative approach to extubation and postoperative monitoring should be used. Finally,

although controversial, multiple studies suggest deleterious effects of anesthesia on the developing

neonate and some recommend postponing elective procedures until children are 3 years of age.116–120

Thermoregulation

Fetal thermoneutrality is maintained in a warm intrauterine environment where the amniotic fluid

reflects the maternal core temperature. In addition, the fetus generates 3 to 4 W/kg heat through an

oxygen consumption of 8 mL/min/kg.121 The placenta eliminates 85% of fetal heat into the maternal

circulation, the remaining 15% is dissipated through conductance to amniotic fluid and to the uterine

wall. The fetus is at 0.5°C to 1.0°C above the maternal core temperature.

In neonates, thermoneutrality is defined as an axillary temperature between 36.7°C and 37.3°C.122

Soon after birth, approximately 135 to 155 W/m2 of heat loss can occur through evaporation, radiation,

convection, and conduction.121 Therefore, a newborn exposed to cold stress must mount a variety of

responses to conserve heat loss, increase heat production, and maintain core temperature. The main

source of heat production is brown adipose tissue, which peaks at term gestation, used for nonshivering

thermogenesis. Term newborns also increase involuntary activity, and have hypothalamic-regulated

vasoconstriction to maintain thermoneutrality.13,121

Prematurity leads to insufficient brown fat for nonshivering thermogenesis, a larger surface area to

body mass ratio, deficient subcutaneous fat and nonkeratinized thin skin, decreased ability to maintain

flexion of extremities, and underdeveloped response of temperature sensors in the posterior

hypothalamus to release thermogenic hormones (thyroxine and epinephrine).13 In low–birth-weight

infants, the use of a servoregular set to 36°C has been shown to increase survival as compared to setting

a constant incubator temperature. Radiant warmers increased insensible water loss and did no better

when compared to incubators for temperature control.123

Neonates needing surgery are frequently transported to and from the neonatal ICU to the operating

room and radiology, leading to increased risk of heat loss. Furthermore, since fever is an infrequent sign

of postoperative infection, monitoring for temperature instability is more effective. Finally,

perioperative issues such as intraoperative irrigation, exposure during positioning, skin preparation, and

operating room temperature can all have ill effects on the susceptible neonate’s thermoregulation.

Skin Integrity

In addition to augmenting the risk of infant heat loss, poor skin integrity of neonates, especially the low

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birth weight or premature, has its own impact on the surgical patient. Beyond thermoregulation, the

thin, underdeveloped skin has several other challenges including the use of local anesthetic, skin

preparation, immune properties, bathing and wound care, and the use of an adhesive dressing. Skin

provides mechanical protection, maintains thermoregulation, provides immunosurveillance, and

prevents insensible loss of body fluids.124 Skin of premature infants is thinner and more dysfunctional.

The inadequate epidermal barrier allows increased water loss, absorption of chemicals, and trauma

causing difficulties with fluid homeostasis, thermoregulation, infection, and toxicity.125

Iatrogenic injury and alteration in skin integrity can occur more often in premature infants due to

several factors. At 26 weeks, the developing epidermis is only 2 to 3 cells thick. At 28 weeks, the skin is

deficient in fat and zinc, increasing the potential for infection, damage, and injury.126 Furthermore, due

to the lack of protein in the subcutaneous layer, increased edema can form in the skin from excess water

and sodium. The lack of sweat glands, a reduced blood supply, and lack of fat and calorie reserves,

result in an increased risk of hypothermia.126

At birth, the baby’s skin is coated with vernix caseosa (a gel like substance that has antibacterial

properties) in addition to blood, meconium, and cellular debris. The baby should not be bathed in the

first 6 hours due to increased risk of hypothermia. Premature infants should have a bathing schedule

approximately once every 4 days.124 In fact, bathing has been shown to reduce skin colonization, which

may increase the risk of pathologic infection. Meticulous umbilical cord cleansing in the first 1 to 2

weeks, however, can markedly reduce infection and neonatal death. Emollients containing a physiologic

balance of epidermal lipids – such as cholesterol, ceramide, palmitate, and linoleate – are optimum for

barrier repair.127

Due to specific properties of neonatal skin, preoperative preparation should be carefully approached.

Since neonatal skin is relatively impermeable to alcohol, it may develop skin burns and necrosis

particularly in premature infants when topical antiseptic is used on skin.124 Therefore, alcoholcontaining skin-cleansing solutions should be used with extreme caution in neonatal units. Iodinated

skin disinfectants can result in significant iodine overload and severe transient hypothyroidism.

Neonatal iodine exposure should be minimized whenever possible and in cases of exposure, thyroidstimulating hormone level should be routinely measured.128 In general, we use betadine for most

neonatal procedures, and chlorprep with hardware implantation (such as central line insertion), though

no consensus currently exists.

Use of topical anesthetic similarly can cause systemic toxicity from absorption. Prilocaine, a

component of topical anesthetics, can cause methemoglobinemia and cyanosis in neonates. Tetracaine

gel can cause contact dermatitis.124 Furthermore, the use of lidocaine or marcaine in the subcutaneous

space needs to be carefully monitored for overdose. We have used pumps that administer local

anesthesia to the incision to limit systemic narcotic use in neonates with modest success.

Dressing the surgical wound in the neonate can create its own challenges. In premature infants,

epidermal stripping secondary to tape and adhesive dressing removal is common and the primary cause

of skin breakdown in babies in the neonatal intensive care units (NICU). On the other hand, adhesive

removers should be avoided due to risk of skin injury and subsequent absorption.129 We routinely use

steristrips as the sole dressing in children; alternatively skin glue can be an adequate dressing protecting

the wound from friction and body fluids (urine, emesis, or feces). For open wounds, the use of a

vacuum-assisted device (WoundVac) has been described and can be used selectively.130–132 For delicate

skin, the use of Duoderm and Montgomery straps with wet-to-dry dressings is a good option.

Infection and Immune Response

Infection is the leading cause of mortality among infants in the first days of life,133 with mortality

related to neonatal sepsis responsible for 40% of the annual 3 million worldwide neonatal deaths.134

Severe infections occur at a higher incidence and have greater mortality in very low–birth-weight

premature neonates, especially in the first 3 to 7 days of life.135 Early-onset sepsis, associated with

Escherichia coli or group B streptococcus (GBS), typically occurs within the first 24 hours, while lateonset sepsis, associated with nosocomial coagulase-negative Staphylococcus epidermidis, typically occurs

after the first 72-hour period, and is most prevalent among very low–birth-weight babies.136 In

neonates, central venous catheters are arguably the largest risk factor for neonatal nosocomial sepsis as

coagulase-negative Staphylococcus and other organisms are the most commonly isolated late-onset

pathogens, as they normally colonize the skin around the site or are acquired from the hands of the staff

caring for the child.137

Maternal factors contributing to the risk of neonatal sepsis include prematurity, low birth weight,

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rectovaginal colonization with GBS, prolonged rupture of membranes, maternal intrapartum fever, and

chorioamnionitis.135 Postnatal factors associated with an increased risk of sepsis include male gender,

birth weight <1,000 g, hypogammaglobulinemia, intravenous alimentation, central venous catheters,

the use of steroids or drugs that decrease gastric acid acidity, and prolonged duration of mechanical

ventilation.135 Although the predominant agents are bacterial, viruses including herpes simplex and

enteroviruses, can cause fatal neonatal sepsis.135 Invasive fungal infections can also contribute to

mortality. Human milk, however, contains lactoferrin, an iron-binding glycoprotein that is important for

innate immune host defenses at birth because it exhibits broad-spectrum antimicrobial activity and

prevents invasive fungal infections.138 Neonates with sepsis may present in or progress to septic shock,

exemplified initially by cardiovascular dysfunction requiring fluid resuscitation or inotropic support.139

Neonates, especially those that are premature, have an “immature” innate immune system, both

quantitatively and qualitatively. For example, neonatal neutrophils have three- to fourfold less

bactericidal permeability-increasing protein per cell than do adult neutrophils.140 The low immunologic

profile of the newborn infant is possibly a reflection of the demands of the fetal environment, which is

inherently considered sterile, and the need to avoid immune responses to maternal antigens.136 The

development of neonatal immunity is influenced by multiple factors including “maternal cytokines,

antigen exposure, and precursor frequency of lymphocytes and antigen presenting cells.”138

Neonates have dampened T-helper (Th) responses compared with adults. In fact, many murine and

clinical studies have demonstrated decreased Th1-polarizing/proinflammatory responses (TNF-α, IFN-g,

IL-12p70, IFN-α, IFN-γ), with increased production of Th2 polarizing (e.g., IL-6) and anti-inflammatory

cytokine production (IL-10), following in vitro stimulation with bacterial products or septic

challenge.136 This inherent bias toward Th2-cell polarizing cytokines and suboptimal Th1 responses and

B-cell differentiation increases neonate susceptibility to acute respiratory and diarrheal diseases.138

Toll-like receptors (TLR), a type of pattern recognition receptors, exist on innate immune cells,

leading to “second messenger-specific intracellular signaling cascadessic [sic] that result in gene

expression, cytokine/chemokine production, and cellular activation.”136 Lipopolysaccharide (LPS,

endotoxin) on gram-negative bacteria is a key mediator of systemic inflammation, septic shock, and

multiorgan failure and death.141 TLR4, a receptor for LPS is critical for innate immune activation in

leukocytes and is expressed on many epithelial cells. Neonatal leukocytes also demonstrate decreased

responsiveness to LPS that signals through TLR4.136 LPS signals primarily through TLR4 in conjunction

with the cell surface adaptor proteins CD14 and MD265.135 Cord blood monocytes exhibit higher

expression of microRNA 146a (which regulates TLR4 signaling through the inhibition of IRAK4 – critical

for downstream signaling) and appear to have higher endotoxin tolerance. Neonatal cord blood

leukocytes also demonstrate reduced MyD88 expression and impaired LPS-induced p38 MAPK

phosphorylation and LPS-induced proinflammatory cytokine production.136 These functional

consequences of TLR activation in neonates are so markedly different from those in adults.

Figure 99-4. Zones of injury in ROP.

At birth, the number of neutrophils ranges from 1.5 to 28 × 109 cells/L blood, compared to steadystate levels of 4.4 × 109/L in adults.142 Neonatal neutrophils also have lower surface expression levels

of TLR4; therefore, the downstream signaling through MyD88 and p38 pathways are defective in

neonates following stimulation. Adherence of neonatal neutrophils is impacted by “low levels of cell

surface L-selectin and Mac-1 (CD11b/CD18) which mediate the initial loose adhesion and subsequent

tight binding of neutrophils to vascular endothelium,” a 50% reduction in transmigration of neonatal

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neutrophils to sites of infection.138 Newborn neutrophils also exhibit a dramatic reduction in chemotaxis

due to “blunted intracellular calcium influx and altered actin polymerization,”138 limiting the ability of

neutrophils to deform and penetrate the vascular endothelial lining.

Innate phagocyte function is impaired and neonatal neutrophils produce decreased extracellular traps,

which phagocytes use to localize and contain pathogens.136 The ability to degrade these pathogens is

also further compromised due to the defective NADPH oxidase system and inability to generate

hydroxyl radicals due to reduced lactoferrin and myeloperoxidase granules. Overall, these defects in

neutrophil amplification, mobilization, and function make neonates particularly susceptible to sepsis.138

Antibody responses in neonates after vaccine administration are also diminished secondary to poor

humoral and/or memory T-cell responses. Pertussis, for example, only produces humoral responses at 3

weeks of life, but not in newborns. Other vaccines, such as those for Streptococcus pneumoniae and

Haemophilus influenza, require multiple boosters. Although, having ability to administer these vaccines

at birth would be ideal, these vaccines are only effective a few months later.136

In our practice, we routinely use prophylactic antibiotics in neonates due to their immature immune

response and susceptibility to sepsis and septic shock. Furthermore, we favor a conservative approach to

decrease postoperative complications from infection and wound-healing issues due to the impaired

abilities of the neonate. When possible, elective procedures should be delayed to allow for immune

development preventing further morbidity.

Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a disorder of low–birth-weight premature infants that could

potentially lead to blindness due to damage of the developing retina. In nearly all term infants, the

retina and retinal vasculature is fully developed, so ROP does not occur. In preterm infants, retinal

development is incomplete and based on degree of immaturity, is at variable risk for damage.

The damage occurs in an orderly fashion progressing from zone 1 (most posterior) symmetrically

surrounding the optic nerve head (the earliest to develop). A larger retinal area is present temporally

(laterally) rather than nasally (medially) (zone III). Only zones I and II are present nasally (Fig. 99-4).

As ROP progression is orderly, timely recognition and treatment can decrease the risk of visual loss.

See Table 99-2 for the schedule for detecting ROP before required treatment based on gestational age at

birth.

Table 99-2 Timing of First Eye Examination Based on Gestational Age at Birth

Though peripheral retinal cryotherapy is effective in decreasing the rate of structural and visual

outcomes, peripheral retinal ablation using laser photocoagulation has similar results and is the

preferred method of ablation.143 Prevention of ROP using lower oxygen saturations (approximately

85%) was historically advocated for premature infants; however, recent randomized clinical trial has

called the practice into question due to the increased mortality with the lower threshold144 and a higher

level of saturation (88% to 92%) is now commonly targeted.

Cardiac Physiology

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The unique aspects of neonatal cardiac physiology, pathophysiology, and treatment approaches will be

highlighted. As children become adolescents, the cardiac physiology and treatment strategy approximate

adults.

5 The neonatal myocardium is immature with less cellular and structural organization, less contractile

proteins, and less compliance. The CO equals the heart rate (HR) multiplied by the stroke volume (SV).

The SV is dependent upon preload, myocardial contractility, and afterload. In the neonate, the response

to volume on the Frank–Starling curve is attenuated compared to mature myocardium. Thus, the

neonatal heart increases its CO primarily through increases in HR. Although HRs about 200 are

sometimes poorly tolerated due to short filling times, caution should be employed when considering

slowing the heart pharmacologically in a sick or stressed infant. The neonatal heart that is volume

overloaded cannot respond to catecholamine inotropic support with the usual increase in contractility,

and it often responds better to diuretics and afterload reduction. The normal HRs of infants and children

are shown in Table 99-3.

Unlike mature cardiac muscle, the neonatal myocardium has an underdeveloped sarcoplasmic

reticulum and is more dependent on extracellular calcium sources. Significant decreases in contractility

and subsequent hypotension can be observed when ionized calcium levels fall, and the drop can be acute

and dramatic. Careful attention to neonatal ionized calcium levels is essential in the perioperative

period, particularly when neonates are not being fed enterally, are stressed or septic, are on loop

diuretics that promote calcium loss such as furosemide, or have conditions associated with

hypoparathyroidism or hypocalcemia, such as DiGeroge syndrome.145

6 Bradycardia can arise from the atrium or the ventricle. In neonatal resuscitation, bradycardia is

concerning when the HR is less than 100 bpm. The primary cause of neonatal bradycardia is hypoxia. As

such, the treatment begins with assessment of the airway and measures to oxygenation and ventilation.

If the HR decreases below 60 bpm despite adequate oxygenation and ventilation, chest compressions are

indicated followed by administration of epinephrine 10 mcg/kg intravenously. Other causes of sinus

bradycardia include hypothermia, hypothyroidism, electrolyte disturbances (hypokalemia,

hypercalcemia, and hypermagnesemia), and medications. If there is hemodynamic stability, treatment

addressed the underlying cause.

Table 99-3 Normal Range of Awake and Sleeping Heart Rates in Infants and

Children

Table 99-4 Normal Range of Blood Pressure in Infants and Children

Tachycardia can arise from the atrium or ventricle. Sinus tachycardia can occur from hyperdynamic

states such as sepsis, fever, seizures, thyrotoxicosis, pain, and hypoglycemia. Treatment is aimed at the

underlying etiology. Tachyarrhythmias include atrial flutter, atrial fibrillation, and paroxysmal atrial

tachycardia. Supraventricular tachycardia can be ectopic with variable rate and respond to esmolol,

sotalol, or flecainide but reentrant SVTs usually have a fixed rate and respond to adenosine. Ventricular

tachycardia and SVTs with hemodynamic instability should be cardioverted.

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