NEONATOLOGY: MANAGEMENT, PROCEDURES, ON-CALL PROBLEMS, DISEASES, AND DRUGS - part 8 ppsx

Garland JS et al: Effect of maternal glucocorticoid exposure on risk of severe intraventricular hemorrhage in surfactant-treated preterm infants.. Volpe JJ: Intraventricular hemorrhage a

3 Consumption of high-dose folic acid must be under a physician's supervision because there

is still little information regarding its long-term effects and symptoms of pernicious anemia may be obscured, with the potential to result in serious neurologic damage

4 Because 4 mg of folic acid did not prevent all NTDs in the MRC study, patients should be

cautioned that folic acid supplementation does not preclude the need for counseling or consideration

of prenatal testing for NTDs

C The American Academy of Pediatrics Committee on Genetics has endorsed the U.S

Department of Health and Human Services (1992) recommendation, as follows:

1 All women of childbearing age (15-44 years) in the United States who are capable of becoming pregnant should consume 0.4 mg of folic acid per day for the purpose of reducing their

risk of having a pregnancy affected by spina bifida or other NTDs This amount of folic acid is

estimated to reduce the NTD risk by 50-70% This amount (0.4 mg) is also the US Recommended Daily Allowance of folic acid

2 An intake of >1 mg is not generally recommended

3 Folic acid should ideally be taken at least 1 month before conception and at least through the

first month of gestation

D Sources of folic acid

1 Dietary The average diet in the United States contains 0.2 mg of folate, which is less

bioavailable than folic acid Folate intake of 0.4 mg/day can be achieved through careful selection of folate-rich foods (spinach and other leafy green vegetables, dried beans, peas, liver, and citrus fruits)

Some breakfast cereals are fortified with folic acid Since January 1998, enriched foods (including flour, cornmeal, pasta, and rice) are fortified in folic acid by order of the US Food and Drug Administration

2 Supplementation Folic acid is available over the counter in dosages up to 0.8 mg Folic acid

is also available by prescription in 1-mg tablets Prenatal vitamins contain 0.8 or 1 mg of folic acid A survey by the March of Dimes revealed that only 27% of nonpregnant women 18-45 years of age took a vitamin preparation containing folic acid in 2001 Awareness of the U.S Public Health Service recommendation regarding folic acid did more than double from 1995 to 2002 (from 15 to 32%) for the same group Multiple sources are available to provide educational material to the public (March

of Dimes: 1-888-MODIMES or http://www.marchofdimes.org, http://www.cdc.gov, http://www.aap.org, http://www.acog.org)

E Current epidemiologic and biochemical evidence suggests that NTDs are not primarily due to

folate insufficiency but rather arise from changes in the metabolism of folate and possibly B12 in predisposed women The mechanisms may also involve homocysteine metabolism Polymorphisms

of methylene tetrahydrofolate reductase and other genes encoding proteins involved in folate

metabolism may be associated with an increased frequency of NTDs Of further interest is that the homocysteine-lowering effect of folic acid supplementation may also reduce the risk for

cardiovascular disease

F Intestinal hydrolysis of dietary folate is not impaired in mothers who have had infants with

NTDs, although the response curve to a folate-enriched meal appears to differ significantly from that

of mothers who have not had infants with NTDs

V Prenatal detection of NTDs

A Prenatal screen using maternal serum AFP at 14-16 weeks' gestation Elevated levels (>2.5

multiples of the mean, which are adjusted to gestational age) are indicative of open NTDs at a

sensitivity of 90-100%, a specificity of 96%, and a negative predictive value of 99-100% but a low positive predictive value

B Prenatal diagnosis Documentation of an elevated maternal serum AFP is followed by:

1 Genetic counseling The physician needs to make sure that the patient receives information

regarding her risk for NTDs and other conditions with elevated AFP (gastroschisis or other

conditions leading to fetal skin defects), to evaluate causes of possible false-positive results

(imprecise dates or twin pregnancies), to learn about options regarding further evaluation (see later discussion), and to provide nondirective counseling regarding treatment options

2 Detailed fetal ultrasonography with anomaly screening In skilled hands, a detailed

ultrasonogram can be extremely sensitive and specific for detection of NTDs Sonographic

determination of the level of the lesion has been shown to be useful in predicting the ambulatory potential of fetuses with NTDs Ultrasonography is also done to rule out other major congenital

defects

3 Measurement of the amniotic fluid AFP and acetylcholinesterase Amniocentesis is

usually done between 16 and 18 weeks' gestation, although it can technically be done as early as 14 weeks' gestation If indicated, karyotype can also be obtained The detection rate for anencephaly and open spina bifida is 100% when results of amniotic fluid acetylcholinesterase and AFP are combined, with a false-positive rate of only 0.04%

VI Management: anencephaly

A Approximately 75% are stillborn, and most live-born infants with anencephaly die within the

first 2 weeks of birth

B Considering the 100% lethality of anencephaly, usually only supportive care is given: warmth,

comfort, and enteral nutrition Support services for the family, including social work and genetic and

general counseling, are essential There are some ethically controversial issues regarding the extent

of care and other issues (eg, organ donation), and it may be advisable to involve other support

systems (eg, ethics committees, support groups, or religious guidance [if desired by the family])

VII Management: encephalocele

A Physical examination and initial management In addition to the general principles of

neonatal resuscitation, an especially careful physical examination is indicated Look for associated

malformations As mentioned in Neural Tube Defects, section III,C, some genetic publications list

up to 50 syndromes associated with NTDs We recommend that the child be given nothing by mouth

until the consultations by subspecialties such as neurosurgery and, if indicated, genetic tests are done and the need for immediate treatment (perhaps surgery) is assessed Imaging studies

(ultrasonography, CT, and MRI) should be arranged

B Neurosurgical intervention may be indicated to prevent ulceration and infection, except in

those cases with massive lesions and marked microcephaly The encephalocele and its contents are often excised because the brain tissue within is frequently infarcted and distorted Surgery may be

deferred, depending on the size, skin coverage, and location Ventriculoperitoneal shunt (VP)

placement may be required because as many as 50% of cases have secondary hydrocephalus

C Counseling and long-term outcome A multidisciplinary approach is necessary to counsel the

family regarding recurrence risk, long-term outcome, and follow-up The family should be informed

about the availability of support groups (March of Dimes and others; March of Dimes Birth Defect Foundation can be reached at 1-888-MODIMES) The degree of developmental deficits is

determined mainly by the extent of herniation and location; cerebral hemispheres from both sides or

one side, the cerebellum, and even the brainstem can be involved Visual deficits are common with occipital encephaloceles Motor and intellectual deficits are found in ~50% of patients

VIII Management: myelomeningocele Although fetal surgery for NTDs remains controversial,

many maternal-fetal specialists believe that this option should be mentioned to parents After birth, a multidisciplinary team approach, including the primary care physician, geneticist, genetic counselor, neonatologist, urologist, neurosurgeon, orthopedic surgeon, and social worker, is necessary

A Physical examination should include careful evaluation for other malformations (see section

VII,A) In addition, special efforts should be made to correlate motor, sensory, and sphincter function and reflexes to the functional level of lesion (Table 72-2)

1 Extent of neurologic dysfunction correlates with the level of the spinal cord lesion

2 Paraplegia below the level of the defect

3 The presence of the anal wink and anal sphincter tone suggests functioning sacral spinal

segments and is prognostically important In one study, 90% of patients with a positive anocutaneous reflex were determined to be "dry" on a regimen of intermittent catheterization as opposed to 50% of those with a negative reflex

B Initial management In addition to following the general principles of neonatal resuscitation

and newborn care, appropriate management of the spinal lesion is essential

1 There are institutional differences in the specifics of how to cover the lesion, and provision of

a sterile cover can be achieved by several means Some surgeons do prefer to have only a sterile

plastic material or wrap applied to the lesion and ask to avoid contact with gauze or other material that could adhere to the tissue and result in mechanical damage when removed It is advisable to try

to keep the defective area moist while avoiding bacterial contamination If tolerated, the patient

should be positioned on the side

TABLE 72-1 CAUSES OF NEONATAL SEIZURES

Perinatal asphyxiaIntracranial hemorrhage Subarachnoid hemorrhage Periventricular or intraventricular hemorrhage Subdural hemorrhage

Metabolic abnormalities Hypoglycemia

Hypocalcemia Electrolyte disturbances: hypo- and hypernatremiaAmino acid disorders

Congenital malformationsInfections

Meningitis Encephalitis Syphilis, cytomegalovirus infections, toxoplasmosis

Cerebral abscessDrug withdrawalToxin exposure (particular local anesthetics)Inherited seizure disorders

Benign familial epilepsy Tuberous sclerosis Zellweger syndromePyridoxine dependency

TABLE 72-2 CORRELATION AMONG LEVEL OF MYELOMENINGOCELE, LEVEL OF CUTANEOUS SENSATION, SPHINCTER FUNCTION, REFLEXES, AND POTENTIAL FOR AMBULATION

(pinprick)

Sphincter

Ambulation potential

Anterior lower thigh and knee (L3)

Medial leg (L4)

 Knee jerk May ambulate with

braces and crutches

May ambulate with

or without short leg braces

Sacral S2-S4

Posterior leg and thigh (S2)

Middle of buttock (S3) Medial buttock (S4)

Bladder and rectal function Anal wink

May ambulate without braces

Voluntary muscle movements are difficult to elicit in newborns with myelomeningocele and are, therefore, not helpful during initial evaluation Furthermore, motor examination may be distorted initially by reversible spinal cord dysfunction above the level of the actual defect induced by exposure of the open cord.

2 Be aware that a high rate of latex allergies has been reported in patients with NTDs In some

centers, all patients with myelodysplasia are, therefore, considered at risk for anaphylaxis and other allergic complications, and latex avoidance is practiced as a preventive protocol One study showed that after 6 years of a latex-free environment the prevalence of latex sensitization fell from 26.7% to 4.5% of children with spina bifida

3 In most centers, patients are started on antibiotics (ampicillin and gentamicin) and are given

nothing by mouth

4 Arrange for imaging studies to evaluate for hydrocephalus or other malformations detected

or suspected on physical examination

C Surgical management Usually, closure of the back lesion is done within 24 or 48 h to prevent

infection and further loss of function

D Hydrocephalus is common and often noncommunicative secondary to Arnold-Chiari

malformation of the foramen magnum and upper cervical canal (usually type II), with resultant

downward displacement of the medulla, pons, and cerebellum and obstruction of CSF flow

1 The risk of hydrocephalus is 95% for infants with thoracolumbar, lumbar, and lumbosacral

lesions and 63% for those with occipital, cervical, thoracic, or sacral lesions

2 In most cases, hydrocephalus is not evident until after closure of the myelomeningocele, and placement of a VP shunt may be required at a later date

3 Aggressive treatment with early VP shunt placement may improve cognitive function

4 Serial ultrasound scans are necessary to monitor progression of hydrocephalus because

ventricular dilation may occur without rapid head growth or signs of increased ICP The

hydrocephalus usually becomes clinically overt 2-3 weeks after birth

5 Despite treatment of the myelomeningocele and hydrocephalus, ~50% of these infants may

still succumb to death from aspiration, laryngeal stridor, and apnea attributable to the hindbrain anomaly

E Urinary tract dysfunction is one of the major causes of morbidity and mortality after the first

year of life

1 More than 85% of myelomeningoceles located above S2 are associated with neurogenic

bladder dysfunction, with urinary incontinence and ureteral reflux Poor bladder emptying

immediately after NTD closure may be temporary ("spinal shock"), and improvement of bladder function may be observed up to 6 weeks after repair

2 Without proper management, hydronephrosis develops with progressive scarring and

destruction of the kidneys Many of these infants succumb to urosepsis

3 Renal ultrasonography and a voiding cystourethrogram may identify patients who could

benefit from anticholinergic medication, clean and intermittent catheterization, prophylactic

antibiotics, or early surgical intervention of the urinary tract

4 Other associated renal anomalies include renal agenesis, horseshoe kidney, and ureteral

duplications

F Orthopedic complications

1 The lower extremities lack innervation and become atrophied

2 Deformities of the foot, knee, hip, and spine are common as a result of muscle imbalance,

abnormal in utero positioning, or teratologic factors

3 Hip dislocation or subluxation is usually evident within the first year of life, especially in

patients with midlumbar myelomeningocele

4 Treatment of orthopedic abnormalities be instituted as soon as there is sufficient healing of

the back wound

5 Physical therapists assist with proper positioning of the extremities to minimize contractures

and to maximize function

G Outcome of aggressive therapy

1 The overall mortality rate is now <15% by 3-7 years of age One study revealed a survival

rate of infants with spina bifida of 87.2% for the first year In multivariable analysis, factors

associated with increased mortality were low birth weight and high lesions

2 Infants with sacral lesions have essentially no mortality

3 The outcome in regard to the highest potential for ambulation depends largely on the level of

the original lesion (see Table 72-2) and is modified by the orthopedic treatment and complications (see section VIII,F)

4 The majority of children with lumbar myelomeningocele score within the normal range on intelligence and achievement tests, with the greatest and possibly progressive deficits on

performance IQ, arithmetic achievement, and visuomotor integration, while keeping pace on reading and spelling

5 An IQ >80 is found in essentially all patients with lesions below S1

6 Approximately 50% of survivors with thoracolumbar lesions have IQ >80

7 Cognitive function is improved in the presence of favorable socioeconomic and

environmental factors

IX Management: spina bifida occulta

A Neonatal features The presence of spina bifida occulta is suggested by overlying abnormal

collections of hair, hemangioma, pigmented macule, aplasia cutis congenita, skin tag, subcutaneous mass, cutaneous dimples, or tracts

B If undetected in the neonatal period, clinical presentation later in infancy includes the

5 A sudden deterioration may represent vascular insufficiency produced by tension on a

tethered cord, angulation of the cord around fibrous or related structures, or cord compression from a tumor or cyst

C Diagnosis

1 Ultrasonography is useful for screening

2 MRI provides superior anatomic details The advantages of MRI are that contrast is not

needed and the infants are not exposed to radiation

D Surgical correction may be necessary in the newborn period to avoid the onset of symptoms

Surgical release of a tethered cord or decompression of the spinal cord within 48 h of sudden

deterioration may completely or partially reverse recently acquired deficits

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CHAPTER 73 Perinatal Asphyxia

MANAGEMENT OUTLINE

I Definition

A Perinatal asphyxia (from the Greek term sphyzein meaning "a stopping of the pulse") is a

condition caused by a lack of oxygen in respired air, resulting in impending or actual cessation of apparent life

B Perinatal asphyxia is a condition of impaired blood gas exchange that, if it persists, leads to

progressive hypoxemia and hypercapnia with a metabolic acidosis

C Essential characteristics defined jointly by the American Academy of Pediatrics (AAP) and

the American College of Obstetricians and Gynecologists (ACOG) should be present: (1) profound

metabolic or mixed acidemia (pH <7.00) on umbilical cord arterial blood sample, if obtained; (2) persistence of an Apgar score of 0-3 for >5 min; (3) neurologic manifestations in the immediate neonatal period to include seizures, hypotonia, coma, or hypoxic-ischemic encephalopathy (HIE); and (4) evidence of multiorgan system dysfunction in the immediate neonatal period

D Biochemical indices There is no specific blood test to diagnose perinatal asphyxia

1 The normal umbilical arterial base excess is a negative 6 mEq/L with -10 to -12 mEq/L as the

upper statistical limit of normal Base excess > -20 mEq/L is required to show neurologic damage associated with metabolic acidosis

2 The precise value that is required to define damaging acidemia is not known A pH <7.0

realistically represents clinically significant acidosis Acidemia alone does not establish that hypoxic injury has occurred

E Apgar score

1 Conceived to report on the state of the newborn and effectiveness of resuscitation It is a poor

tool for assessing asphyxia Low Apgar scores are unlikely to be the cause of morbidity but rather the results of prior causes

2 An infant with an Apgar score of 0-3 at 5 min, improving to ≥4 by 10 min, has >99% chance

of not having cerebral palsy (CP) at 7 years of age; 75% of children who develop CP have normal Apgar scores at birth

3 A 1996 revised AAP/ACOG statement again emphasized that the Apgar score alone should

not be used as evidence that neurologic damage was caused by hypoxia resulting in neurologic injury

or by inappropriate intrapartum management

II Incidence of asphyxia and its relationship to CP The incidence of HIE is 2-9 in 1000 live term

births The incidence of CP has not fallen despite improved obstetric and neonatal interventions and remains at 1-2 in 1000 live term births Only 8-17% of CP in term infants is associated with adverse perinatal events suggestive of asphyxia; the cause of ≥90% of cases remains unknown One cannot

state with a reasonable degree of medical certainty that CP in a given child was due to

intrapartum asphyxia merely because the physician can find no other explanation The death

rate in term infants with HIE is ~11% and ~0.3 in 1000 live term births are severely affected The incidence of HIE, deaths, and handicap rates are all significantly higher for premature infants

III Mechanisms of asphyxia during labor, delivery, and the immediate postpartum period

A Interruption of the umbilical circulation (cord compression)

B Inadequate perfusion of the maternal side of the placenta (maternal hypotension,

hypertension, abnormal uterine contractions)

C Impaired maternal oxygenation (cardiopulmonary disease, anemia)

D Altered placental gas exchange (placental abruption, previa, insufficiency)

E Failure of the neonate to accomplish lung inflation and successful transition from fetal to

neonatal cardiopulmonary circulation

IV Pathophysiology Figure 73-1 shows the corresponding respiratory and cardiovascular effects

during prolonged asphyxia

A Adaptive responses of the fetus or newborn to asphyxia The fetus and neonate are much

more resistant to asphyxia than adults In response to asphyxia, the mature fetus redistributes the blood flow to the heart, brain, and adrenals to ensure adequate oxygen and substrate delivery to these vital organs

B Impairment of cerebrovascular autoregulation results from direct cellular injury and cellular

necrosis from prolonged acidosis and hypercarbia

C The majority of neuronal disintegration occurs after termination of the asphyxial insult

because of persistence of abnormal energy metabolism and low adenosine triphosphate (ATP) levels

A cascade of deleterious events is triggered, resulting in formation of free radicals, increased

extracellular glutamate, increased cytosolic Ca2+, and delayed cell death

1 Effects of increased cytosolic Ca 2+

a Degradation of cellular lipids, proteins, and DNA via activation of phospholipases, proteases, and nucleases

b Uncoupling of oxidative phosphorylation

c Increased release of glutamate

d Production of free radicals as the result of oxygenation of arachidonic acid and

hypoxanthine and accumulation of nitric oxide via activation of nitric oxide synthetase

2 Effects of increased extracellular glutamate Immediate neuronal death (in minutes) as a

FIGURE 73-1 Respiratory and cardiovascular effects during prolonged asphyxia.

result of osmolar lysis from influx of Na+, Cl-, and H2O; delayed neuronal death (in hours) from activation of glutamate receptors, Ca2+ influx, and the effects of increased cytosolic Ca2+

D Major circulatory changes during asphyxia

1 Loss of cerebrovascular autoregulation under conditions of hypercapnia, hypoxemia, or

acidosis Cerebral blood flow (CBF) becomes "pressure passive," leaving the infant at risk for

cerebral ischemia with systemic hypotension and cerebral hemorrhage with systemic hypertension

2 Increase in CBF secondary to redistribution of cardiac output, initial systemic hypertension,

loss of cerebrovascular autoregulation, and local accumulation of vasodilator factors (H+, K+,

adenosine, and prostaglandins)

3 With prolonged asphyxia, there is a decrease in cardiac output, hypotension, and a

corresponding fall in CBF In general, brain injury occurs only when the asphyxia is severe enough to impair CBF

E The postasphyxial human newborn is in a persistent state of vasoparalysis and cerebral hyperemia, the severity of which is correlated with the severity of the asphyxial insult

Cerebrovascular hemorrhage may occur on reperfusion of the ischemic areas of the brain However, when there has been prolonged and severe asphyxia, local tissue recirculation may not be restored because of collapsed capillaries in the presence of severe cytotoxic edema

F Cerebral edema is a consequence of extensive cerebral necrosis rather than a cause of ischemic

cerebral injury

G Regional vulnerability changes with postconceptional age (PCA) and as the infant matures

1 Periventricular white matter is most severely affected in infants <34 weeks' PCA The

"watershed" areas between the anterior and middle cerebral arteries and between the middle and posterior cerebral arteries are predominantly involved in term infants

2 Areas of brain injury in profound asphyxia correlate temporally and topographically with the

progression of myelinization and of metabolic activity within the brain at the time of the injury

White matter is, therefore, more susceptible to hypoxic injury

3 The topography of brain injury observed in vivo corresponds closely to the topography of

glutamate receptors

4 When CBF is increased in response to asphyxia, regional differences exist such that there is

relatively more blood flow to the brainstem than to higher cerebral structures

V Neuropathologic findings

A Cortical changes Cortical edema, with flattening of cerebral convolutions, is followed by

cortical necrosis until finally a healing phase results in gradual cortical atrophy Cortical atrophy, if

severe, may result in microcephaly

B Selective neuronal necrosis is the most common type of injury observed in neonatal HIE

C Other findings seen in term infants include status marmoratus of the basal ganglia and

thalamus (the marbled appearance is a result of the characteristic feature of hypermyelinization) and parasagittal cerebral injury (bilateral and usually symmetric, with the parieto-occipital regions

affected more often than those regions anteriorly)

D Periventricular leukomalacia (PVL) is hypoxic-ischemic necrosis of periventricular white

matter resulting from cerebral hypoperfusion and the vulnerability of the oligodendrocyte within the white matter to free radicals, excitotoxin neurotransmitters, and cytokines Injury to the

periventricular white matter is the most significant problem contributing to long-term neurologic deficit in the premature infant, although it does occur in sick full-term infants as well The incidence

of PVL increases with the length of survival and the severity of postnatal cardiorespiratory

disturbances PVL involving the pyramidal tracts usually results in spastic diplegic or quadriplegic

CP Visuoperception deficits may result from involvement of the optic radiation

E Porencephaly, hydrocephalus, hydranencephaly, and multicystic encephalomalacia may

follow focal and multifocal ischemic cortical necrosis, PVL, or intraparenchymal hemorrhage

F Brainstem damage is seen in the most severe cases of hypoxic-ischemic brain injury and

results in permanent respiratory impairment

VI Clinical presentation

A The majority of infants who experience intrauterine hypoxic-ischemic insults do not exhibit

overt neonatal neurologic features or subsequent neurologic evidence of brain injury It is

generally accepted that after acute perinatal asphyxia there should be an acute encephalopathy, often accompanied by multiorgan malfunction

B Occurrence of neonatal neurologic syndrome shortly after birth is a sine qua non for recent

(ie, intrapartum) insult Prenatal insult may also have occurred The primary signs of central nervous

system (CNS) injury in the term infant include seizures, abnormal respiratory patterns (apnea),

posturing and movement disorders, impaired suck, and jitteriness The absence of this neonatal

neurologic syndrome rules out intrapartum insult as the cause of major brain injury

C The severity of HIE correlates with the duration and severity of the asphyxial insult A

constellation of neurologic signs evolves over the first 72 h of life best characterized by Sarnat and Sarnat in 1976: stage I (hyperalert, awake state), stage 2 (lethargic, obtunded, hypotonic, seizures), and stage 3 (stuporous, comatose, flaccid, posturing) Moderately to severely affected infants are usually obtunded if not comatose, with generalized hypotonia and paucity of spontaneous

movements Depressed reflexes and cranial nerve palsies are common findings Presentation of

hypertonicity and irritability generally are not noted until the second week of life

D Occurrence of seizures within the first 12-24 h after birth is indicative of intrapartum insult

until proven otherwise Seizures may also be secondary to hypoglycemia Perlman and Risser (1996) showed that the combination of a 5-min Apgar score of ≤5 and the need for intubation in the delivery room in association with an umbilical cord arterial pH ≤7.00 has an odds ratio of 340 for the

development of seizures in the first 24 h of life

E Hypoxic-ischemic spinal cord injury Ischemic injury to anterior horn cells within the spinal

cord gray matter is relatively common among hypotonic and hyporeflexic neonates after severe

perinatal hypoxia-ischemia Electromyographic examinations show injury to the lower motor neuron above the level of the dorsal root ganglion (Clancy et al, 1989)

F Clinical presentation may be further obscured by the coexistence of skull fracture, subdural

hematoma, or subarachnoid hemorrhage resulting from traumatic delivery

G Multiple organ involvement A prospective study by Martin-Ancel et al (1995) showed that

involvement of 1 or more organs occurred in 82% of infants with perinatal asphyxia The central nervous system (CNS) was the organ most frequently involved (72%) Severe CNS injury always occurred with involvement of other organs, although moderate CNS involvement was isolated in 20%

of the infants Renal involvement occurred in 42% of the infants, pulmonary involvement in 26%, cardiac involvement in 29%, and gastrointestinal involvement in 29% Fifteen percent of neonates experienced renal failure, and 19% had respiratory failure All of the infants in this study with an Apgar score <5 at 5 min had severe involvement of at least 1 organ, whereas 90% of the infants with

an Apgar score ≥5 at 5 min did not have severe involvement of any organ

1 Cardiovascular system Shock, hypotension, tricuspid insufficiency, myocardial necrosis,

congestive heart failure, and ventricular dysfunction

2 Renal function Oliguria-anuria, acute tubular or cortical necrosis (hematuria, proteinuria),

and renal failure

3 Hepatic function Elevated serum γ-glutamyl transpeptidase activity, ammonia and indirect bilirubin, and decreased clotting factors at 3-4 days' postnatal age in moderate to severe asphyxia

4 Gastrointestinal tract Paralytic ileus or delayed (5-7 days) necrotizing enterocolitis

5 Lungs Respiratory distress syndrome (see Chapter 74) from surfactant deficiency or

dysfunction, pulmonary hemorrhage (shock lung), and persistent pulmonary hypertension (see

Chapter 62)

6 Hematologic system Thrombocytopenia can result from shortened platelet survival or

disseminated intravascular coagulopathy Increased numbers of nucleated red blood cells have been reported (see later discussion)

7 Metabolic Acidosis, hypoglycemia (hyperinsulinism), hypocalcemia (increased phosphate

load, correction of metabolic acidosis), and hyponatremia/syndrome of inappropriate antidiuretic hormone secretion (SIADH)

8 Acute Perinatal Asphyxia Scoring System A simple scoring system can be used to identify

those newborns depressed at birth who are at greatest risk for multiple organ system sequelae The scoring system is composed of the 5-min Apgar, umbilical artery base deficit, and fetal heart rate (FHR) monitor tracing (Carter et al, 1998) Multiple organ system morbidity was more likely to occur

when the score exceeds 6

VII Diagnosis Recognition of neonatal HIE depends principally on information gained from a

careful history and a thorough physical examination with appropriate laboratory studies as outlined previously Neurodiagnostic and neuroimaging studies can help determine the extent of the injury and may also be of value prognostically

A Antenatal indicators of uteroplacental insufficiency or fetal compromise (see also Chapter

1) may include the following:

1 Reactive FHR and subsequent prolonged FHR deceleration suggestive of a sudden

catastrophic event (pattern of acute asphyxia)

2 Reactive FHR, which, during labor, becomes nonreactive, associated with rising FHR baseline and repetitive late decelerations (pattern of intrapartum asphyxia)

3 A persistent nonreactive FHR tracing with a fixed baseline rate, from admit until

delivery, is suggestive of prior neurologic injury This FHR pattern is often associated with reduced

fetal movement, old passage of meconium, oligohydramnios, and abnormal fetal pulmonary

vasculature (persistent pulmonary hypertension)

4 FHR patterns are not always specific, with a substantial false-positive rate Improving the

predictive value of FHR pattern in detecting intrapartum asphyxia may require supplementary tests:

a Fetal vibroacoustic stimulation

b Fetal pulse oximetry

c A decreased biophysical profile score

d An amniotic fluid index ≤5

e An increased pulsatility index in the umbilical artery or decreased fetal cerebral resistance

on Doppler ultrasonography

5 ACOG cautions against using terms such as asphyxia, hypoxia, and fetal distress when

applied to continuous electronic fetal monitoring or auscultation

B EEG Evolution of EEG changes may provide information on the severity of the asphyxial

injury, and the type of EEG abnormality may be indicative of a specific pathologic variety

Identification of EEG abnormalities within the first hours after delivery may be helpful in selecting infants for treatment with neuroprotective agents

C Computed tomography (CT) scan The value of CT in the assessment of diffuse cortical

neuronal injury is most apparent several weeks after severe asphyxial insults It is of particular value

in the identification of focal and multiple ischemic brain injury During the first week after an insult, the striking, bilateral, diffuse hypodensity reflects marked cortical neuronal injury, with associated edema corresponding closely to the occurrence of maximum intracranial pressure

D Ultrasonography is the method of choice for routine screening of the premature brain It is

of major value in the identification of intraventricular hemorrhage and necrosis of basal ganglia and thalamus It is superior to CT in identifying both the acute and subacute-chronic manifestations of periventricular white matter injury Its limitations in the first weeks of life include its inability to reliably identify mild injury, to visualize lesions that are peripherally located, and to distinguish

between hemorrhagic and ischemic lesions in the cerebral parenchyma

E Magnetic resonance imaging (MRI) is the technique of choice for evaluation of

hypoxic-ischemic cerebral injury in term and premature newborns The advantages of MRI include the

following:

1 It does not expose the neonate to radiation

2 It demonstrates better anatomic imaging detail and resolution than CT, especially of the deep

cortical structures (eg, the basal ganglia and thalamus) and corticospinal tracts

3 It clearly demonstrates the myelinization delay that almost invariably accompanies asphyxial

brain injury MRI may provide insight into the timing and duration of the asphyxial injury Delayed myelinization is a negative predictor of long-term neurodevelopmental outcome

4 MRI is probably the best method available to diagnose hypoxic brain injuries in mildly to

moderately affected patients and to detect discrete lesions of the cerebellum and brainstem

5 It may provide clues to other disorders (eg, metabolic or neurodegenerative disorders) that

may also present as obtundation or coma in the newborn period

6 In experienced hands, ischemic lesions can be identified as early as 24 h after the insult

7 MRI can help differentiate between partial asphyxia and anoxia

a Partial asphyxia Injury is caused primarily by mild or moderate hypoxia or hypotension

Regions of the brain with the most tenuous perfusion are affected, and susceptibility varies as the infant matures (ie, periventricular white matter in premature infants and "watershed" areas in term infants) Deep gray matter structures of the cerebrum are typically spared

b Anoxia Injury is the result of a cardiorespiratory arrest or profound hypotension The

volume of damaged brain varies with the duration of the injury An arrest of long duration (≥25 min) damages nearly the entire brain Arrests of shorter duration show specific patterns that vary with PCA: at 26-32 weeks, the lateral thalami are primarily affected; at 34-36 weeks, the lentiform nucleus and hippocampus and the perirolandic cortex are affected; and by 40 weeks, the corticospinal tracts from the internal capsule to the perirolandic cortex are affected More severe or prolonged events result in injury to the optic radiations

8 MRI demonstrates the structural sequelae of asphyxial injury on follow-up and has prognostic

value Repeat MRI at 3 months of age will usually show the full extent of brain injury

F Evoked electrical potentials (auditory, visual, or somatosensory) performed within the first

hours of life may help to select infants for treatment with neuroprotective agents They also have prognostic value in defining areas of CNS damage Persistence of deficits beyond the neonatal period correlates with persistence of other signs of brain injury

G Potentially useful techniques

1 Magnetic resonance spectroscopy (MRS) provides a measure of "energy reserve." Using

phosphorus-/(31P) MRS, it has been shown that asphyxiated newborns tend to have lower

phosphocreatine/inorganic phosphate ratios (impaired brain oxidative phosphorylation) and lower ATP/total phosphorus ratios than normal patients

2 Proton MRS allows noninvasive observations to be made of the derangement of cerebral

metabolites (N-acetylaspartate (NAA) and lactic acid) when oxidative phosphorylation is impaired

The normalization of phosphorous metabolite ratios with time may reflect loss of severely affected neurons Neuronal loss, gliosis, and delay in myelination would be reflected by a relative loss of NAA

3 Near-infrared spectroscopy on the first day after injury may demonstrate increased cerebral

venous oxygen saturation and decreased cerebral oxygen extraction, despite increased cerebral

oxygen delivery, suggestive of a postasphyxial decrease in oxygen utilization

VIII Management

A Optimal management is prevention The first goal is to identify the fetus being subjected to or

likely to experience hypoxic-ischemic insults with labor and delivery

B Immediate resuscitation Any newborn that is apneic at birth must be promptly resuscitated

because it cannot be determined whether the infant is in primary or secondary apnea

1 Maintenance of adequate ventilation Use an assisted ventilatory rate to maintain

physiologic levels of PCO2 Hypercarbia can further increase cerebral intracellular acidosis and

impair cerebrovascular autoregulation, whereas hypocarbia (PaCO2 <20-25 mm Hg) has been

associated with PVL in preterm infants and late-onset sensorineural hearing loss in full-term infants

2 Maintenance of adequate oxygenation (PaO2 >40 in premature infants and PaO2 >50 in term infants) Avoid hyperoxia (see later discussion), which may lead to additional brain injury from possible reduction in CBF and vaso-obliterative changes

3 Maintenance of adequate perfusion Maintain arterial blood pressure in the "normal" range

for gestational age and weight Volume expanders and inotropic support are often required With the loss of cerebrovascular autoregulation, it is important to avoid systemic hypotension and

hypertension

4 Correct metabolic acidosis with cautious use of volume expanders The primary objective is

to sustain tissue perfusion Perfuse or lose! Use bicarbonate only when cardiopulmonary resuscitation

(CPR) is prolonged and the infant remains unresponsive Bicarbonate administration may lead to hypercarbia and intracellular acidosis and increase lactate

5 Maintain a normal serum glucose level (~75-100 mg/dL) to provide adequate substrate for

brain metabolism Avoid hyperglycemia to prevent hyperosmolality and a possible increase in brain lactate levels

6 Control of seizures

a Phenobarbital is the drug of choice It is usually continued until the EEG is normal and

there are no clinical seizures for ≥2 months The benefit of prophylactic therapy remains

controversial High-dose phenobarbital (40 mg/kg) reduced the incidence of seizures and improved

neurologic outcome at 3 years in term asphyxiated newborns (Hall et al, 1998)

b If seizures persist despite therapeutic phenobarbital levels, diazepam, lorazepam, and

phenytoin may be used (for dosages and other pharmacologic information, see Chapter 80)

7 Prevention of cerebral edema The cornerstone of prevention of serious brain swelling is avoidance of fluid overload Maintain slight to moderate fluid restriction (eg, 60 mL/kg) If cerebral

edema is severe, further restriction of fluid intake to 50 mL/kg is imposed Observe the infant for SIADH Glucocorticoids and osmotic agents are not recommended

C Potential new therapies should aim at preventing delayed neuronal death once an

asphyxial insult has occurred It is estimated that there is a 6- to 12-h window of opportunity after

acute asphyxia whereby administration of a neuroprotective agent could reduce or prevent brain damage Protecting the brain from injury would depend on the baseline fetal brain status

1 Magnesium has an inhibitory effect on excitation of the N-methyl-D- aspartate type of

glutamate receptors and competitively blocks Ca2+ entry through voltage-dependent Ca2+ channels during hypoxia Apnea may occur, and higher doses carry a significant risk of hypotension Use of magnesium sulfate (MgSO4) remains controversial

2 Prevention of free radical formation

a Xanthine oxidase inhibitor In a pilot study (Van Bel et al, 1998), allopurinol reduced free

radical formation and enhanced electrical brain activity in severely asphyxiated newborns In

addition, allopurinol reduced nonprotein iron (a prooxidant)

b Resuscitation with room air In the Resair 2 trial (Saugstad 2001), room air-resuscitated

infants recovered more quickly as assessed by time to first cry, 5-min Apgar score, and sustained pattern of respiration Neonates resuscitated with 100% oxygen manifest biochemical changes

indicative of prolonged oxidative stress at 4 weeks of age (Vento et al, 2001)

3 Excitatory amino acid antagonists

4 Calcium channel blockers

5 Inhibition of nitric oxide production Increased plasma nitric oxide levels has been shown

as a marker for severity of brain injury and poor neurologic outcome (Shi et al, 2000)

6 Selective head cooling Hypothermia is thought to protect the brain from injury by preventing

the decline in high-energy phosphates Phosphocreatine and adenosine triphosphate are maintained while cerebral lactate levels are reduced Selective head cooling coupled with mild systemic

hypothermia was found to be safe in a group of asphyxiated term infants (Gunn et al, 1998)

7 Any multicentered trial testing a new therapy to prevent or limit brain injury will require early

enrollment soon after birth in infants at greatest risk of developing the sequelae of HIE

IX Prognosis Most survivors of perinatal asphyxia do not have major sequelae Peliowski and

Finer (1992) showed that the overall risk of death for children with all stages of HIE combined was 12.5%, 14.3% for neurologic handicap, and 25% for death plus handicap Depressed FHR, meconium-stained amniotic fluid, low "extended" Apgar scores, low scalp and cord pH, or clinical signs of

neurologic depression soon after birth signify the acute clinical condition of the newborn However, their predictive value for later neurodevelopmental outcome is less than satisfactory, especially when taken individually Furthermore, environmental, psychosocial, behavioral, and developmental

influences may significantly affect long-term outcome

A Findings associated with increased risk of neurologic sequelae

1 Apgar score of 0-3 at 20 min of age

2 Presence of multiorgan failure, particularly oliguria persisting beyond 24 h of life

3 Severity of the neonatal neurologic syndrome Severe HIE (Sarnat stage 3) carries a

mortality rate of ~80%, and survivors often have multiple disabilities, including spastic CP, severe or profound mental retardation, cortical blindness, or seizure disorder (Robertson & Finer, 1993) There

is no permanent sequelae for mild HIE (Sarnat stage 1) Moderately affected (stage 2) patients have outcomes that vary with their overall clinical course and duration of their neurologic condition Stage

2 beyond 5 days is a poorer prognostic sign

4 Duration of neonatal neurologic abnormalities Disappearance of neurologic abnormalities

by 1-2 weeks and the ability to nipple feed normally is an excellent prognostic sign

5 Presence of neonatal seizures, especially if they occur within the first 12 h after birth and are

difficult to control

6 An abnormal MRI obtained in the first 24-72 h is associated with a poor outcome,

irrespective of birth variables On the other hand, a normal MRI obtained in the first 24-72 h almost always predicts a favorable outcome, even in a severely asphyxiated infant (Martin & Barkovich, 1995) An abnormal signal in the posterior limb of the internal capsule predicted an unfavorable outcome in 33 of 36 infants with Sarnat stage 2 HIE (Rutherford et al, 1998) The prognostic value is improved by repeating the study after several months, when delayed myelinization and structural damage are better appreciated

7 Severity and duration of EEG abnormalities Normal to mildly abnormal EEG patterns

within the first days after delivery are significantly correlated with normal outcomes, and moderately

to severely abnormal EEG patterns are significantly related to abnormal outcomes (van Lieshout et al,

1995) A burst-suppression or isoelectric pattern on any day and prolonged EEG depression after day

12 are associated with a poor outcome Recovery of normal EEG background by day 7 is associated with a normal outcome The early presence (within the first days after birth) of a normal or near-normal EEG, even in a "comatose" child, is a strong predictor of a good neurologic outcome

8 Persistent abnormalities of brainstem function are generally incompatible with long-term

survival

9 Abnormal visual, auditory, or somatosensory evoked potentials persisting beyond day 7 of

life Normal somatosensory evoked potentials (SSEPs) are highly predictive of a normal outcome Eken et al (1995) showed that SSEPs performed within 6 h after delivery had a positive predictive value of 82% for moderate to severe HIE and a negative predictive value of 92% Abnormal visual evoked potential (VEP) throughout the first week of life or an absent VEP at anytime guaranteed an abnormal outcome in asphyxiated full-term infants (Muttitt et al, 1991)

10 Subsequent hearing is normal in most children who have suffered perinatal or

postnatal asphyxia Children with residual neurodevelopmental deficits have more frequent

peripheral hearing loss and more abnormalities of the central components of auditory evoked

potentials than those who do not have neurodevelopmental deficits, suggestive of residual

dysfunction in the rostral brainstem (Jiang, 1995; Jiang & Tierney, 1996)

11 Microcephaly at 3 months of age is predictive of poor neurodevelopmental outcome

(Shankaran et al, 1991) A decrease in head circumference (HC) ratios (actual HC/mean HC for age × 100%) of >3.1% between birth and 4 months of age is highly predictive of the eventual development

of microcephaly before 18 months of age (Cordes et al, 1994) Suboptimal rate of head growth

associated with moderate cerebral white matter changes on MRI may be a better predictor of poor neurodevelopmental outcome (Mercuri et al, 2000)

12 Decreased cerebral concentrations of phosphocreatine or ATP at birth on quantitative

31 P MRI (Martin et al, 1996)

13 Elevated brain lactate levels (Leth et al, 1996), elevated ratio of lactate to

N-acetylaspartate(Penrice et al, 1996) and lactate to choline (Barkovich et al, 1999) on proton MRS, and low CSF cyclic adenosine monophosphate (cAMP) levels (Pourcyrous et al, 1999)

14 Increased CBF on Doppler sonography in the first 3 days after birth (Leth et al, 1996)

15 Decreased cerebral resistive index on Doppler sonography (Gonzalez de Dios et al, 1995)

16 The presence of optic atrophy is an indicator of poor visual outcome (Luna et al, 1995)

Many children with postasphyxial CNS abnormalities have lower visual acuity scores and smaller visual fields

B Nondisabled survivors of moderate HIE have delayed skills in reading, spelling, or arithmetic

and have more difficulties with attention and short-term recall than survivors of mild HIE and normal individuals

X Ethics Decision making is often difficult, but it is easier if the medical team and families

communicate openly and clearly (See also Chapters 15 and 32.) Shared decision making creates a partnership between parents and the physician and potentially reduces conflicts Discussing best- and worst-case outcomes may help to define the range of potential outcome

XI Medicolegal issues

A Fetal monitoring In the presence of a reactive FHR pattern and normal fetal movement, the

key is to monitor the baseline rate (Phelan & Kim, 2000) A rise or fall in FHR baseline should alert the labor and delivery team to impending fetal asphyxia

B Timing of asphyxia to the intrapartum period may be the cause of CP if there is no evidence

of an antenatal injury (clinically or neuroimaging study) and there is classic criteria of severe

asphyxia (ACOG) while excluding other causes of neonatal encephalopathy

C Nucleated red blood cells (nRBCs) Phelan et al (1998) attempted to time asphyxia to the

magnitude of nRBC count They showed that preadmission asphyxia resulted in a higher nRBC count than acute asphyxia Adopting nRBC count to time asphyxia may be misleading because the

magnitude of elevation not only relates to the duration of the asphyxia but to the severity of the

asphyxia as well Increased nRBC count may also be seen in prematurity, intrauterine growth

retardation (IUGR), chorioamnionitis, and diabetes

D When asked whether an identified event led to a subsequent adverse outcome, it is

important to realize that the baseline fetal brain status is unknown

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CHAPTER 74 Pulmonary Diseases

AIR LEAK SYNDROMES

I Definition The pulmonary air leak syndromes (pneumomediastinum, pneumothorax, pulmonary

interstitial emphysema [PIE], pneumopericardium, pneumoperitoneum, and pneumoretroperitoneum) comprise a spectrum of disease with the same underlying pathophysiology Overdistention of alveolar sacs or terminal airways leads to disruption of airway integrity, resulting in dissection of air into surrounding spaces

II Incidence Although the exact incidence of the air leak syndromes is hard to determine, they are

most commonly seen in infants with underlying lung disease (such as respiratory distress syndrome [RDS], meconium aspiration, and pulmonary hypoplasia) who are on ventilatory support in the

neonatal intensive care unit (NICU) In general, the more severe the lung disease, the higher is the incidence of pulmonary air leak Whereas air leak syndromes are seen most commonly in infants on ventilatory support, they all have been reported to occur spontaneously

III Pathophysiology Overdistention of terminal air spaces or airwaysthe common denominator in

all the pulmonary air leakscan result from uneven alveolar ventilation, air trapping, or injudicious use of alveolar distending pressure in infants on ventilatory support As lung volume exceeds

physiologic limits, mechanical stresses occur in all planes of the alveolar or respiratory bronchial wall, with eventual tissue rupture Air can track through the perivascular adventitia, causing PIE, or dissect along vascular sheaths toward the hilum, causing pneumomediastinum Rupture of the

mediastinal pleura results in pneumothorax Pneumoretroperitoneum and pneumoperitoneum may occur when mediastinal air tracks downward to the extraperitoneal fascial planes of the abdominal wall, mesentery, and retroperitoneum and eventually ruptures into the peritoneal cavity

A Barotrauma The common denominator of the air leak syndromes is barotrauma Barotrauma

results whenever positive pressure is applied to the lung; it cannot be avoided in the ill newborn

infant needing ventilatory support, but its effects should be minimized

1 Peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), inspiratory time (IT), respiratory rate, and the inspiratory waveform play important roles in the development

of barotrauma It is difficult to determine which of these parameters is the most damaging and which plays the largest role in the development of the air leaks

2 Inadvertent PEEP secondary to a very rapid rate and a short expiratory time may also be

important

B Other causes of lung overdistention Barotrauma is not the only cause of lung overdistention

Atelectatic alveoli in RDS may cause uneven ventilation and subject the more distensible areas of the lung to receive high pressures, placing them at risk for rupture Small mucous plugs in the airway in meconium aspiration may cause gas trapping secondary to a ball-valve effect Other events, such as inappropriate intubation of the right main stem bronchus, failure to wean after surfactant replacement therapy, and vigorous resuscitation or the development of high opening pressures with the onset of air breathing, can also lead to overdistention, with rupture of airway integrity at birth

C Lung injury

1 Large tidal volume It has long been considered that lung injury is primarily a result of

high-pressure ventilation (barotrauma) Although reports show variable relationships between airway pressures and lung injury, more recent studies support the concept that lung overdistention resulting from high maximal lung volume ("volutrauma") and transalveolar pressure, rather than high airway pressure, is the harmful factor In infants with low lung compliance, a high PIP may cause only small alveolar distention that may not be associated with significant injury

2 Atelectasis The alveolar units in patients with RDS are subjected to a cycle of recruitment

and derecruitment Strategies to decrease this mechanism of atelectatic traumaoptimizing lung recruitment and decreasing lung injury and severity of lung diseasewill lessen the risk for

pulmonary air leak

IV Risk factors

A Ventilatory support The infant on ventilatory support has an increased risk of developing one

of the air leak syndromes Some investigators report an incidence as high as 12% in infants on any type of ventilatory support

B Meconium staining Other infants at risk include those who are meconium stained at birth In

these infants, meconium may be plugged in the airways, with resultant air trapping During

inspiration, the airway expands, allowing air to enter However, during exhalation, there is airway collapse with resultant trapping of air behind meconium plugs

C Failure to wean after surfactant therapy Studies have shown that prophylactic use of

surfactant therapy in infants at risk for RDS is associated with a decrease in the incidence of

pneumothorax and PIE Similar findings were noted in treating premature newborns with established RDS With the return of pulmonary compliance after receiving surfactant, appropriate decreases in pressure support and more cautious ventilatory management of these infants is necessary immediately after therapy The clinician must closely watch for improvement in the infant's arterial blood gas levels and must wean ventilatory support as required

V Clinical presentation Air leak syndromes are potentially lethal, and a high index of suspicion is

necessary for the diagnosis of air leak syndromes On clinical grounds, respiratory distress or a

deteriorating clinical course strongly suggests air leak See section IX: Specific Air Leak Syndromes

VI Diagnosis The definitive diagnosis of all of these syndromes is made radiographically An

anteroposterior (AP) chest x-ray film along with a cross-table lateral film is essential in diagnosing an air leak

VII Prevention The best mode of treatment for all of the air leak syndromes is prevention and

judicious use of ventilatory support, with close attention to distending pressure, PEEP, and IT

Despite the availability of surfactant and high-frequency ventilators and advancements in respiratory monitoring, air leak syndromes continue to be a problem in neonatal care Barotrauma remains a prominent disadvantage to ventilatory support The judicious use of ventilatory pressures and the adjustment of ventilator settings to provide a minimum of barotrauma are extremely important in the

NICU The use of surfactant therapy for RDS has been shown to substantially decrease the incidence

of pneumothorax and PIE Although studies report that high-frequency ventilation (HFV) reduced the incidence of air leaks, the use of this strategy in infants exposed to antenatal steroids and postnatal surfactant remains to be confirmed

VIII Prognosis The prognosis for the infant in whom an air leak develops depends on the

underlying condition In general, if the air leak is treated rapidly and effectively, the long-term

outcome should not change However, it must be remembered that early-onset PIE (>24 h of age) is associated with a high mortality rate Chronic lung disease (CLD) of the newborn, or

bronchopulmonary dysplasia (BPD), is also associated with severe pulmonary air leak syndromes

IX Specific air leak syndromes

A Pneumomediastinum

1 Definition Pneumomediastinum is air in the mediastinum from ruptured alveolar air that has

traversed fascial planes

2 Incidence The incidence of pneumomediastinum before the era of neonatal intensive care

was approximately 2 in 1000 live births The exact incidence is related to the degree of ventilatory support and is clearly higher today It has been reported to occur in at least 25% of patients with coexisting pneumothorax

3 Pathophysiology Pneumomediastinum is preceded by PIE in almost every instance After

alveolar rupture, air traverses fascial planes and passes into the mediastinum

4 Risk factors See section IV: Risk Factors

5 Clinical presentation Unless accompanied by pneumothorax, a pneumomediastinum may be

totally asymptomatic Spontaneous pneumomediastinum may develop in term infants not on

ventilatory support and may be accompanied by mild respiratory distress Physical findings in

addition to respiratory distress may include an increase in AP diameter of the chest and difficulty in auscultating heart sounds

6 Diagnosis On the radiograph, pneumomediastinum may present in several ways The classic

description is that of a "wind-blown spinnaker sail" (a lobe or lobes of the thymus being elevated off the heart) In other cases, a halo may be seen around the heart in the AP projection, or evidence on this projection may be completely absent The cross-table lateral projection will show an anterior collection of air that may be difficult to distinguish from a pneumothorax

7 Management There is no definitive treatment for pneumomediastinum One should resist the

temptation to insert a drain into the mediastinum because it will not be beneficial and may cause more problems than it will solve An oxygen-rich environment can be used in the term infant to

attempt nitrogen washout if the pneumomediastinum is believed to be clinically significant

8 Prognosis The prognosis is good because recovery is frequently spontaneous without

treatment

B Pneumothorax

1 Definition Pneumothorax is air between the visceral and parietal pleural surfaces

2 Incidence The incidence of pneumothorax varies between units Before the modern era of

neonatal intensive care, the incidence of pneumothorax was 1-2% With the advent of neonatal

ventilator care, however, the incidence has risen dramatically Although the exact incidence is

difficult to determine, it is directly related to the degree of ventilatory support delivered

3 Pathophysiology

a The term infant not on ventilatory support Pneumothorax may develop spontaneously

It usually occurs at delivery, when a large initial opening pressure is necessary to inflate collapsed alveolar sacs The overall frequency based on radiographic surveys is approximately 1% of all live births

b The infant on ventilatory support will have alveolar overdistention secondary to either

injudicious use of distending pressure or failure to wean ventilatory pressure when compliance begins

to return Pneumothorax is usually preceded by rupture of the alveoli, with the interstitial air then traversing via fascial planes to the mediastinum The air breaks through the mediastinal pleura to form a pneumothorax

4 Risk factors See section IV: Risk Factors

5 Clinical presentation The clinical presentation of the neonate with pneumothorax depends

on the setting in which it develops

a Term infants with a spontaneous pneumothorax may be asymptomatic or only mildly

symptomatic These infants usually have tachypnea and mild oxygen needs early but may progress to the classic signs of respiratory distress (grunting, flaring, retractions, and tachypnea)

b The infant on ventilatory support will generally have a sudden, rapid clinical

deterioration characterized by cyanosis, hypoxemia, hypercarbia, and respiratory acidosis The most common time for the development of this complication is either immediately after the initiation of ventilatory support or when the infant begins to improve and compliance returns (eg, after surfactant therapy) In either case, other clinical signs may include decreased breath sounds on the involved side, shifted heart sounds, and asynchrony of the chest When compression of major veins and

decreased cardiac output occur because of downward displacement of the diaphragm, signs of shock may be evident

6 Diagnosis A high index of suspicion is necessary for the diagnosis of pneumothorax

a Transillumination of the chest With the aid of transillumination, the diagnosis of

pneumothorax may be made without a chest x-ray film A fiberoptic light probe placed on the infant's chest wall will illuminate the involved hemithorax Although this technique is beneficial in an

emergency, it should not replace a chest x-ray film as the means of diagnosis

b Chest x-ray films Radiographically, pneumothorax is diagnosed on the basis of the

following characteristics:

i Presence of air in the pleural cavity separating the parietal and visceral pleura The area

appears hyperlucent with absence of pulmonary markings

ii Collapse of the ipsilateral lobes

iii Displacement of the mediastinum to the contralateral side

iv Downward displacement of the diaphragm In infants with RDS, the compliance may

be so poor that the lung may not collapse, with only minimal shift of the mediastinal structures The anteroposterior x-ray film may not demonstrate the classic radiographic appearance if a large amount

of the intrapleural air is situated just anterior to the sternum In these situations, the cross-table lateral x-ray film will show a large lucent area immediately below the sternum, or the lateral decubitus x-ray film (with the suspected side up) will show free air

c Transcutaneous carbon dioxide (tcPCO 2 ) Reference percentiles for tcPCO2 level and slope of the trended tcPCO2 over various time intervals have been used to detect the occurrence of pneumothorax preclinically The area under the curve (AUC) for 5 consecutive minutes with a 5-min tcPCO2 slope more than the 90th percentile shows good discrimination for a pneumothorax

However, false-positive results such as presence of a blocked or misplaced endotracheal tube may be encountered If the problem with tcPCO2 persists after appropriately suctioning the endotracheal tube, then a confirmatory x-ray film should be ordered

7 Management Treatment of pneumothorax depends on the clinical status of the infant

a Oxygen supplementation In the term infant who is mildly symptomatic, an oxygen-rich

environment is often all that is necessary The inspired oxygen facilitates nitrogen washout of the blood and tissues and thus establishes a difference in the gas tensions between the loculated gases in the chest and those in the blood This diffusion gradient results in rapid resorption of the loculated gas, with resolution of the pneumothorax This mode of therapy is not appropriate in the preterm infant because of the high oxygen levels needed for washout and resulting increase in oxygen

saturation This makes it unsuitable for premature infants with risk for retinopathy of prematurity (ROP)

b Decompression In the symptomatic neonate or the neonate on mechanical ventilatory

support, immediate evacuation of air is necessary The technique is described in Chapter 51, p 293, section V,A Placement of a chest tube of appropriate size will eventually be necessary (see Chapter 19)

C PIE

1 Definition PIE is dissection of air into the perivascular tissues of the lung from alveolar

overdistention or overdistention of the smaller airways

2 Incidence This disorder arises almost exclusively in the very low birth weight infant on

ventilatory support It may also emerge in the extremely low birth weight infant without mechanical ventilation but receiving ventilatory support by continuous positive airway pressure (CPAP) It has been reported to occur in at least one third of infants <1000 g who have RDS on the first day of life

If seen within the first 24 h of life, it generally is associated with a poor prognosis As time passes, its occurrence is less common, but it may be seen at any time during ventilatory management

3 Pathophysiology PIE may be the precursor of all other types of pulmonary air leaks With

overdistention of the alveoli or conducting airways, or both, rupture may occur, and there may be dissection of the air into the perivascular tissue of the lung The interstitial air moves in the

connective tissue planes and around the vascular axis, particularly the venous ones Once in the

interstitial space, the air moves along bronchioles, lymphatics, and vascular sheaths or directly

through the lung interstitium to the pleural surface The extrapulmonary air is trapped in the

interstitium (PIE), or it may extend and cause pneumomediastinum, pneumopericardium, or

pneumothorax PIE may exist in two forms: localized (which involves one or more lobes) or diffuse (bilateral)

4 Risk factors See section IV: Risk Factors

5 Clinical presentation The patient in whom PIE develops may have sudden deterioration

More commonly, however, the onset of PIE will be heralded by a slow, progressive deterioration of arterial blood gas levels and the apparent need for increasing ventilatory support Invariably, a

diffusion block develops in these patients, with the alveolar membrane becoming separated from the capillary bed by the interstitial air The response to increased ventilatory support in the face of poor arterial blood gas levels may lead to worsening of PIE and sudden clinical deterioration However, some infants with severe PIE may actually improve if the PIE progresses to pneumothorax

6 Diagnosis In infants with PIE, the chest x-ray film will generally reveal radiolucencies that

are either linear or cyst-like in nature The linear radiolucencies vary in length and do not branch; they are seen in the periphery of the lung as well as medially and may be mistaken for air

bronchograms The cyst-like lucencies vary from 1.0-4.0 mm in diameter and can be lobulated

7 Management

a Lessening lung injury In general, once PIE is diagnosed, an attempt should be made to

decrease ventilatory support and lessen lung trauma Decreasing the PIP, decreasing the PEEP, or shortening the IT may be required All of these maneuvers will decrease injury and possibly improve PIE During this time, some degree of hypercarbia and hypoxia may have to be accepted

b Positioning of the infant with the involved side down has also proved beneficial in some

cases of unilateral PIE

c Other treatments More invasive measures include selective collapse of the involved lung

on the side with the worse involvement, with selective intubation or even the insertion of chest tubes before the development of pneumothorax In cases of severe PIE, surgical resection of the affected lobe may be considered

d HFV has proved useful in infants with severe PIE and with other types of pulmonary air

leak Both high-frequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV)

have been used effectively in the treatment of PIE and other types of air leak syndromes Although these treatment modalities may improve survival of the infant with PIE, the long-term pulmonary outcome remains uncertain; however, randomized controlled trials have been completed and have revealed good results The earlier that HFV is initiated after the onset of PIE or pulmonary air leak, the greater are the chances for survival

8 Prognosis See section VIII: Prognosis

D Pneumopericardium

1 Definition Pneumopericardium is air in the pericardial sac, which is usually secondary to

passage of air along vascular sheaths It is always a complication of mechanical ventilatory support

2 Incidence Pneumopericardium is a rare occurrence In a study of extremely low birth weight

infants who were ventilated and 41% having pulmonary air leak, 2% were found to have

pneumopericardium

3 Pathophysiology It is often said that pneumopericardium is always preceded by

pneumomediastinum, but this is not universally true The mechanism by which pneumopericardium develops is not well understood, but it is probably due to passage of air along vascular sheaths From the mediastinum, air can travel along the fascial planes in the subcutaneous tissues of the neck, chest wall, and anterior abdominal wall and into the pericardial space, causing pneumopericardium

4 Risk factors See section IV: Risk Factors

5 Clinical presentation The clinical signs of pneumopericardium range from asymptomatic to

the full picture of cardiac tamponade The first sign of pneumopericardium may be a decrease in blood pressure or a decrease in pulse pressure There may also be an increase in heart rate with

distant heart sounds

6 Diagnosis Pneumopericardium has the most classic radiographic appearance of all the air

leaks A broad radiolucent halo completely surrounds the heart, including the diaphragmatic surface This picture is easily distinguished from all the other air leaks by its extension completely around the heart in all projections

7 Treatment Treatment of pneumopericardium is essential and requires the placement of a

pericardial drain or repeated pericardial taps The procedure is described in Chapter 26

E Pneumoperitoneum

1 Definition Pneumoperitoneum is air in the peritoneal cavity that is usually caused by

gastrointestinal perforation, but it can also be caused by air that has ruptured from the mediastinum into the peritoneum

2 Incidence Pneumoperitoneum from passage of air into the chest is rare

3 Pathophysiology Pneumoperitoneum in the newborn most commonly arises from a

perforated hollow viscus or a preceding abdominal operation It can also be secondary to

ventilator-assisted pulmonary air leakage Air from the ruptured alveoli can flow transdiaphragmatically along the great vessels and esophagus into the retroperitoneum When air accumulates in the

retroperitoneum, rupture into the peritoneal cavity can occur

4 Risk factors See section IV: Risk Factors

5 Clinical presentation Depending on the cause and severity, pneumoperitoneum can present

with or without associated abdominal findings Because pneumoperitoneum can occur as a result of pneumothorax, pneumomediastinum, and pulmonary interstitial air, infants can present with signs of respiratory distress, as mentioned earlier

6 Diagnosis Pneumoperitoneum can be detected in radiographic films as free air under the

diaphragm Pneumothorax, pneumomediastinum, PIE, and pneumopericardium may precede its

occurrence if the pneumomediastinum is caused by pulmonary air leak However, the absence of these air leaks cannot be considered proof that gastrointestinal perforation is the cause The presence

of an intra-abdominal air-fluid level, leakage of radiographic isotonic contrast agents, analysis of oxygen saturation levels or PO2 in intraperitoneal air can be used to distinguish whether the air leak is pulmonary or gastrointestinal in origin

7 Treatment Conservative management may be strongly considered if evidence of pulmonary

air leak precedes or simultaneously appears with pneumoperitoneum In cases of bowel perforation, laparotomy is usually required

APNEA AND PERIODIC BREATHING

I Definitions Simply defined, apnea is the absence of respiratory gas flow for a period of 20 s or

greater or of shorter duration if associated with bradycardia or significant desaturation

A Central apnea is of central nervous system (CNS) origin and is characterized by the absence of

gas flow with no respiratory effort

B Obstructive apnea is continued respiratory effort not resulting in gas flow

C Mixed apnea is a combination of the central and obstructive types

D Periodic breathing, defined as three or more periods of apnea lasting 3 s or more within a 20-s

period of otherwise normal respiration, is also common in the newborn period Currently, it is not known whether there is an association between apnea and periodic breathing

II Incidence The incidence of apnea and periodic breathing in the term infant has not been

adequately determined More than 50% of infants weighing <1500 g and 90% of infants weighing

<1000 g will have apnea Mixed apnea is the most common type, followed by central and obstructive Another 30% will have periodic breathing

III Pathophysiology Apnea and periodic breathing probably have a common pathophysiologic

origin, apnea being a step further along the continuum than periodic breathing Although the exact pathophysiology of these events has not yet been elucidated, there are many theories

A Immaturity of respiratory control Because apnea is seen most commonly in the premature

infant, some type of immaturity of the respiratory control mechanism is thought to play a role in most cases of apnea

1 Hypoxic response The preterm infant is known to have an abnormal biphasic response to

hypoxia: a brief period of tachypnea followed by apnea This response is unlike that seen in the adult

or older child in whom hypoxia produces a state of prolonged tachypnea

2 Carbon dioxide response The carbon dioxide response curve is shifted in the preterm infant;

higher levels of carbon dioxide are required before respiration is stimulated

B Sleep-related response Sleep states may also play an important role in the development of

apnea in the preterm infant A shift from one sleep state to another is often characterized by

instability of respiratory activity in the adult The preterm infant is sleeping approximately 80% of the time and has difficulty making the transition between the sleeping and waking states This may be associated with an increased risk for apnea

C Protective reflexes such as the apneic response to noxious substances in the airway may also

play a role in apneic episodes in the newborn infant

D Muscle weakness Overall muscle weakness (of both the muscles of respiration and the

muscles that maintain airway patency) also plays an important role in pathophysiology

E All of these factors point to an immature respiratory control mechanism in the preterm infant Whether the immaturity is operational at the level of the brainstem, the peripheral

chemoreceptors, or the central receptors has yet to be determined What is likely is that apnea results from a combination of immature afferent impulses to the respiratory control centers along with

immature efferents from these receptor sites, giving rise to poor ventilatory control

F Pathologic states can also lead to apnea in the infant The following disorders have all been

associated with apnea in the neonatal period

1 Hypothermia and hyperthermia

2 Metabolic disturbances such as hypoglycemia and hyponatremia

3 Sepsis

4 Anemia

5 Hypoxemia

6 CNS abnormalities such as intraventricular hemorrhage (IVH) or stroke

7 Necrotizing enterocolitis (NEC)

8 Drug withdrawal and drug effects (eg, maternal antepartum magnesium therapy)

9 Gastroesophageal reflux

IV Risk factors

A Preterm infants The preterm infant is at the greatest risk for apnea Because apnea is believed

to develop secondary to an immature or poorly developed respiratory control mechanism, this

association is especially noted in extremely low birth weight infants

B Sleep positioning The "back to sleep" campaign, which was initiated in 1992, has led to a 40%

reduction in the incidence of sudden infant death syndrome (SIDS)

C Neurologic disorders Because respiration depends on the integration of numerous CNS

functions, the child with certain neurologic diseases may be at increased risk for apnea Examples of central neurologic disorders include CNS infection and structural abnormalities (eg,

holoprosencephaly), and peripheral disorders include Werdnig-Hoffman in Dorland's and myasthenia gravis

D Sibling with SIDS The Collaborative Home Infant Monitoring Evaluation (CHIME) study

showed that the incidence of apnea was the same in siblings of SIDS and normal term infants

Evidence supports an increased chance of obstructive sleep apnea (OSA) in infants with a family history of OSA, SIDS, and apparent life-threatening event

E Gastroesophageal reflux Its relationship to apnea has been the source of much debate; some

studies show no temporal relationship to apnea of prematurity, but it is a cause of apnea in the term infant

V Clinical presentation

A Apnea within 24 h after delivery Although apnea may be present at any time during the

neonatal period, if it presents within the first 24 h of life, it is usually not simple apnea of

prematurity Apnea during this period must be suspected as being associated with infant or maternal conditions (eg, neonatal sepsis, hypoglycemia, intracranial hemorrhage, maternal antepartum

magnesium treatment, or maternal exposure to narcotics)

B Apnea after the first 24 h of life When apnea occurs after the first 24 h of life and is not

associated with any other pathologic condition, it may be classified as apnea of prematurity Apnea may also occur after weaning from prolonged ventilatory support and may be associated with

intermittent hypoxia secondary to hypoventilation or atelectasis

VI Diagnosis A high index of suspicion is necessary to diagnose apnea If significant apnea is

detected, an extensive workup is required to make an accurate diagnosis and develop a logical

treatment plan

A Monitoring of infants at risk All preterm infants should be closely monitored for the

development of this often life-threatening condition Close attention should be paid to the type of monitoring that is given to infants in intensive care units Preterm infants are commonly on heart rate monitors only, and they will be identified as having apnea only if the heart rate drops below the monitor alarm limit (usually set at 80 beats/min) In this case, these infants may suffer profound hypoxia before bradycardia develops, or they may have apnea with significant hypoxemia but

without a drop in heart rate In order to detect apnea, these infants should have continuous monitoring

of respiratory activity or monitoring of oxygenation, or both, using either transcutaneous oximetry or pulse oximetry

B History A thorough review of maternal septic risk factors, medications, and birth history are

required Additional history of feeding intolerance along with abdominal distention might suggest NEC

C Physical examination Specific attention should be paid to physical findings such as lethargy,

hypothermia or hyperthermia, cyanosis, and respiratory effort A thorough physical examination, including neurologic exam, should also be performed

D Laboratory studies

1 Sepsis screen, including complete blood cell count with differential, platelet count, and serial

C-reactive proteins, will help to rule out sepsis and anemia

2 Pulse oximetry will screen for hypoxia, with arterial blood gas when indicated

3 Serum glucose, electrolyte, and calcium levels will aid in the diagnosis of metabolic

disturbances

E Radiographic studies

1 Chest x-ray study to detect evidence of pathologic lung changes (eg, atelectasis, pneumonia,

or air leak)

2 Abdominal x-ray study to detect signs of NEC (see Chapter 71)

3 Ultrasonography of the head to detect IVH or other CNS abnormality

4 Computed tomography (CT) scan of the head may also be appropriate in infants with

definite signs of neurologic disease

F Other studies

1 Electroencephalography An electroencephalogram (EEG) may be necessary to complete

the workup if there is any question about the neurologic status of the infant Apnea as the sole

presentation of seizures is uncommon

2 Pneumography A pneumogram is another tool in the diagnosis of apnea Pneumography is

especially useful in the infant whose cause of apnea has not yet been identified Chest leads provide a tracing that gives a continuous recording of heart rate, chest wall movement, pulse oximetry, and airflow via a nasal thermistor With the addition of a thermistor, central apnea can easily be

distinguished from obstructive apnea The addition of the pulse oximeter helps in determining

whether there are oxygen desaturations during periods of apnea or heart rate drops This distinction is important for the treatment of the disorder and should be directed specifically to the type of apnea that is detected A pH probe for the detection of gastroesophageal reflux is also important for