Congenital Diaphragmatic Hernia:Maximizing Survival

Mark F. Weems, MD,* Tim Jancelewicz, MD, MA,† Hitesh S. Sandhu, MBBS‡

Divisions of *Neonatal-Perinatal Medicine, †Pediatric Surgery, and ‡Critical Care, Department of Pediatrics,

University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN.

Education Gaps

1. Overall mortality for patients with diaphragmatic hernia remains nearly

30% but can be greatly reduced by following a standardized protocol

focused on lung-protective strategies.

2. Early repair before or during extracorporeal membrane oxygenation

support may benefit patients with severe pulmonary hypertension.

Abstract

Congenital diaphragmatic hernia occurs when a portion of the fetal diaphragm is

absent, allowing abdominal contents to enter the thorax, and is associated with

impaired pulmonary development. Although overall mortality is near 30%, a

mortality rate less than 15% may be possible by following a standardized

multidisciplinary care plan. Fetal diagnosis and evaluation can improve

coordination of care, but there is no clear role for fetal intervention. After birth,

gentle ventilation with permissive hypercapnia supports the infant while

minimizing lung injury. Appropriate cardiovascular support, treatment of

pulmonary hypertension, and extracorporeal membrane oxygenation may

benefit some patients. Timing of surgical repair depends on disease severity.

All patients should have close follow-up after discharge.

Objectives After completing this article, readers should be able to:

1. Describe fetal development, assessment, and interventions for

diaphragmatic hernia.

2. Define gentle ventilation and its role in themanagement of diaphragmatic

hernia.

3. Demonstrate the recommended preoperative stabilization of patients

with diaphragmatic hernia.

4. Recognize the value of extracorporealmembrane oxygenation for patients

with diaphragmatic hernia.

5. Discuss surgical planning for diaphragmatic hernia repair.

AUTHOR DISCLOSURE Drs Jancelewiczand Sandhu have disclosed no financialrelationships relevant to this article.Dr. Weems disclosed that he is a consultant tothe American Academy of Pediatrics, asassociate editor of Pediatrics in Review. Thiscommentary does contain a discussion of anunapproved/investigative use of acommercial product/device.

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INTRODUCTION

Congenital diaphragmatic hernia (CDH) is an uncom-

mon and complex condition that carries a high mortality

rate. Over the past 20 years, overall survival has improved

gradually from 63% to more than 70%. (1) Further advance-

ment remains elusive because clinical trials and univer-

sally accepted standards of care for CDH management are

lacking. However, implementation and adherence to a CDH

protocol may improve outcomes. (2) Management at cen-

ters reporting survival of 85% to 90% features several

common elements, including gentle ventilation, permissive

hypercapnia, cardiovascular support, early use of extracor-

poreal membrane oxygenation (ECMO), and delayed sur-

gical repair. (2)(3)(4)(5) However, it must be remembered

that the survival rate is a function of the denominator that

is used. Case series from tertiary centers do not include

the sickest infants who die in utero, in the delivery room,

or soon after admission but before transfer to a tertiary

center. (6)

Although survival rates have improved, patients with

CDH are at risk for long-term morbidity. Long-term follow-

up is recommended to monitor neurodevelopmental delay,

hearing loss, pulmonary and gastrointestinal complications,

and CDH recurrence. (7)

EPIDEMIOLOGY AND FETAL DEVELOPMENT

The estimated prevalence of CDH varies between 2.4

and 4.1 per 10,000 births. The European Surveillance

of Congenital Anomalies (EUROCAT) data from 1980

to 2009 show an isolated CDH prevalence of 1.6 per

10,000 births and a total (including isolated cases)

nonsyndromic CDH prevalence of 2.3 per 10,000 births.

These data exclude multiple births, but include all

other pregnancies of more than 20 weeks of gestation.

The prevalence of CDH has risen slowly over time, but

the rate of therapeutic abortion has increased, result-

ing in a dramatically decreased incidence among live

births. (8)

The diaphragm begins as the septum transversum and

2 triangular pleuroperitoneal folds (PPFs) separate the

pleural cavity from the peritoneal cavity. The mesodermal

PPFs migrate across the septum transversum and give rise

to muscle connective tissue fibroblasts to form the connec-

tive tissue structure of the diaphragm. Somatic muscle

precursor cells then migrate across the muscle connective

fibroblasts to complete muscularization of the diaphragm

by embryonic day 16.5 in the mouse model (correlating with

the 10th week of human gestation). (9)

In the case of CDH, mutated PPF-derived muscle con-

nective tissue fibroblasts prevent muscularization in spe-

cific areas adjacent to fully muscularized regions. The

relatively weak nonmuscularized area eventually fails under

pressure, allowing viscera to enter the thorax (Fig 1). The

physical presence of abdominal contents inhibits lung

growth and leads to pulmonary hypoplasia. (9) A 2-hit hypoth-

esis has also been proposed, suggesting that genetic muta-

tions leading to CDH may directly inhibit lung growth, but

this is less clearly described.

ASSOCIATED ANOMALIES

Isolated CDH occurs in 58% to 64% of antenatally diag-

nosed CDH cases. (8)(10) EUROCAT data show that chro-

mosomal anomalies occur in 7.2%, genetic syndromes

occur in 3.5%, and nonsyndromic associated anomalies

occur in 25% of singleton CDH cases. Among the chromo-

somal anomalies, the most common are trisomy 18 (4.2%),

trisomy 13 (1.1%), and trisomy 21 (0.9%). (8)

Fryns syndrome is the most common nontrisomy gene-

tic syndrome associated with CDH; it is found in at least

0.5% of CDH cases. Other syndromes associated with

CDHinclude Pallister-Lillian,Wolf-Hirschorn, and Cornelia

de Lange. (8)

Nonsyndromic anomalies are common, occurring in up

to 42% of CDH pregnancies. Described anomalies include

cardiac (most common), urinary, musculoskeletal, and neu-

rologic. Genetic syndromes and other anomalies confer a

poor prognosis and increased mortality. (8)(10)

BENEFITS OF COORDINATED CARE

Individual cases vary widely with regard to severity of ill-

ness, size of defect, degree of pulmonary hypoplasia, and

response to pulmonary vasodilators. As such, there are

many different opinions about appropriate CDH treatment,

and management varies from center to center. Despite

these differences, several recent studies have shown the bene-

fits of standardized care (Table 1). The details of each proto-

col differ, but they generally describe gentle ventilation,

permissive hypercapnia, cardiovascular support, early use of

ECMO, and delayed surgical repair. (2)(3)(4)(5)

PRENATAL MANAGEMENT

DiagnosisRecent data from the CDH Study Group revealed that 68%

of 4,029 live-born infants with CDH were diagnosed ante-

natally. (11) Fetal ultrasonography is part of routine prenatal

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obstetric care, but its usefulness in diagnosing CDH is

variable. Diagnostic sensitivity has regional variation and

depends on operator experience, defect laterality (left is

easier to identify than right CDH), “late” herniation of

viscera, and the presence of other anomalies. In theory, it

is possible to diagnose CDH any time after completion of

diaphragmatic development and return of the intestines to

the abdominal cavity, which occurs before the end of the first

trimester. However, many cases may not be diagnosed until

after 24 weeks of gestation, which could exceed the latest

legal fetal age for pregnancy termination. (6)

Diagnostic features of CDH on ultrasonography include

primary signs such as viscera in the chest and secondary

signs such as mediastinal shift, polyhydramnios, and car-

diac malposition or abnormal cardiac axis. Fluid-filled vis-

cera, most commonly the stomach, may be identified at the

level of the 4-chamber heart view. Once CDH is identified,

magnetic resonance imaging (MRI) can more reliably deter-

mine liver herniation, provide 3-dimensional (and poten-

tially more accurate) visualization of the lungs, and detect

associated anomalies. (6) However, acquisition early in preg-

nancy may yield images with inadequate resolution.

Once the diagnosis of CDH is made, multidisciplinary

consultation with maternal-fetal medicine, pediatric sur-

gery, and neonatology should be arranged to establish a

plan for further evaluation, surveillance, delivery, and post-

natal management.

Markers of SeverityIn the fetus with CDH, the prognosis is largely determined

by gestational age, degree of lung hypoplasia, and the

presence or absence of other anomalies. In addition to

detection of congenital anomalies, prenatal imaging enables

CDH severity to be estimated by directly measuring the size

of the lungs or by assessing surrogate variables that indirectly

quantify the amount of functional lung that will be available

at birth.

A large diaphragmatic defect results in more lung com-

pression and lung hypoplasia, leading to pulmonary hyper-

tension (PHTN) and severe disease. Prenatal identification

of liver in the chest (“liver up”) implies a large defect

and thus represents a more severe subset of CDH, but it

can be difficult to distinguish between lung and liver on

ultrasonography. (6) In addition, some “liver up” patients

may have good outcomes. (12) In general, liver position is

not as accurate in mortality prediction as other measures,

though volume of herniated liver measured with MRI may

provide a better survival estimate. (13)

Figure 1.Mouse model showing the development of congenital diaphragmatic hernia (CDH). A. CDH arises from early genetic mutations in a subset ofPPF-derived muscle connective tissue fibroblasts (mutant fibroblasts are yellow, wild-type fibroblasts are green). B–D. Mutant fibroblasts clonallyexpand and inhibit muscle progenitors from developing in these regions (via decreased proliferation and increased apoptosis of muscle progenitors),resulting in local regions (shown in yellow) that are amuscular but contain connective tissue fibroblasts and their associated extracellular matrix. D, E.Amuscular regions are thinner and more compliant than surrounding thicker and stiffer muscularized diaphragm and allow herniation of abdominalcontents into the thoracic cavity. E¼esophagus; NT¼neural tube; PPF¼pleuroperitoneal fold; So¼somite; ST¼septum transversum; (Reprinted withpermission from Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G. Muscle connective tissue controls development of the diaphragm and is asource of congenital diaphragmatic hernias. Nat Genet. 2015;47(5):496–504.)

TABLE 1. Successful Diaphragmatic HerniaProtocols

AUTHOR YEAR

PRE-PROTOCOLSURVIVAL

PROTOCOLSURVIVAL P-VALUE

Bagolan et al (3) 2004 50% 86% 0.02

Tracy et al (4) 2010 52% 85% 0.006

Antonoff et al (5) 2011

All CDH 67% 88% 0.015

CDH on ECMO 20% 82% 0.002

van den Houtet al (2)

2011 67% 88% 0.004

CDH¼congenital diaphragmatic hernia; ECMO¼extracorporealmembrane oxygenation.

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First reported in 1996, lung-to-head ratio (LHR) is a ratio

of the contralateral area of the 2-dimensional lung to the

head circumference, as measured with ultrasonography.

LHR is the most widely validated marker of CDH severity,

and is most reliable between 22 and 26 weeks of gestation.

Observed/expected (O/E) LHR is preferred because the

LHR will change over time due to disparate growth rates

of the lung and head during gestation. (14) Ultrasonography

operator dependence and interobserver variability can

hamper the predictive value of LHR. An O/E LHR less

than 25% portends less than 30% survival and an O/E

LHR greater than 46% is associated with greater than 85%

survival. (15)

MRImay afford better visualization of the lung and liver

than ultrasonography, and is less dependent on maternal

and fetal positioning. (16) Serial MRI can accurately mon-

itor CDH with less operator dependence than ultrasonog-

raphy. (14) Currently, MRI is the most accurate way to

calculate total lung volume, and use of O/E total lung

volume has been shown to have the best predictive value

for mortality in a study comparing several common pre-

dictors. (16) For fetuses with an O/E total lung volume less

than 25%, survival is less than 15%, and for those with O/E

total lung volume greater than 35%, survival may be greater

than 80%. (13)

Fetal InterventionPrenatal therapy for CDH has included both surgical and

nonsurgical approaches, with invasive measures typically

undertaken only for those fetuses with severe CDH (low

LHR and liver herniation). Various pharmacologic treatments

and stem cell therapy have been studied, but no definitive

survival benefit has yet been demonstrated.

Although open fetal repair of the diaphragm is possible, it

has fallen out of favor because it failed to improve mortality.

Over time, prospective, randomized, controlled trials of fe-

tal tracheal occlusion have shown increasing promise for

select populations of patients with CDH, despite the findings

of the original trial that outcomes were equivalent to those

of standard management. (17) This procedure, now performed

using a small instrument that percutaneously delivers a

removable balloon to the fetal trachea, accelerates lung

growth and appears to ameliorate the effects of the CDH on

lung development. A randomized European study demon-

strated 50% survival with tracheal occlusion compared to

4.8% survival with standard management among fetuses

with severe isolated CDH. (18) An ongoing international

randomized trial, the Tracheal Occlusion To Accelerate

Lung growth (TOTAL) trial, may provide further evidence

supporting the use of percutaneous tracheal occlusion for

severe CDH. However, currently such therapy remains

experimental and is only being undertaken in the context

of clinical trials.

DELIVERY AND RESUSCITATION

Patients with CDH who are born at a high-volume center

using a resuscitation protocol may have a survival advan-

tage. Grushka et al report that patient risk factors were

equal in both high- and low-volume centers, but the

survival was improved in centers delivering more than

6 patients with CDH annually. (19) The mode of delivery,

vaginal versus caesarian, does not seem to affect survival

and should be determined based on maternal indications.

(20)

There are no data to determine best practices for

delivery room resuscitation of patients with CDH. Most

published protocols recommend immediate intubation

with gentle ventilation, oro- or nasogastric decompression,

and avoidance of mask ventilation. (4)(5)(21) The purpose

of these steps is to minimize the amount of swallowed

air (Fig 2) that will inflate the thoracic bowel and limit

lung expansion. The 2015 update to the CDH EURO

Consortium Consensus suggests that spontaneous breath-

ing could be offered to low-risk patients, but it is un-

clear which population might benefit from this practice.

(22)

Delayed cord clamping is appropriate for most term and

preterm infants, but it cannot currently be recommended

for patients with CDH because it would interfere with the

goal of immediate intubation.

Surfactant therapy has frequently been used in these pa-

tients, but supporting data are controversial. Retrospec-

tive data from the CDH Study Group show that surfactant

therapy is associated with worse outcomes. Of 522 term

infants, those who received surfactant therapy were less

likely to survive (57.3% vs 70.0%, P ¼ .0033), more likely

to receive ECMO (69.8% vs 50.6%, P ¼ .04), and more

likely to develop chronic lung disease (59% vs 47.6%, P ¼.0066). However, it should be recognized that this was not a

randomized controlled trial, and a significant selection bias

may have skewed the findings. (23) Similarly, surfactant use

in preterm infants (mean, 34 weeks) was associated with a

significantly greater odds of death than controls (odds ratio

[OR]¼ 2.17; 95% confidence interval [CI]¼ 1.5–3.2; P< .01).

After controlling for gestational age and Apgar score, there

was no benefit associated with surfactant use (OR ¼ 1.58;

95% CI ¼ 0.99–2.52; P ¼ .05). (24) Thus, routine use of

surfactant therapy cannot be recommended for patients

with CDH.

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Vascular access should be established early to provide

fluids, nutrition, and medications. Umbilical venous cath-

eters (UVCs) are commonly placed in neonates, but CDH

anatomy is distorted, making radiographic evaluation of

UVC position challenging (Fig 2). Alternative central

venous access is preferred over placement of UVCs in

patients with CDH. If possible, an umbilical arterial catheter

should be placed; arterial access is helpful for measuring

blood gases and monitoring blood pressure in critically ill

patients with CDH.

RESPIRATORY SUPPORT

Before the widespread acceptance of gentle ventilation for

patients with CDH, ventilator-induced lung injury was very

prevalent, and nearly all nonsurvivors had significant lung

injury. In what was the largest study of autopsy findings

from CDH nonsurvivors, 91% of infants with CDH on

whom autopsies were performed had evidence of diffuse

alveolar damage, 65% had evidence of air-leak, and 50%

had evidence of pulmonary hemorrhage, with destruction

of the alveolar-capillary interface. (25) It has been estimated

that 25% of CDH deaths occur due to the adverse effects

of aggressive care. (26)

Wung et al first championed gentle ventilation with

permissive hypercapnia for neonates with PHTN in 1985.

(26) They successfully applied this strategy to patients with

CDH; other studies have since supported the association

between gentle ventilation and improved survival. (2)(3)(4)

(5)(27)(28) The specifics of gentle ventilation are loosely

defined. For conventional mechanical ventilation (CMV),

many recommend limiting the peak inflation pressure to

25 cm H2O or less with positive end-expiratory pressure 3

to 5 cm H2O. Respiratory rate is generally recommended

between 40 and 60 breaths per minute. Volume-targeted

ventilation is gaining popularity in neonatal medicine, but

data suggesting optimal tidal volume in the CDHpopulation

are limited. Smaller-than-normal tidal volumes are often

targeted due to presumed pulmonary hypoplasia associated

with CDH. Te Pas et al report that patients with CDH with

spontaneous respirations have a mean tidal volume of 3.8 –1.9 mL/kg. (29) Sharma et al documented a mean tidal

volume requirement of 4.6 mL/kg to achieve mean partial

pressure of arterial carbon dioxide (PaCO2) of 46 mm Hg

(6.1 kPa), similar to tidal volumes in infants without dia-

phragmatic hernia. They pointed out that the metabolic carbon

dioxide production in infants with CDH is no different from

that in other infants of a similar size, and therefore it is not

surprising that they should require similar alveolar minute

ventilation. (30) In our practice, we target a tidal volume

of 4 mL/kg and increase to 6 mL/kg if needed to achieve a

goal partial pressure of carbon dioxide (PCO2) of 50 to

65 mm Hg (6–8.6 kPa).

Many have proposed high-frequency oscillatory ventila-

tion (HFOV) as a means of improving oxygenation with a

lower risk of alveolar damage, but observational data on

HFOV in patients with CDHare conflicting. (31) To date, the

VICI Trial is the only randomized, prospective, multicenter

trial comparing CMV to HFOV. One hundred seventy-one

patients were randomized to receive either CMV or HFOV,

and the remainder of each patient’s treatment followed

guidelines set by the CDHEUROConsortium. (21) Baseline

characteristics were similar, and there was no difference

in the primary outcome of death or bronchopulmonary dys-

plasia. Secondary outcomes favored CMV (Table 2), suggesting

that CMV may be associated with improved hemodynamics

Figure 2. Radiographs showingdiaphragmatic hernia. A. A large amount of aircan be seen in the thoracic bowel within theleft chest and dextroposition with minimalaeration of the right lung. Umbilical arterialcatheter is in good position. The umbilicalvenous catheter tip appears to be at the levelof the diaphragm, but echocardiographyreveals that the tip does not extend beyondthe liver. B. After gastric decompression, theair in the thoracic bowel is decreased andaeration of the right lung is increased.

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compared to HFOV, as used in the VICI trial, in patients with

CDH. (31) We recommend starting with CMV, but HFOV

remains a reasonable option for those patients who require

excessive peak inflation pressure on CMV.

Very little literature is available on the role of high-

frequency jet ventilation (HFJV) in patients with CDH,

but it may be a reasonable alternative to HFOV, because

HFJV is associated with improved hemodynamics and

lower airway pressures compared with HFOV. Kuluz et al

demonstrated that HFJV is an acceptable mode of ventila-

tion with patients with CDH, but no data are available that

directly compare HFJV to other modes. (32)

In addition to limiting peak inflation pressure, the sec-

ond focus of gentle ventilation is permissive hypercapnia.

Historically, induced respiratory alkalosis was standard

treatment for patients with CDH to control PHTN. (27)

This strategy has since been associated with several nega-

tive outcomes. In the lungs, respiratory alkalosis leads

to increased lung injury, because of the substantially

higher minute ventilation required to drive down the Paco2,

bronchoconstriction, pulmonary edema, intrapulmonary

shunting, and increased alveolar-to-arterial oxygen gradi-

ent. In other organs, including the brain and myocardium,

respiratory alkalosis worsens tissue injury by decreasing

oxygen delivery and increasing metabolic demand. (33) In

contrast, hypercapnia increases spontaneous respiratory

effort, improves V/Q mismatch, increases cardiac output,

improves oxygen delivery, and may attenuate pulmonary

inflammation and injury because smaller tidal volumes

are required. (34) Permissive hypercapnia is now preferred

over induced respiratory alkalosis, and most experts feel

comfortable allowing PCO2 values as high as 60 to 70 mm

Hg (8–9 kPa). (3)(4)(22)(26)(35) In our practice, we target

PCO2 values of 50 to 65 mm Hg (6–8.6 kPa) if the pH values

are greater than 7.20. However, acidosis is known to increase

pulmonary vascular resistance, and in some infants, ade-

quate oxygenation may not be achieved until a more normal

pH is established.

Optimal oxygen delivery in patients with CDH has not

been defined. Because oxygen is an effective pulmonary

vasodilator, delivery of 100% oxygen was once used to treat

PHTN. However, hyperoxia and 100% oxygen should be

avoided because it increases pulmonary vascular resistance

by increasing oxidative stress, increasing pulmonary

vascular contractility, and blunting the response to nitric

oxide. (36) Most recent reports recommend targeting

oxygen saturation to 85% to 95%. (3)(4)(5)(27)(37) How-

ever, the EURO Consortium has taken an even stronger

stand against hyperoxia and now recommends targeting

preductal oxygen saturation greater than 70% in the first

2 hours after birth followed by target saturation of 80% to

95%. (22)

PULMONARY HYPERTENSION

PHTN is one of the most important prognostic factors in

the survival of patients with CDH. PHTN in CDH has 2

components. The first is a structural or fixed component due

to pulmonary hypoplasia with decreased airway branching

and alveolar development. This is associated with under-

development of the pulmonary vascular bed and hypertro-

phy of vascular smooth muscle that can take weeks to

TABLE 2. VICI Trial: Secondary Outcomes by Ventilation Group Correctedfor Center

VARIABLE HFOV (N [ 80) CMV (N [ 91) P

Length of ventilation (days) 13.0 (8.0–23.0) 10.0 (6.0–18.0) .03

ECMO (in ECMO centers only) 24/47 (51.1%) 16/61 (26.2%) .007

Inhaled nitric oxide 45 (56.2%) 39 (42.9%) .045

Phosphodiesterase inhibitor 5 (Sildenafil) 25 (31.2%) 11 (12.1%) .004

Vasoactive medication 73 (91.2%) 73 (80.2%) .08

Duration vasoactive medication (days) (in survivors only) 8.0 (4.3–19.0) 6.0 (3.3–11.8) .02

Number of treatment failures 27 (33.8%) 20 (22.0%) .01

Results presented as n (%) or median (IQR). CMV¼conventional mechanical ventilation; ECMO¼Extracorporeal membrane oxygenation; HFOV¼high-frequency oscillatory ventilation.Adapted from Snoek KG, Capolupo I, van Rosmalen J, et al. Conventional mechanical ventilation versus high-frequency oscillatory ventilation forcongenital diaphragmatic hernia: a randomized clinical trial (the VICI-trial). Ann Surg. 2016;263(5):867–874.

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months to overcome. The second is a reversible component

due to multiple factors, including imbalanced innervation of

the smooth muscles, increased reactivity to noxious stimuli,

ventilator-induced lung injury, metabolic derangements,

and decreased response to endogenous and exogenous

vasodilators. (37)

Assessment of Pulmonary HypertensionThe presence of PHTN is clinically assessed by the pre- and

postductal saturation gradient. The difference indicates

shunting of blood from the pulmonary artery (PA) across

the patent ductus arteriosus to the aorta due to suprasyste-

mic PA pressure. The absence of pre-/postductal gradient

suggests that the PApressure is less than systemic pressure,

but that may not be the case if the ductus arteriosus is no

longer patent.

Echocardiography should be used to assess cardiac anat-

omy and to screen for PHTN. Doppler echocardiography

defines significant PHTN as PA pressure greater than two-

thirds of systemic pressure with possible decreased right

ventricular function in the absence of a shunt. Detailed

protocols using echocardiographic indices such as PA size

and the McGoon index may predict long-term prognosis,

but they require further validation. The absence of tricuspid

regurgitation in 30% to 60% of echocardiograms can limit

the use of this modality to quantify PHTN (37); the degree

of PHTN is then deduced by subjective parameters such as

septal wall position and right ventricular volume or function.

ManagementThe evidence for medical management of PHTN in CDH is

mostly derived from subgroup analyses of PHTN trials that

included patients with CDH. These studies uniformly show

that PHTN due to CDH confers a worse prognosis than

PHTN alone. Subgroup analyses of several trials show that

inhaled nitric oxide does not have a meaningful clinical

effect and is associated with a slightly increased risk of re-

quiring ECMO. (38)(39) These results are contrary to the

effects of inhaled nitric oxide in patients without CDH, who

show improvement in Pao2 and survival. We follow other

institutional practices to start inhaled nitric oxide in CDH

cases with persistent hypoxemia in an attempt to overcome

the reversible component of PHTN; inhaled nitric oxide

should be discontinued if there is no improvement in the

saturation or Pao2. (21)(35) Although inhaled nitric oxide

rarely leads to sustained improvement in oxygenation, the

transient benefit that is often seen may be sufficient to

stabilize the patient until ECMO can be instituted.

Other pharmacologic agents have been used for non-

CDH PHTN with varying degree of success but have not

been well studied in the CDH population. The level of

evidence for the use of these agents is low; therefore, they

cannot be recommended as standard practice. Five case

series with a total of 22 patients describe the use of silde-

nafil, a phosphodiesterase-5 inhibitor that increases cyclic

guanosine monophosphate levels in the pulmonary vascu-

lature, increasing nitric oxide activity and vasodilation. In

studies by Noori et al and Bialkowski et al, an improvement

in oxygenation was noted after starting intravenous silde-

nafil, and improvement in cardiac output was seen on echo-

cardiography. (40)(41) The EURO Consortium recommends

sildenafil in the setting of refractory PTHN with failure of

inhaled nitric oxide treatment. (21)

Milrinone, a phosphodiesterase-3 inhibitor, may improve

both systolic and diastolic function and has been advocated

as potentially beneficial in infants with CDHwho often have

significant left ventricular hypoplasia and dysfunction. (42)

Prostacyclin, prostaglandin E1, and bosentan, an endothelin-1

inhibitor, have each been reported as possible therapeutic

options with limited supporting data. (35) If PHTN per-

sists despite gentle ventilation, inhaled nitric oxide, and

other PHTN therapy, early use of ECMO is recommended.

Milrinone is currently the subject of a clinical trial under

way in the Eunice Kennedy Schriver National Institute of

Child Health and Human Development Neonatal Research

Network.

EXTRACORPOREAL MEMBRANE OXYGENATION

ECMO is a temporizing therapy that supports respiratory

and cardiac function during recovery from a reversible

cause. In the case of CDH, it is usually refractory PHTN

or right ventricular failure that causes the vicious cycle

of worsening hypoxia, hypotension, and acidosis despite

increasing ventilator and inotropic support. Extracorporeal

Life Support Organization (ELSO) data show that over 7,500

patients with CDH have been placed on ECMO with a

survival rate of 51%. (43) Despite the introduction of

PHTN-specific treatment such as inhaled nitric oxide and

sildenafil, ECMO is the only therapy proven to reduce

mortality in neonates with PHTN. The role of ECMO in

patients with CDH, however, remains controversial. Parallel

studies comparing frequent ECMO use (50%) with rare

ECMO use (1%) in patients with CDH report similar out-

comes. (44)(45) Some nonrandomized studies report in-

creased survival among patients with CDH treated with

ECMO, (46) but ELSO data show that ECMO survival

among patients with CDH has declined in recent years.

(47) It is likely that ECMO offers benefit when used as part

of a multipronged lung-protective strategy.

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Historically, venoarterial ECMO has been the mode of

choice in this population, but both venoarterial and venove-

nous modes have been used. ELSO data show that 82% of

patients were placed on venoarterial ECMO. Adjusted mor-

tality is similar for both venovenous and venoarterial modes,

but venoarterial ECMO carries an increased risk of neuro-

logic complications whereas venovenous ECMO is associated

with increased risk of renal complications. (48) It is com-

mon practice to choose venoarterial ECMO for higher-risk pa-

tients with CDH to provide hemodynamic support in addition

to respiratory support. Some centers use the ex utero intra-

partum therapy strategy in addition to ECMO for high-risk

CDH. It involves placing the patient on ECMO immediately

after delivery while connected to the placenta. However,

Stoffan et al showed no survival benefit to this strategy. (49)

The timing of ECMO for patients with CDH has evolved

over the last few decades. ECMO is now applied to over-

come refractory PHTN before correcting the defect, with

ECMO seldom being necessary after operation. (11) Early

ECMO has the additional advantage of decreasing ventilator-

associated lung injury. Recent studies have suggested that

the best outcomes are from corrective surgery early with

ECMO or after the resolution of PHTN and decannulation

fromECMO. (50) Duration of ECMO is generally longer than

in other neonatal conditions, with an average run time of

more than 10 days. (43) CDH accounts for 69% of neonatal

cases of ECMO for more than 3 weeks. (51) Increased length

of ECMO and second courses are associated with increased

complications and poorer outcomes. However, Kays et al re-

port survival rates of 43% and 25% after ECMO durations

of 4 and 5 weeks, respectively, and 44% survival after a sec-

ond course of ECMO. (52) These data indicate that there are

no absolute limits for ECMO survival, and ECMO decisions

should be made on a case-by-case basis.

ECMO entry criteria are center-specific, with significant

variation among centers. ECMO may be considered for a

patient with CDH who is unable to stay within goal param-

eters of a gentle ventilation strategy or who is excessively

hypotensive and unresponsive to interventions.

OTHER MEDICAL SUPPORT

SedationMinimal stimulation and adequate analgesia are recom-

mended to ensure a calm and soothing environment for

the newborn and to minimize adverse physiologic responses

during invasive procedures such as intubation or central line

placement. Opioids in the form of fentanyl and morphine

are the most common choices. (22) Sedation may be aug-

mented with benzodiazepines or other agents according to

local practices. Neuromuscular blockade has been associ-

ated with increased mortality in patients with PHTN and is

generally not recommended for CDH. (22)(53)

Blood PressureThe goal of an age-appropriate blood pressure is to ensure

adequate end-organ perfusion. If hypotension is noted, the

first step is to ensure adequate intravascular volume. (22)

After hypovolemia is corrected, inotropes may help support

decreased left ventricular function, and pulmonary vasodi-

lators may improve right ventricular failure. Inotropic

agents have been poorly studied in the CDH population,

therefore the choice of therapy is determined by local

practice. However, the value of inotropic therapy has been

questioned by Buijs et al, who showed that dopamine,

norepinephrine, and epinephrine each increased blood pres-

sure but had no effect on the impaired microcirculation of

patients with CDH. (54)

Those with catecholamine-resistant hypotension may

benefit from the addition of vasopressin and/or hydrocor-

tisone. Acker et al reported improved hemodynamics and

gas exchange after starting vasopressin, but hyponatremia

was common. (55) Kamath et al reported that patients

with CDH with random cortisol level less than or equal to 15

mg/dL had increased severity of illness, but there are no

data to suggest that empiric treatment with hydrocortisone

improves outcomes in these patients. (56) Hydrocortisone

has been shown to decrease the need for inotropes in

neonates with refractory hypotension and may be appropri-

ate for patients with CDH with catecholamine-resistant

hypotension followed by the use of ECMO. (22)

SURGICAL REPAIR

History and TimingThe surgical management of CDH is characterized by com-

plex decision-making regarding the timing of a concep-

tually straightforward operation. For clinicians treating

infants with severe CDH, there may be great angst over the

decision, and there is no definitive evidence for the “ideal”

timing of surgical repair. Over time, care has evolved from

emergent repair immediately after delivery to delayed repair

once pulmonary hypertension has subsided. The hope is

that a more stable infant can better tolerate surgery after 48

to 72 hours at most centers. The pendulum may be swing-

ing back; evidence is emerging that earlier repair (before

ECMO) for the most severely affected newborns may im-

prove survival. (12) For low-risk infants, delayed repair until

stabilization remains the standard of care, but consensus

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agreement regarding “stability” is elusive and criteria vary

from center to center. (1)

For severe CDH, controversy exists regarding the tim-

ing of repair in relation to ECMO, because repair while the

infant is receiving ECMO involves a high risk of bleeding

and other complications. However, delaying repair until

after ECMO may not allow the lungs “room” to improve

during ECMO. (52) Evidence exists both for and against

operating during ECMO versus after decannulation, and

no agreement has yet been reached in the absence of high-

quality evidence. A recent systematic review suggests that

repair undertaken early during ECMO has better outcomes

than late repair. Patients fared poorly when repair was

planned after decannulation, but had late repair during

ECMO after it was found that they could not be weaned off

ECMO. (35) Unfortunately, all these recommendations

are based on evidence level 3 to 4, leaving much room

for interpretation.

TechniqueThe basic operative approach to repair CDH has not

changed over the past several decades. The defect is closed

by primary approximation of the diaphragmatic edges (pri-

mary repair) or a prosthetic patch is used when the edges

cannot be approximated without tension (patch repair).

Most surgeons use a subcostal laparotomy on the side of

the defect. Although the choice of material used for patch

repair of the defect has been debated, it is probably safest

to use an oversized dome-shaped polytetrafluoroethylene

patch because this approach has the lowest recurrence

rate. (35) Recurrence is always a risk with patch repair

because the patch does not grow with the patient. Need for

a patch means the defect is large and thus the patient is

more likely to be a high-risk patient with CDH requiring

protracted care.

The thoracoscopic versus open approach for stable

patients with CDH has also been debated, but evidence

supports open repair because minimally invasive repair has

been associatedwith increased arterial carbon dioxide levels,

lower pH, and higher recurrence rates. (35)

OUTCOMES AND FOLLOW-UP

Long-term follow-up into adolescence is recommended for

all patients with CDH because multisystem adverse out-

comes are common. (7) Particularly with severe CDH, close

surveillance is required in the first months and years after

birth to enable timely intervention and prevent significant

disability. Problemsmay be pulmonary, gastrointestinal and

nutritional, neurodevelopmental, or surgical. Hearing loss

is also common.

PHTN may persist after discharge, requiring supple-

mental oxygen and pulmonary vasodilators. Long-term

survival with significant PHTN is uncommon. Other pul-

monary sequelae include pneumonia, bronchospasm, ob-

structive airway disease, and reactive airway disease, all

of which will be more common in patients with severe CDH

(such as those who received prolonged intubation, ECMO,

and/or supplemental oxygen at discharge). Pulmonary

function testing may be persistently abnormal in nearly

one-third of children older than 5 years, and in up to 50% of

adult survivors. (57)

Gastrointestinal morbidity occurs in the form of symp-

tomatic gastroesophageal reflux and nutritional failure due

to oral aversion and feeding intolerance. In a large series,

25% of patients received fundoplication and 31% had a

gastrostomy tube placed. (58) Overall, 33% to 50% of patients

with CDH may suffer significant growth and nutritional

failure. (7)

Neurodevelopmental delay, especially with motor rather

than cognitive function, is of great concern in patients

who suffered long and difficult hospitalizations. (59) Delay

may be mild and may improve with time, but outcomes are

inconsistent from center to center; the prevalence of adverse

neurodevelopmental outcomes may approach 50%. (7)(59)

In addition, treatment-related hearing loss is common, but

that may largely reflect the now outmoded hyperventila-

tion approach. Close monitoring and serial developmental

testing, along with audiometry, is warranted in patients

with severe CDH. (7)

Although the true incidence of hernia recurrence is not

known, rates of up to 50% have been reported; patch repair

is the single greatest risk factor. (7) Recurrence may happen

years later in an otherwise asymptomatic patient who “out-

grows” his or her patch. (60) Surgical techniquewith the use

of a large, redundant patch may reduce recurrence risk. (61)

Other surgical complications may include bowel obstruc-

tion and orthopedic (chest and spinal) deformity in 25% to

50% of patients. (7)(58)(60) All CDH survivors should be

followed up annually, and clinic visits should include chest

radiography to monitor for CDH recurrence.

CONCLUSIONS

Treatment of infants with CDH remains difficult due to

widely variable disease severity and limited evidence to

guide practice. With adherence to a standard protocol and

a multidisciplinary commitment to lung-protective strate-

gies, survival can be greater than 85%. After surgical repair

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and improvement of PHTN, patients with CDH should

receive close follow-up to monitor for recurrence of herni-

ation or PHTN, failure to thrive, neurodevelopmental delay,

and other consequences of their condition.

ACKNOWLEDGMENT

The authors would like to thank Dr Hugh Allen for his

review of this article.

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American Board of PediatricsNeonatal—Perinatal ContentSpecifications• Plan appropriate therapy for an infant with extrapulmonarycauses of respiratory distress

• Plan the ventilatory therapy for infants with respiratory failure ofdifferent etiologies

• Know the indications for and techniques of high-frequencyventilation

• Know the indications, techniques, effects, and risks ofextracorporeal membrane oxygenation (ECMO)

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30. Sharma S, Abubakar KM, Keszler M. Tidal volume in infantswith congenital diaphragmatic hernia supported withconventional mechanical ventilation. Am J Perinatol. 2015;32(6):577–582

31. Snoek KG, Capolupo I, van Rosmalen J, et al; CDH EUROConsortium. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatichernia: a randomized clinical trial (the VICI-trial). Ann Surg.2016;263(5):867–874

32. Kuluz MA, Smith PB, Mears SP, et al. Preliminary observations ofthe use of high-frequency jet ventilation as rescue therapy in infantswith congenital diaphragmatic hernia. J Pediatr Surg. 2010;45(4):698–702

33. Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002;347(1):43–53

34. Curley G, Laffey JG, Kavanagh BP. Bench-to-bedside review: carbondioxide. Crit Care. 2010;14(2):220

35. Puligandla PS, Grabowski J, Austin M, et al. Management ofcongenital diaphragmatic hernia: a systematic review from theAPSA outcomes and evidence based practice committee. J PediatrSurg. 2015;50(11):1958–1970

36. Steinhorn RH. Diagnosis and treatment of pulmonaryhypertension in infancy. Early Hum Dev. 2013;89(11):865–874

37. Pierro M, Thébaud B. Understanding and treating pulmonaryhypertension in congenital diaphragmatic hernia. Semin FetalNeonatal Med. 2014;19(6):357–363

38. The Neonatal Inhaled Nitric Oxide Study Group (NINOS).Inhaled nitric oxide and hypoxic respiratory failure in infantswith congenital diaphragmatic hernia. Pediatrics. 1997;99(6):838–845

39. Finer NN, Barrington KJ. Nitric oxide for respiratory failure ininfants born at or near term. Cochrane Database Syst Rev. 2006;(4):CD000399

40. Noori S, Friedlich P, Wong P, Garingo A, Seri I. Cardiovasculareffects of sildenafil in neonates and infants with congenitaldiaphragmatic hernia and pulmonary hypertension. Neonatology.2007;91(2):92–100

41. Bialkowski A, Moenkemeyer F, Patel N. Intravenous sildenafil inthe management of pulmonary hypertension associated withcongenital diaphragmatic hernia. Eur J Pediatr Surg Z Kinderchir.2013;25(2):171–176

42. Patel N.Use ofmilrinone to treat cardiac dysfunction in infants withpulmonary hypertension secondary to congenital diaphragmatichernia: a review of six patients. Neonatology. 2012;102(2):130–136

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45. Wilson JM, Lund DP, Lillehei CW, Vacanti JP. Congenitaldiaphragmatic hernia–a tale of two cities: the Boston experience.J Pediatr Surg. 1997;32(3):401–405

46. Morini F, Goldman A, Pierro A. Extracorporeal membraneoxygenation in infants with congenital diaphragmatic hernia: asystematic review of the evidence. Eur J Pediatr Surg. 2006;16(6):385–391

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48. Guner YS, Khemani RG, Qureshi FG, et al. Outcome analysis ofneonates with congenital diaphragmatic hernia treated withvenovenous vs venoarterial extracorporeal membrane oxygenation.J Pediatr Surg. 2009;44(9):1691–1701

49. Stoffan AP,Wilson JM, Jennings RW,Wilkins-Haug LE, BuchmillerTL. Does the ex utero intrapartum treatment to extracorporealmembrane oxygenation procedure change outcomes for high-riskpatients with congenital diaphragmatic hernia? J Pediatr Surg.2012;47(6):1053–1057

50. Congenital Diaphragmatic Hernia Study Group, Bryner BS, WestBT, Hirschi RB, et al. Congenital diaphragmatic hernia requiringextracorporeal membrane oxygenation: does timing of repairmatter? J Pediatr Surg. 2009;44(6):1165–1171

51. Prodhan P, Stroud M, El-Hassan N, et al. Prolonged extracorporealmembrane oxygenator support among neonates with acuterespiratory failure: a review of the Extracorporeal Life SupportOrganization registry. ASAIO J. 2014;60(1):63–69

52. Kays DW, Islam S, Richards DS, Larson SD, Perkins JM, Talbert JL.Extracorporeal life support in patients with congenitaldiaphragmatic hernia: how long should we treat? J Am Coll Surg.2014;218(4):808–817

53. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonaryhypertension of the newborn in the era before nitric oxide: practicevariation and outcomes. Pediatrics. 2000;105(1 Pt 1):14–20

54. Buijs EA, Reiss IK, Kraemer U, et al. Increasing mean arterial bloodpressure and heart rate with catecholaminergic drugs does notimprove the microcirculation in children with congenitaldiaphragmatic hernia: a prospective cohort study. Pediatr Crit CareMed. 2014;15(4):343–354

55. Acker SN, Kinsella JP, Abman SH, Gien J. Vasopressin improveshemodynamic status in infants with congenital diaphragmatichernia. J Pediatr. 2014;165(1):53–58.e1

56. Kamath BD, Fashaw L, Kinsella JP. Adrenal insufficiency innewborns with congenital diaphragmatic hernia. J Pediatr. 2010;156(3):495–497.e491

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57. Muratore CS, Kharasch V, Lund DP, et al. Pulmonary morbidity in100 survivors of congenital diaphragmatic hernia monitored in amultidisciplinary clinic. J Pediatr Surg. 2001;36(1):133–140

58. Jancelewicz T, Vu LT, Keller RL, et al. Long-term surgicaloutcomes in congenital diaphragmatic hernia: observations froma single institution. J Pediatr Surg. 2010;45(1):155–160,discussion 160

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60. Jancelewicz T, Chiang M, Oliveira C, Chiu PP. Late surgicaloutcomes among congenital diaphragmatic hernia (CDH) patients:why long-term follow-up with surgeons is recommended. J PediatrSurg. 2013;48(5):935–941

61. Tsai J, Sulkowski J, Adzick NS, Hedrick HL, Flake AW. Patch repairfor congenital diaphragmatic hernia: is it really a problem? J PediatrSurg. 2012;47(4):637–641

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NeoReviews QuizThere are two ways to access the journal CME quizzes:

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1. A term infant with prenatally diagnosed congenital diaphragmatic hernia (CDH) isadmitted to the NICU. The surgical team is consulted. The patient is receiving mechanicalventilation. Which of the following practices has been associated with centers that havehigher survival rates for patients with CDH?

A. Later use of extracorporeal membrane oxygenation.B. Early surgical repair.C. Permissive hypercapnia.D. Birth at smaller, nonsurgical center with subsequent transfer to higher level of care.E. Early aggressive ventilation with maximal settings for peak inspiratory and end-

expiratory pressures.

2. A woman presents late for prenatal care at the clinic at an estimated 28 weeks’ gestationalage. Ultrasonography reveals CDH. Which of the following statements regarding diagnosisand incidence of CDH is correct?

A. The estimated prevalence of CDH is between 2.4 and 4.1 per 1,000 live births.B. Even for those women who receive prenatal care, the antenatal diagnosis rate for

CDH is less than 50%.C. Generally, left-sided CDH is harder to diagnose antenatally than right-sided CDH.D. Secondary signs such as mediastinal shift, polyhydramnios, and cardiac malpo-

sition or abnormal cardiac axis may aid in diagnosis.E. Ultrasonography is preferred to other imaging modalities, such as magnetic

resonance imaging, for the purpose of identifying liver herniation.

3. A woman undergoing routine ultrasonography at 20 weeks of gestation is noted to have afetus with CDH. Ameetingwith amultidisciplinary team is scheduled to discuss the optionsfor management and prognosis. Which of the following statements concerning prognosisis correct?

A. Liver herniation into the chest is the most accurate prediction of mortality.B. Lung-to-head ratio on the contralateral area of the 2-dimensional lung to the head

circumference measured by ultrasonography is a validated marker of CDH severityand is most reliable between 22 and 26 weeks of gestation.

C. Although magnetic resonance imaging can provide better visualization of thelungs than ultrasonography, it is highly dependent on maternal and fetalpositioning.

D. The lung-to-head ratio should stay consistent over time, because it is notdependent on gestational age.

E. An observed to expected lung-to-head ratio of less than 65% is almost alwaysassociated with fetal death or early neonatal death.

4. A fetus is diagnosed as having CDH on ultrasonography at a prenatal visit during the 22ndweek of gestation. Which of the following factors is accurately described in the context ofmanagement for this condition?

A. Tracheal occlusion in the fetus has demonstrated efficacy in producing higher lungvolumes for moderate and severe CDH, but no differences in mortality have everbeen demonstrated in any trials.

B. Open fetal repair of the diaphragm has shown benefit for neonatal survival inseveral trials and is the current preferred fetal therapy, but is not widely offered dueto increased risk of uterine bleeding in the mother.

C. For those receiving postnatal treatment without fetal intervention, the level of careof the NICU and the number of patients with CDH cared for in the NICU does notappear to have an impact on outcomes.

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D. The mode of delivery, vaginal versus cesarean, does not appear to have an impacton neonatal survival, and should be based on maternal indications.

E. The current best practice for immediate management of CDH after delivery,regardless of severity, is to attempt noninvasive, “regular baby” practices, such asdelaying cord clamping, avoiding intubation, and refraining from vascular accessuntil explicitly necessary.

5. A term male infant with left-sided CDH is born after cesarean delivery. He undergoesintubation in the delivery room and is transported to the NICU. He is given mechanicalventilation. Sensors demonstrate a pre- and postductal oxygen saturation gradient. Yoususpect pulmonary hypertension (PHTN). Which of the following statements regarding thispatient is correct?

A. Unlike in non-CDH cases, PHTN in CDH is only associated with a structural or fixedcomponent of PHTN, and is not a reversible component.

B. The pre-/postductal gradient is indicative of a closed ductus arteriosus, with lack ofability of adequate “normal” shunting during the transition from in utero to thenewborn period.

C. The absence of tricuspid regurgitation on echocardiography can be used todiagnose PHTN.

D. PHTN in the presence of CDH has a worse prognosis compared to PHTN alone.E. Inhaled nitric oxide should be used in all cases of CDH combined with PHTN, even

in milder cases, to avoid the need for extracorporeal membrane oxygenation.

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DOI: 10.1542/neo.17-12-e7052016;17;e705NeoReviews 

Mark F. Weems, Tim Jancelewicz and Hitesh S. SandhuCongenital Diaphragmatic Hernia: Maximizing Survival

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