Congenital Diaphragmatic Hernia:

Trials and Tribulations

Roman Sydorak, MD, MPH

 Congenital Diaphragmatic
Hernia
 One of most common congenital anomalies
 1 per 2000 to 4000 births
 2x more common than childhood cancers
 1-2% of infant mortality in US
 Survival still only 60-70%
 Difficult challenge for obstetricians, neonatologists,
and pediatric surgeons to manage
 Congenital Diaphragmatic
Hernia
 Defect allows bowel,
organs to herniate into
chest

 Lungs do not develop

properly
 Pathophysiology

 Pulmonary hypoplasia
 Decreased number of alveoli, bronchioles
 Bilateral disease, affected lung worse
 Dysfunction in surfactant system
 Pulmonary hypertension
 Decrease in cross-sectional area of pulmonary
vasculature – decreased blood flow
 Smooth muscle hypertrophy
 CDH

 Severity depends on :
 timing of defect
 volume of organs
 Morbidity/Mortality
high despite extensive
research
 History

 First description in early 18th century

 1st successful repair—Gross 1946 Boston
Children’s Hospital
 Literature over next decade described
techniques of surgical repair
 History

 1960s Areechon and Reid – mortality related

to degree of lung hypoplasia
 Over last 20 years recognition that major
mortality due to:
 Pulmonary hypoplasia and pulmonary
hypertension
 History

 Recent years further recognition of

contribution of:
 Surfactant system
 Underlying cardiac dysfunction
 Continued lack of improvement in outcome
 Search for additional therapies
 International CDH registry

 CDH Study Group

 Established 1995
 Gather prospective observational data
 More than 100 centers
 1000s infants listed to date
 Overall survival 60-70%
 Congenital Diaphragmatic
Hernia
 3 types of defects in
neonates:
 Foramen of Morgagni
hernia
 Hiatal hernia
 Bochdalek hernia –
90%
 Congenital Diaphragmatic
Hernia
 Left-sided hernias – 84%
 Herniation of small bowel, large bowel, solid
organs
 Right-sided – 13%
 Herniation of liver and large bowel
 Bilateral – 2%
 Rare and nearly always fatal
 Epidemiology

 M:F – 3:2
 10% present past
neonatal period
 Outcome extremely
good
 50% isolated condition
 50% associated with
additional
abnormalities
 Associated Malformations

 Multiple malformations 50%

 Cardiovascular – 50%
 VSD/ASD
 Genitourinary – 23%
 Gastrointestinal – 10%
 Atresia, malrotation
 Musculoskeletal – 10%
 Limb/vertebral abnormalities
 Lethal anomalies 16%
 Genetics

 Familial CDH rare

 Risk of recurrence for siblings 2%
 Twin cases exceedingly rare
 No genetic linkage identified
 Multifactorial
 Inherited genetic (autosomal recessive)
 Environmental
 Genetic mutation
 Chromosomal Abnormalities

 Karyotype
abnormalities
 Up to 25%
 Trisomy 13, 18, 21
 Associated with defect
in nearly every
chromosome
 Teratogens

 Association seen with drugs:

 Thalidomide
 Quinine
 Anti-epileptic drugs
 Nitrofen (derivative of DDT) – rats
 Failure of closure of pleuroperitoneal folds
 Defective migration of muscle/nerve cells from
cervical somites to diaphragm
 Prenatal Diagnosis

 Screening U/S -- Increased number of

diagnoses made over last 2 decades
 More than 1/2 of diagnoses made prenatally
 Varies among centers
 Allows increased patient education,
identification of worst outcome cases, and
possible prenatal intervention
 Prenatal Diagnosis

 Ultrasound imaging
 Diagnosis in about
60% of fetuses
 Detection increases
with additional
anomalies, large
defects, advancing age
 Prenatal Diagnosis

 Differential diagnosis
 CPAM

 Bronchogenic cyst

 Diaphragmatic

eventration
 Fetal MRI to enhance
diagnostic accuracy
 Fetal ECHO
 Genetic Evaluation
 Prenatal Assessment of
Prognosis
 Poor prognostic factors:
 Diagnosis prior to 25 weeks’ gestation
 Intrathoracic stomach bubble
 Polyhydramnios
 Hydrops
 Liver herniation
 Lung to head ratio < 1.4
 Liver herniation

 Postnatal survival decreased when liver has

moved up into the thorax
 About 75% of all CDH patients have some
portion of the liver herniated into the chest
 Liver down survival 91% with only 24%
requiring ECMO
 Liver up survival 51% with 79% of patients
requiring ECMO
 Lung to head ratio (LHR)

 Quantify amount of lung tissue

 Ratio of opposite lung at 24-26 weeks’
gestation to head circumference
 The higher the LHR, the better the survival
 Significant improvement in survival at LHR
>1
 Lung to Head ratio
 High LHR values
 LHR greater than 1.4
 Survival rate 80-85%
 25% require ECMO

 Intermediate LHR values

 LHR 1.0-1.4
 Survival rate 79%
 69% require ECMO

 Low LHR values

 LHR less than 0.9
 Survival rate 44 to 62%
 Almost all survivors require ECMO

Survivors mean LHR 1.4 +/- 0.33 vs

Nonsurvivors 1.05 +/- 0.3
CDH – High Risk Patients

TREATMENT (AFTER BIRTH)

MORTALITY
MORBIDITY
1/3 Good -0- Low
1/3 Moderate 20% High
1/3 Bad 60% Awful
BAD PROGNOSIS CDH = UNSOLVED PROBLEM
 Fetal Surgery

 Postnatal care does not cure pulmonary hypoplasia

 Prenatal intervention to improve lung development
 Anatomical and physiological components studied
 Numerous animal studies – rats, sheep, monkeys
 UCSF – Harrison
 1980s to today
 Fetal Surgery

 Advantages:
 Prenatal intervention
 Disadvantages:
 PTL
 PROM
 CAS
 Maternal safety
 Fetal Surgery

 Team Approach
 Anesthesia
 Pediatric Surgery
 Ob/Gyn
 Ultrasonographer
 Neonatologist
 Summary of Results of Fetal
Surgery for CDH
Author Year Criteria # Survival
Open Repair UCSF 1990 None 1 100%
UCSF 1990 None 6 0%
UCSF 1993 None 14 29%
UCSF 1997 Liver-down 4 75%
Open T.O. UCSF 1998 Liver-up 13 15%
CHOP 2000 Up, LHR<1 15 33%
Fetoscopic UCSF 2003 Up, LHR<1.4 19 68%/53%
T.O. UCSF 2003 Up, LHR<1.4 11 73%*
Europe 2004 None 134 43%
 Summary of Results of Fetal
Surgery for CDH
Author Year Criteria # Survival
Open Repair UCSF 1990 None 1 100%
UCSF 1990 None 6 0%
UCSF 1993 None 14 29%
UCSF 1997 Liver-down 4 75%
Open T.O. UCSF 1998 Liver-up 13 15%
CHOP 2000 Up, LHR<1 15 33%
Fetoscopic UCSF 2003 Up, LHR<1.4 19 68%/53%
T.O. UCSF 2003 Up, LHR<1.4 11 73%*
Europe 2004 None 134 43%
 Fetal Tracheal Occlusion

 CHAOS
 Fetal lung secretes
fluid actively
 Fetal lamb model
 Reverses lung
hypoplasia, pulmonary
hypertension
 Summary of Results of Fetal
Surgery for CDH
Author Year Criteria # Survival
Open Repair UCSF 1990 None 1 100%
UCSF 1990 None 6 0%
UCSF 1993 None 14 29%
UCSF 1997 Liver-down 4 75%
Open T.O. UCSF 1998 Liver-up13 15%
CHOP 2000 Up, LHR<1 15 33%
Fetoscopic UCSF 2003 Up, LHR<1.4 19 68%/53%
T.O. UCSF 2003 Up, LHR<1.4 11 73%*
Europe 2004 None 134 43%
 EXIT procedure

 Special delivery
 Designed to safely
deliver fetuses with
tracheal occlusion
 Hysterotomy
 Placental support
 Remove balloon
 Intubate
 UCSF—NIH RCT (NEJM)

 24 mothers randomized
 LHR<1.4, liver up
 13 conventional treatment
 11 fetal surgery
 GA delivery 37 weeks vs. 31 weeks
 Survival: 10/13 (77%), 8/11 (73%)
 Trial stopped – no difference
 EuroFetus

 Surgery at 26 to 28 weeks’ gestation

 Percutaneous approach
 Balloon deployed – fetal bronchoscopy
 Reversed at 34 weeks’ gestation
 U/S guided needle puncture
 43% survival (58/134)
 Average GA at delivery 32-34 weeks
 EuroFetus

LHR Liver # Survival

<1 Up 37 3/37 (8%)
Down 17 7/17 (41%)
1-1.4 Up 29 14/29 (48%)
Down 17 9/17 (53%)
>1.4 Up 9 7/9 (78%)
Down 25 18/25 (72%)
 FETO

 Current status still investigational therapy at select

centers
 Intervention for LHR<25th %ile at around 28 wks’
gestation with reversal at 34 wks
 May improve survival in severe cases—decrease
mortality from 49 to 24 %
 TOTAL trial ongoing (Tracheal Occlusion to
Accelerate Lung Growth) in Europe and NA
 Postnatal Treatment

 Optimally delivered in high volume center

 Cyanosis, respiratory distress shortly after
birth
 Ideal to recognize defect early
 Controversies regarding optimal
management
 Management

 Correction and stabilization of oxygenation,

BP, and acid-base status
 Acidosis and hypoxia increase risk of pulmonary
HTN
 Hypotension increase risk of R to L shunting
across PDA, worsening tissue hypoxia
 Surgical repair when appropriate
 Ventilation

 Endotracheal intubation
 Avoid bag-mask ventilation
 Air distention and further pulmonary
compromise
 Orogastric tube
 Harder to avoid if no prenatal diagnosis
 UA, UV lines for monitoring
 Ventilation

 Avoid high airway

pressures—minimize
barotrauma
 PIP < 25 cm H20 or
HFOV
 pH (>7.25), pCO2 (45-
65 mm Hg), PO2
(>85%)
 PTX – Higher mortality
 Corticosteroids

 ? Improvement in lung maturation when given

prenatally
 No controlled trials
 Recommended for infants delivering from 24 to 34
weeks’ gestation
 Unclear if any benefit
 Some benefit postnatally, up to 2/3 of patients have
adrenal insufficiency
 Surfactant

 Deficiency in CDH
 Animal studies – lung specimens
 Surface tension reduced
 Alveoli may function better
 Increased lung compliance
 No RCTs
 Incorporated into many treatment protocols
worldwide
 No hard data to support its use
 iNO

 Normal infant, PVR falls dramatically at

birth
 Infant with CDH – PVR can remain at
suprasystemic levels (R to L shunting)
 Nitric Oxide—EDRF
 Lower PVR
 Up to 20 ppm
 iNO

 NINOS 1997 Pediatrics

 20 ppm vs. 100% oxygen
 RCT
Control NO
Mortality 12 (43%) 12 (48%)
ECMO 15 (54%) 20 (80%)*
 Perfluorocarbons

 Studied in animal models of lung injury

 Partial liquid ventilation
 Preliminary study of 13 patients – all on
ECMO
 8 PFC, 5 conventional ventilation
 No difference in survival
 Feasible but ? benefit
 Pulmonary Hypertension

 ECHO to assess
 RV contractility, enlarged R heart, PV/TV
regurgitation, ductal shunting
 PGE1 may be beneficial
 Sildenafil (Viagra), Milrinone may be
beneficial
 Surgical repair delayed until resolution
 ECMO

 Over 100 centers in US

 Use when optimal medical, ventilator
intervention do not maintain optimal
oxygenation and perfusion
 Adaptation of cardiopulmonary bypass
 ? Data to support its use
 Can it reverse pulmonary hypertension,
hypoplasia?
ECMO

 Traditional criteria for

ECMO/CDH
 1) OI>40 [MAP x
FiO2/PaO2]
 2) severe barotrauma/air leak
 3) Refractory hypercarbia
 4) PaO2<50, PaCO2>50
 5) Preductal saturation <85%
 6) Resistant hypotension
 ECMO

 Exclusion criteria
 1) Prematurity (<34 wks)
 2) <2 kg
 3) IVH
 4) Contraindication to anticoagulation
 5) Irreversible end organ failure
 6) Chromosomal anomalies
 ECMO

 No RCTs
 May be some benefit but no clear data
 Tale of Two Cities Paper -- 1997 Toronto, Boston
 Boston ECMO
 98/196 patients
 53% survival
 Toronto ECMO
 3/223 patients
 54% survival
 Lung Transplantation

 Transplantation of single lung has been

reported
 1994 Starnes (Stanford)
 Single lobe from 6 week old transplanted to
right thorax of infant s/p ECMO and
decannulation
 Limited number of case reports
 Operative Repair

 Reduction of abdominal viscera

 Closure of diaphragmatic defect
 Sutures alone
 Patch closure (larger defects)
 Closure of abdomen
 Delayed or patch in 10%
 Operative Repair

 Laparotomy vs.
Thoracotomy vs.
Minimally invasive
 Patch (1/3-1/2)
 Goretex
 Dacron
 SIS
 When to repair?
 CDH Repair--History

 Different ears
 1970s – urgent surgical correction
 1980s – delayed repair with aggressive
preoperative hyperventilation
 1990s – delayed repair with permissive
protective ventilation
 Paradigm Change

 Sakai 1987
 9 patients with CDH (5 survived)
 Measured respiratory compliance postop
 1 improved, 1 no change—survived
 7 worse—10 to 77% of properative value
 4 with >50% decrease in compliance all died
 When to repair -- criteria

 No hard data
 ? Decrease in pulmonary hypertension by ECHO
 ? Better lung compliance
 ? Better CXR, Minimal vent settings
 Langer, Toronto 1988 -- Delayed surgery
until PCO2 below 40 and hemodynamically
stable
 No decrease in survival
 Hard Data

 Cochrane Database Review 2002

 Early (<24 hours) vs. late (>24 hours)
 Only 2 RCTrials (both small N)
 No significant difference in mortality
 Conclusion: no clear evidence
 1st RCTrial

 CHLA 1994
 RCT early (<6 hours) vs. late (96+ hours) repair
 32 patients (14 Group A, 18 Group B)
 75% group A and 72% group B survived
 No difference in bleeding, ECMO requirement
 2nd RCT

 De la Hunt (Newcastle, England) 1996

 RCT
 N=54 (early repair--<4 hours vs. >24 hours)
 57 vs. 46% survival for delayed group
 Not significant
 ECMO Repair

 When to repair then?

 Stable on ECMO
 Ready to wean from ECMO
 After decannulation
 ECMO Repair

 Repair on ECMO
 Advantage—lung rest postop, facilitate lung
recruitment postop
 Risk—hemorrhage in fully heparanized patient
 Lower risk recently with fibrin glue, amicar
 One Study

 Multicenter study (5 centers) 1992 --

retrospective
 All repaired on ECMO
 42 infants (18 survivors—43%)
 No survivors < 37 weeks
 10/24 nonsurvivors required reop for
bleeding vs. 1/18 survivors
 ECMO repair

 Vazquez Texas 1994

 Reviewed ELSO registry
 483 neonates with CDH, repair on ECMO
 Bleeding complications higher for those
repaired on ECMO (58%) versus those
repaired before (37%) or after (21%)
 After decannulation ?

 Sigalet 1995
 Retrospective
 Repair on ECMO vs. repair after decannulation
 Increased survival, fewer OR complications, and
less need for blood transfusion after
decannulation
 No evidence of rebound pulmonary hypertension
after repair
 ECMO--Amicar

 Wilson 1994 Boston

 31 repairs of CDH while on ECMO
 9 unweanable after 7 days, repair, no AMICAR
 23 stabilized, given AMICAR
 4/9 in group I required reexploration for bleeding
 No patients in group II
 ECMO--Amicar

 Horwitz, Lally (Houston, 1998)

 RCT of Amicar on ECMO
 N=29
 No difference in ICH, thrombotic
complications
 Morbidity

 Acute:
 PPHN, hemorrhage, chylothorax, infection
 Late:
 CLD, recurrent hernia, spinal/chest wall
abnormalities, GI, neurological
 Intestinal obstruction – up to 10% adhesions,
malrotation
 CDH -- Morbidity

 Chronic lung disease – up to 50%

 Home Oxygen
 Diuretics
 Steroids
 Neurologic 10-20%
 Hearing loss
 Neurocognitive deficits 30-80%
 Behavioral problems
 CDH -- Morbidity

 Gastrointestinal – higher incidence with patch repair

 GERD – up to 50%, antireflux surgery 10-20%
 FTT – liberal use of gastrostomies
 Over 50% below the 25th %ile for height/weight
 Recurrent CDH
 Overall 20%
 Up to 50% recurrence with patch repair within 3 years
 Larger patches can lead to chest wall abnormalities
 Mortality

 Difficult to determine
 Do not reflect “hidden mortality”
 Bias
 Institutions do not report in utero deaths, still
births, and deaths prior to transfer
 Mortality may be anywhere between 10 to 30%
 Even higher with associated anomalies
 Survival

 Prematurity – Preterm 54% vs. 73% FT

 Cardiac – 36% vs. 70% no anomaly
 Need for transport – lower survival
 Defect size—Type A-D
 Low preductal O2 saturation (<85%)
 R sided lesions – may have higher mortality
 ECMO--Prognosis

 Overall survival of 40-50% on ECMO

 UK Study – 5 year follow-up
 73 infants with CDH and ECMO
 42 survived to hospital discharge
 27 survived > 1 yr
 Only 7 problem-free
 ELSO database
 89% of infants treated with ECMO for indication other than
CDH neurologically normal
 60% of CDH infants normal
 CDH—Trials and Tribulations

 Many decades of study about CDH

 Several RCTs
 Numerous innovative strategies
 High degree of frustration
 Fetal Surgery – no benefit
 Steroids/Surfactant/PFCs/iNO – unclear benefit
 ECMO – may benefit
 Timing of repair – still unknown
 Prognosis – little improvement in last 20-30 years
QUESTIONS?