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Congenital Diaphragmatic Hernia in 120 Infants Treated

Consecutively With Permissive Hypercapnea/Spontaneous


Respiration/Elective Repair
By Judd Boloker, David A. Bateman, Jen-Tien Wung, and Charles J.H. Stolar
New York, New York

Background/Purpose: Poor prognosis (approximately 50%


survival rate and significant morbidity) traditionally has been
associated with congenital diaphragmatic hernia (CDH). The
authors reviewed a single institution experience and challenged conventional wisdom in the context of a care strategy
based on permissive hypercapnea/spontaneous respiration/
elective repair.
Methods: From August 1992 through February 2000, all infants with CDH and (1) respiratory distress requiring mechanical ventilation, (2) in-born or (3) transferred preoperatively within hours of birth are reported. All respiratory care
strategy used permissive hypercapnea/spontaneous respiration and combined with elective repair. Arterial blood gas
values and concomitant ventilator support were recorded.
Outcome markers were (1) need for extracorporeal membrane oxygenation ECMO, (2) discharge to home, (3) supplemental oxygen need at discharge, and (4) influence of
non-ECMO ancillary therapies (surfactant, nitric oxide, highfrequency oscillatory ventilation).
Results: One hundred twenty consecutive infants were reviewed. Overall survival rate was 75.8%, but, excluding 18 of

120 not treated (6 lethal anomalies, 10 overwhelming pulmonary hypoplasia, 3 prerepair ECMO-related neurocomplications), 84.4% survived to discharge. A total of 67/120 were
inborn. Non-ECMO ancillary treatments had no impact on
survival rate. ECMO was used in 13.3%. Surgery was transabdominal; prosthetics were used in 7%. Tube thoracostomy
was rare. Every inborn patient (n 11) requiring a chest tube
for pneumothorax died. Respiratory support before surgery
was peak inspiratory pressure (PIP), 22, FIO2, .43 with PaO2, 66
torr; PaCO2, 41 torr; and pH, 7.32. The survivors discharged on
oxygen (n 2) died at 4 and 7 months.

Conclusions: The majority of infants with life-threatening


CDH treated with permissive hypercapnea/spontaneous respiration/elective surgery survive to discharge with minimal
pulmonary morbidity.
J Pediatr Surg 37:357-366. Copyright 2002 by W.B.
Saunders Company.
INDEX WORDS: Congenital diaphragmatic hernia; permissive hypercapnea, delayed surgery; extracorporeal membrane oxygenation.

ESPITE ADVANCES in technologies applied to


neonatal care over the last 2 decades, the diagnosis
of congenital diaphragmatic hernia (CDH) is reported to
carry a high mortality rate.2-4 With the addition of synchronized ventilation, high-frequency oscillatory ventilation (HFOV), nitric oxide (iNO), and extracorporeal
membrane oxygenation (ECMO) to the treatment arsenal, survival rates currently range from 63% to 69% in
multicenter studies,2-4 and 53% to 78% in large singlecenter (level 3 nursery) cohorts.5-7 The CDH patient,
often complicated by multiple factors including pulmonary hypoplasia,8 persistent pulmonary hypertension
(PPHN),8 and the need for complex surgical repair,
continues to present an especially difficult challenge for
both the pediatric surgeon and neonatologist.
Until the early 1990s, treatment was based on 2
primary tenets: the first was that CDH was a surgical
emergency necessitating early repair. The second was
that persistent pulmonary hypertension of the newborn
(PPHN) was to be vigilantly controlled, a strategy that
often included deliberate, aggressive hyperventilation
designed to alkalinize the patient and artificially maintain
postductal arterial oxygen saturations (SaO2) greater than

90%. This strategy frequently used extremely high peak


inspiratory pressures (PIP), ventilator rates, and oxygen
concentrations. Although some patients had an initial
period of stability after successful emergency surgery, a
phenomenon that became known throughout the literature as the honeymoon period,9,10 many often deteriorated postoperatively. Additionally, survival often was
complicated by iatrogenic chronic lung disease.
In the last 2 decades, both tenets have been questioned. The first notion of CDH as a surgical emergency
was challenged by Sakai et al,11 who showed deterioration in respiratory compliance post-CDH repair,11 and

Journal of Pediatric Surgery, Vol 37, No 3 (March), 2002: pp 357-366

357

From the Childrens Hospital of New York, Divisions of Neonatology and Surgery, New York Presbyterian Hospital and Columbia
University, College of Physicians and Surgeons, New York, NY.
Presented at the 32nd Annual Meeting of the American Pediatric
Surgical Association, Naples, Florida, May 20-23, 2001.
Sponsored in part by The Charles Edison Fund and The Anya Fund.
Address reprint requests to Jen-Tien Wung, MD, Childrens Hospital
of New York, Room BHN 1201, 3959 Broadway, New York, NY 10032.
Copyright 2002 by W.B. Saunders Company
0022-3468/02/3703-0018$35.00/0
doi:10.1053/jpsu.2002.30834

358

BOLOKER ET AL

Nakayama et al12 who provided evidence of improved


outcome and compliance using preoperative stabilization. With the acceptance of a delayed CDH repair
strategy, the atraumatic reversal of PPHN assumed even
greater importance as the primary treatment goal. Minimizing iatrogenic barotrauma is achieved by avoiding
harmful overventilation, a respiratory care strategy that
regularly results in pulmonary interstitial emphysema or
broncho-pulmonary dysplasia. This was first shown to
have potential benefit in babies without CDH suffering
from persistent fetal circulation in 1985.13 Applying this
strategy to the CDH patient has helped improve survival
rate in a number of institutions.1,6,7
This report concerns a single institution experience
treating 120 consecutive CDH patients with gentle ventilation (defined as a respiratory strategy characterized
by preservation of spontaneous respiration, permissive
hypercapnea, and avoidance of high ventilator pressures), elective surgery, and no prophylactic chest tube
placement during operative repair. The data characterize
the respiratory, medical, and surgical management of the
nonhyperventilated CDH patient. We asked if correlations existed between patient origin (inborn versus outborn transfers), adjuvant treatments (inhaled nitric oxide
[iNO], high-frequency oscillatory ventilation [HFOV],
surfactant, chest tubes, ECMO), and survival.
MATERIALS AND METHODS

Study Population
Data from 120 consecutive neonates with CDH admitted between
August 1992 and February 2000 was analyzed retrospectively with
approval from the institutional review board. All CDH newborns were
included regardless of associated anomalies, degree of pulmonary
hypoplasia, and medical condition at birth or on arrival. All patients
had respiratory insufficiency severe enough to require intubation,
mechanical respiratory support, and supplemental oxygen. Patients
transferred postoperatively were not included.

Respiratory Care Strategy


All inborn babies were treated with the same strategy (outborn
infants were converted to this strategy on arrival). Infants were intubated nasally and ventilated with a time-cycled, pressure-limited,
constant flow, conventional infant ventilator (Heathdyne or Infant Star
500; Infrasonics Inc, San Diego, CA). Patients were not placed on
synchronized mode. All patients were allowed to breathe spontaneously. No patient received muscle relaxants. Precipitous changes in
ventilator settings were avoided. Barring severe decompensation (indicated by progressive preductal oxygen desaturation to SaO2 70%
accompanied by progressive metabolic acidosis and multiple organ
failure), infants were given ample time to accommodate (usually at
least 30 minutes) before any changes in respiratory strategy were
considered.
The conventional ventilator was configured in 1 of 2 modes. Conventional low rate ventilation always was the first mode applied,
initiated at settings of intermittent mandatory ventilation (IMV), 40;
inspiratory time, 0.5; gas flow, 5 to 7 L/min, peak inspiratory pressure
(PIP), 20 cm H2O, and positive end-expiratory pressure (PEEP) of 5 cm
H2O, with FIO2 1.0. Indications that this ventilation mode was not

sufficient included severe paradoxical chest movement, severe retractions, tachypnea, inadequate or labile oxygenation (preductal
SaO2 80%), or PaCO2 greater than 60 mm Hg. In this case, the second
configuration, high-frequency positive pressure ventilation (HFPPV),
was used. To deliver HFPPV, the ventilator was set at an IMV, 100;
inspiratory time, 0.3; gas flow, 10 to 12 L; PIP, 20; and PEEP, 0 (to
account for inadvertent PEEP generated by the short expiratory time).
Respiratory rates between 40 and 100 very rarely were used. For both
configurations, PIP was adjusted as needed based on chest excursion,
with care taken to avoid excessive chest movement. Similarly, for both
modes, attempts were made to limit PIP to 25, though occasionally a
PIP up to 30 was used briefly. A PIP of greater than 30 was used only
when all other advanced ventilation techniques including HFOV and
inhaled iNO means had failed. HFOV (SensorMedics 3100A; SensorMedics, Yorba Linda, CA) was used for hypoxia (preductal saturation
consistently 80%) and/or persistent hypercarbia (pCO2 65) refractory to an adequate trial (usually 30 minutes to 1 hour) of HFPPV.
Oxygen administration was monitored by pulse oximetry, aiming for
a preductal saturation between 90% and 95%, with 80% to 89%
tolerated if the infant appeared comfortable, and other organ function
was stable. Only the minimum supplemental FIO2 was administered to
maintain a preductal saturation within this range. FIO2 was weaned
aggressively to avoid excessive oxygen delivery. Permissive hypercapnia (60 to 65 mm Hg) was accepted as long as the infant appeared
comfortable, with, again, ample time given for stabilization. Infants
never were hyperventilated to induce alkalosis. Pressure and rate were
weaned as oxygenation and pCO2 improved. Babies requiring HFPPV
were weaned directly from a rate of 100 to conventional ventilation at
a rate of 40 as tolerated.
Postoperatively, infants were extubated when they had been weaned
to minimal ventilator support: IMV, 10; PIP, 20; PEEP, 5; and FIO2 less
than 0.4. All were extubated to bubbly nasal continuous positive
airway pressure (CPAP) of 5 cm H2O. CPAP was delivered via the
Hudson CPAP system (Hudson-RCI, Temecula, CA) with flow of 8
L/min provided by blended wall oxygen and positive pressure generated by immersion of the distal expiratory tubing in a bottle of acetic
acid to a depth of 5 cm. Weaning from CPAP was based on oxygen
saturation and clinical assessment of work of breathing.

Medications
After 1994, any infant failing to achieve a stable preductal pO2 of
greater than 80% despite good chest excursions while breathing 100%
oxygen was treated with iNO at 25 ppm, rather than continuing to
increase PIP. From 1992 to 1994, babies with similar hypoxemia were
treated with an intravenous tolazoline bolus of 1 mg/kg followed by a
drip of 1 mg/kg/h if improvement had been seen. Surfactant (Survanta
4 ml/kg) was only given as a rescue therapy to the most severe infants
failing to improve despite iNO therapy. A successful response to
surfactant and iNO was recorded based on clinical observation of
increased SaO2 and a decrease in FIO2 requirement of 0.15 for more
than 1 hour.
No patients were given muscle relaxants. Spontaneous breathing
was preserved. Sedation was avoided by vigilantly emphasizing airway care, developmentally appropriate positioning, and environmental
maintenance. Rare patients required intermittent doses of analgesia and
sedation preoperatively for excessive agitation despite good airway
maintenance and comfort measures (morphine [0.1 mg/kg], fentanyl [2
g/kg], versed [0.05 to 0.1 mg/kg], or phenobarbitol [5mg/kg]). Narcotics were given liberally postoperatively as needed for pain management. Continuous infusions were not used. Cardiac inotropic support
(dopamine and dobutamine, 5 to 10 g/kg/min) and fluid boluses were
used to maintain adequate perfusion as indicated but rarely were
required. Sodium bicarbonate was only administered for severe metabolic acidosis (respiratory acidosis was not treated with medication).

PERMISSIVE HYPERCAPNEA FOR CDH

ECMO
Prerepair ECMO was reserved for patients without lethal anomalies,
no ECMO contraindications, and able to maintain preductal saturations
greater than 85% using the outlined strategy for at least 1 hour at any
time in their clinical course. This was interpreted as evidence of
adequate lung parenchyma.26 Ventilator pressures considered were
generally maximal at a PIP of 30 with conventional ventilation modes
(includes HFPPV) or MAP of 20 with HFOV. Patients failing to meet
the preductal saturation goal despite maximal support were considered
to have strong evidence for lethal lung hypoplasia.26 ECMO rescue was
only instituted in babies displaying a reasonable expectation of adequate lung parenchyma and potentially reversible pulmonary hypertension. If ECMO criteria were met, support was considered in any infant
with evidence of inadequate oxygen delivery, progressive metabolic
acidosis, and/or organ failure despite maximal therapy. ECMO support
was initiated before extreme ventilator pressures were required. A
declining preductal oxygen saturation below 80% (refractory to ventilator manipulation, iNO, and 100% oxygen) generally was considered
an indication for ECMO. Initiation of ECMO was a decision made by
the pediatric surgeon and neonatologist based on the infants clinical
course, rather than any calculated respiratory index (ie, oxygenation
index).
Either venovenous (VV) or venoarterial (VA) ECMO was used. The
(VA) extrathoracic cannulation was accomplished at the bedside using
a 10F to 12F end-hole arterial perfusion canula and a 12F to 14F
multiple side-hole venous drainage catheter (Biomedicus, San Diego,
CA). VV canulation was undertaken using a double lumen 12F to 14F
cannula (Jostra/Origen, Rotterdam, The Netherlands). ECMO support
was carried out via standard techniques previously outlined.14 Patients
placed on ECMO preoperatively underwent CDH repair after maximal
reduction of ECMO flows. ECMO was discontinued as soon as possible
after repair.

Surgery
Surgical repair was delayed until the preductal to postductal saturation gradient had subsided, echocardiographic examination confirmed
minimal evidence of pulmonary hypertension, and ventilator support
had minimized. An abdominal approach was taken for all diaphragm
repairs. A subcostal exposure allowed reduction of abdominal viscera
from the ipsilateral thorax. Primary repair of the defect was undertaken
only if minimal dissection was required. For more extensive cases, a
Gore-tex (W.L. Gore and Associates, Flagstaff, AZ) prosthesis (1 mm)
was fixed in an anatomic position with nonabsorbable, interrupted
sutures. No prophylactic ipsilateral tube thoracostomy was performed.
Special adjuncts, including soft tissue flaps, abdominal wall stretching,
manual extrusion of meconium through the anus, and correction of
malrotation with appendectomy were not performed. A second GoreTex prosthesis was used if the abdominal wall could not be closed
without undue tension. Infants requiring abdominal wall prosthesis
underwent serial reduction and subsequent primary abdominal wall
closure. Patients who underwent repair while on ECMO support were
treated with Amikar (- caproic acid) preoperatively, and most cut
surfaces were treated with calcium-activated fibrinogen intraoperatively to assist hemostasis.

Data Analysis
Statistical analysis of the data was performed with the SPSS 8.0 for
Windows and Episode statistics programs. Continuous variables were
compared using a Students t test for independent variables. Categorical
variables were compared with statistical analysis of 2 2 tables as
calculated via 2 analysis with Yates correction. The FIO2 as well as
arterial blood Ph and PaCO2 were recorded at 6-hour intervals using the
blood gas closest to each interval midpoint provided that the gas was

359

within 2 hours of the desired point. Mean, maximum, and minimum


PaCO2 during the first 24 hours was calculated using all blood gases
collected during the first day of life. A patient was counted as having
been treated with either HFPPV or HFOV even if this treatment was
brief or considered a failure. Mean airway pressure (MAP) was estimated by (PIP PEEP) (Ti [Ti Te]) PEEP. Oxygenation Index
(OI) was calculated by ([MAP] [FIO2][100]) PaO2.

RESULTS

General Characteristics
Associated anomalies. All general characteristics of
patients are shown in Table 1. Inborn CDH infants had a
25% (17 of 67) incidence of associated secondary anomalies. Of the 17 infants with anomalies, 9 had severe
congenital heart disease: 3 with hypoplastic left heart
syndrome, 2 atrial-ventricular canal, 2 tetrology of Fallot, and 2 coarctation of the aorta. CDH with isolated
severe cardiac disease was not considered, a priori, a
lethal anomaly. Six of the 17 infants were considered to
have a hopeless, lethal constellation of defects: 1 pentology of Cantrell, 1 Fryns syndrome, 2 infants with
bilateral diaphragmatic defects and multiple anomalies,
and 2 with unilateral defects and multiple anomalies.
Two of these 6 infants had severe congenital heart
disease as part of their constellation of defects.
Outborn infants tended to have fewer anomalies than
their inborn counterparts (6 of 53 v 17 of 67; P value, not
significant). They had significantly less associated cardiac disease, noting only 1 infant with tetralogy of Fallot
(1 of 53 v 9 of 67; P .05). Only one outborn infant was
noted to have a syndrome (Killian-Teschler-Nicola).
This suggested a preselection of infants before transfer
referral.
Preoperative Respiratory Management
Intubation. A total of 97% (65 of 67) of the inborn
infants were intubated immediately in the delivery suite
as part of the management of prenatally diagnosed CDH.
Table 1. Perinatal Data

Gestational age (wk)


Birth weight (kg)
37 weeks gestation
APGAR (1 and 5
minutes)
Left CDH
Right CDH
Bilateral CDH
Overall anomalies*
Severe cardiac disease

Inborn
(n 67)

Outborn
(n 53)

Analysis

37.9 2.0
2.98 .59
8 (12%)

38.0 2.0
3.03 .64
4 (8%)

Not significant
Not significant
Not significant

4.6/7.0
58 (87%)
7 (10%)
2 (3%)
17 (25%)
9 (13%)

5.6/7.3
39 (74%)
14 (26%)
0
6 (11%)
1 (2%)

Not significant
Not significant
P .05
Not significant
Not significant
P .05

*Includes any second anomaly noted in addition to CDH (including


cardiac disease).
Includes 3HLHS, 2 A-V Canal, 3 tetrology of Fallot, and 2 coarctation of aorta. It does not include PDA, isolated ASD, or isolated VSD.

360

The remaining 2 patients were intubated within 4 hours


of life for respiratory distress and postnatal diagnosis. A
total of 47.2% (25 of 53) of outborn patients were
intubated immediately in the delivery suite given their
predetermined diagnosis. A total of 86.7% (45 of 53)
were intubated within 4 hours of life. All outborn infants
were intubated before transfer for respiratory distress.
Conventional ventilation: Peak ventilator pressure.
Figure 1 compares the maximum PIP used to ventilate
inborn survivors versus inborn deaths. No inborn survivor required a PIP greater than 25. Fifty-eight percent of
inborn deaths (11 of 19) required PIP escalation above
25, after failing to stabilize with HFOV or conservative
ventilator management using peak pressures of 20 to 25.
In outborn infants, 23.4% (11 of 47) of survivors and
66% of deaths (4 of 6) used a PIP greater than 25, often
before the time of transfer. This suggested more aggressive ventilation before transfer.
Conventional ventilation: HFPPV. Inborn preoperative ventilator choice differed between survivors and
deaths (Table 2). Inborn survivors often required the use
of HFPPV to adequately ventilate, using this mode in
50% of cases (22 of 44). This compared with 78.2% of
inborn babies that died that were treated with HFPPV
during their clinical course (18 of 23; P .05).
Outborn survivors showed similar high levels of
HFPPV use when compared with inborn survivors
(40.4%, 19 of 47, P value, not significant). This suggested that more severely affected infants with CDH
would need HFPPV for ventilation strategy.
Preoperative advanced ventilation techniques and
medical management. Additional adjuvant therapies
were used commonly after failure of initial conventional
ventilation techniques (Table 2). A total of 21.7% (5 of
22) of inborn survivors did not respond to management

BOLOKER ET AL

with HFPPV and required escalation of respiratory support. More advanced technologies were used infrequently in inborn survivors. HFOV use (5 of 44; 11%),
and inhaled nitric oxide (5 of 44; 11%) use was low with
only 1 patient showing a response. Surfactant was only
used in 2 inborn patients without response in either.
Compared with inborn survivors, the rate of HFPPV
failure in inborn patients who died was higher, with 66%
(12 of 18) being treated with advanced technologies
(P .05). Overall, 52% attempted HFOV (12 of 23; P
.05). Inhaled nitric oxide was provided to 12 of 23
patients (52%; P .05) with only 3 (25%; P value, not
significant) demonstrating response. Again, surfactant
administration rarely was attempted (2 patients) with no
response.
Preoperatively, outborn survivors had statistically similar needs for adjuvant therapies, although they tended to
require more HFOV (21%, 10 of 47; P value, not
significant) and iNO (19%, 9 of 47; P value, not significant) than their inborn counterparts. Outborn survivors
only tended to be more likely to respond to iNO (77%, 7
of 9; P value, not significant). Surfactant administration
rates were low as well (9%, no responders).
ECMO. ECMO was used infrequently, in only 8.9%
of inborn patients (6 of 67) and 18.9% of outborn
patients (10 of 53; P value, not significant).
Blood Gas and Oxygenation Data: Inborn Group
(outborn data were too incomplete for analysis)
Blood gases. Inborn blood gas data were plotted in
Fig 2 and 3 to show trends in pH and pCO2, showing
improvement in survivor blood gases over the first 24
hours followed by a plateau in values. The inborn death
group values are graphed for comparison, although the
plot was influenced heavily by the high death rate over
the time period (only 3 patients remained in the death
group by 36 hours). The inborn deaths tended to have
worse pH and pCO2 values at all time-points than the
death group despite using higher peak inspiratory pressures (P value, not significant).
Oxygen requirement. Inborn FIO2 requirement is
shown in Fig 4, with inborn survivors exhibiting decreasing oxygen requirements over the first 36 hours of life.
Carbon dioxide range. In the first 24 hours of life,
inborn survivors showed an average PaCO2 of 47.2 9.3,
ranging from 35.5 7.4 (average best PaCO2) to 68.6
20.9 (average worst PaCO2). In 63.6% of inborn survivors
(28 of 44), the worst PaCO2 was the first blood gas drawn
after intubation and umbilical line placement.
Perioperative Data

Fig 1. Maximum peak inspiratory pressure required in inborn


survivors versus deaths. Survivors (n 44), Deaths (n 19). Data not
available for 4 deaths.

Immediate preoperative data. In their final blood gas


analysis before surgery, inborn infants had stable values

PERMISSIVE HYPERCAPNEA FOR CDH

361

Table 2. Respiratory Management Data


Inborn (n 67)
Survivors

Number
Surfactant
HFPPV
HFOV
iNO
ECMO

Outborn (n 53)
Deaths

Survivors

Deaths

Preoperative

Postoperative

Preoperative

Preoperative

Postoperative

Preoperative

44
2 (5%)
22 (50%)*
5 (11%)*
5 (11%)
3 (7%)

44
0
16 (36%)
1 (2%)
1 (2%)
0

23
2 (9%)
18 (78%)
12 (52%)
12 (52%)
3 (13%)

47
4 (9%)
19 (40%)
10 (21%)
9 (19%)
7 (15%)

47
0
16 (34%)
4 (9%)
3 (6%)
0

6
2 (33%)
5 (83%)
5 (83%)
5 (83%)
3 (50%)

NOTE. Percentages reported as percentages of the total number.


*A significant difference (P .05) between inborn preoperative survivor and inborn preoperative deaths management. No significant
difference was detected between survivor preoperative management inborn versus outborn, survivor postoperative management inborn versus
outborn, deaths preoperative management inborn versus outborn, or outborn preoperative survivor versus outborn preoperative deaths.

with an average preoperative pH of 7.38 .06, pCO2 of


42.8 7.7 torr, PaO2 of 66 9 torr, and FIO2 requirement of 0.37 0.11.
Surgical timing. Inborn survivors underwent surgery
at 98 38 hours of life compared with 118 76 hours
for outborn survivors (P value, not significant). No infant
had surgical repair before 36 hours of life.

pared with inborn survivors, 34% of outborn survivors


required HFPPV postoperatively (16 of 47; P value, not
significant), whereas 12.7% of outborn survivors required initiation of either iNO or oscillation after surgery
(6 of 47; P values, not significant). Importantly, no
patient, inborn or outborn, required ECMO postoperatively (if not treated preoperatively).

Postoperative Characteristics

Mortality Rate

Length of postoperative intubation. Postoperative


length of intubation for inborn infants averaged 4.7
4.8 days versus 5.9 8.8 postoperative days for outborn
transfers (P value, Not significant).
Postoperative advanced ventilation techniques and
medical management. Only a moderate escalation in
ventilator management was noted postoperatively in either group (Table 2). A total of 36.4% of inborn (16 of
44) survivors required HFPPV postoperatively, most
having been treated with this mode before surgery. Only
4.5% of inborn survivors required initiation of iNO or
oscillation postoperatively (2 of 44). Similarly, as com-

Overall survival rate. Morbidity and mortality data


for the 3 groups are summarized in Table 3. Overall
survival rate was 75.8%. Inborn survival rate excluding
lethal congenital anomalies (n 6), pre-ECMO neurocomplications (n 4), and lethal lung hypoplasia (n
10) was 86.3%. Overall outborn survival rate was 88.7%.
Early deaths. In the inborn group, 60.8% of deaths
occurred before 24 hours of life (14 of 23), 69.5% (16 of
23) before 36 hours of life. All autopsies (n 7)
obtained on patients that died within 24 hours showed
severe, bilateral lung hypoplasia (lung weight 5%
predicted). Based on the autopsy evidence and clinical

Fig 2. Ph variability over the first 36 hours in inborn survivors


versus deaths. Survivors (n 44) for all time-points, Deaths (n 19)
at hour 1, (n 18) at hour 6, (n 11) at hour 12, (n 7) at hour 18
and 24, (n 5) at hour 30, (n 3) at hour 36. [- - - -], denotes error
bars for survivor group; {- - - -}, denotes error bars for the death
group.

Fig 3. pCO2 variability over the first 36 hours in inborn survivors


versus deaths. Survivors (n 44) for all time-points, Deaths (n 19)
at hour 1, (n 18) at hour 6, (n 11) at hour 12, (n 7) at hour 18
and 24, (n 5) at hour 30, (n 3) at hour 36. [- - - -], denotes error
bars for survivor group; {- - - -}, for the death group.

362

Fig 4. FIO2 variability over the first 36 hours in inborn survivors


versus deaths. Survivors (n 44) for all time-points, Deaths (n 19)
at hour 1, (n 18) at hour 6, (n 1) at hour 12, (n 7) at hour 18 and
24, (n 5) at hour 30, (n 3) at hour 36. [- - - -], denotes error bars for
survivor group; {- - - -}, for the death group.

course, deaths occuring at less than 24 hours of life were


presumed to represent lethal pulmonary hypoplasia.
Late deaths. Deaths after 1 week of life occurred
infrequently in the inborn group and consisted of 5
deaths: at 8 days, caused by ECMO-related intracranial
bleeding; 11 days, obstructed airway; 17 days, necrotizing enterocolitis with septic shock; 21 days, associated
anomalies including hypoplastic left heart syndrome; and
70 days, died in operating room during third repair of
recurrent CDH. Three late deaths were seen in the
outborn group with all (at 20 day, 34 day, and 35 day)
occurring secondary to chronic, recurrent PPHN.
ECMO. Overall ECMO mortality rate for the 2
groups combined was 6 of 16. Three of 6 inborn ECMO
patients died: 2 with intracranial hemorrhage and 1 with
cerebral infarction. Twenty of the 23 inborn deaths were
not offered ECMO therapy secondary to failure to meet
ECMO entry criteria. In the outborn group, 3 of 10
ECMO patients died. One infant had support withdrawn
because of poor neurologic outcome after a prolonged
cardiac arrest, whereas the other 2 infants died after
decanulation (at 20 days and 35 days) secondary to
chronic PPHN.
Risk Factors
Emergent tube thoracostomy. Rates of emergent preoperative chest tube placement in the transitional nursery
secondary to pneumothorax were similar in inborn and
outborn groups (16.4%, 11 of 67 and 18.8%, 10 of 53,
respectively; P value, not significant). Patients in both
groups requiring an emergent preoperative chest tube
had a 71.4% mortality rate (15 of 21). This mortality rate
reached 100% in the 11 inborn patients requiring emergent thoracostomy (despite initial treatment with the
gentle ventilation strategy). As shown in Fig 1 and Table
2, the respiratory management of inborn deaths escalated

BOLOKER ET AL

in intensity after the infants failed to maintain adequate


oxygenation using conservative treatment, increasing
their risk for pneumothorax.
Oxygenation index. The use of the oxygenation index (OI) of 40 as a measure of ECMO need was altered
in this experience because of the ventilator strategy
based on low pressure use. An OI of greater than 20 at 6
hours of life was used to identify inborn patients at high
risk for mortality (infants with cyanotic cardiac disease
were excluded). Both inborn survivors and deaths tended
to have low OIs secondary to the low ventilator pressures
used in the gentle ventilation strategy. All 37 patients
with an OI less than 20 survived, and none of these
survivors required ECMO (positive predictive value of
survival was 88% sensitive, 100% specific). Of the 25
patients with an OI greater than 20, 20 died (2 survivors
required ECMO). The 6-hour OI greater than 20 showed
positive predictive value for mortality of 80% (100%
sensitivity, 80% specificity).
DISCUSSION

This report shows consistency in survival with an


earlier smaller cohort.1 The overall 75.8% survival rate
including all infants with anomalies and lethal lung
hypoplasia, compares favorably with other reported series (53% to 78%).2-7 This series additionally has a high
rate of inborn patients (55.8%), as opposed to the 29%
inborn rate reported in one multicenter series with 69%
survival rate.2 Survival rate in this multicenter cohort
may have been increased artificially secondary to the
hidden mortality in outborn patients (exclusion of
associated congenital anomalies and severe lung hypoplasia pretransfer) previously described in the literature.15 Survival rate was nearly identical to that reported
by Kays et al7 (78%), who used a similar preoperative
strategy after abandoning deliberate hyperventiation
(though ECMO use was higher, 43%). The 13.3%
ECMO rate was lower than the 46% reported in multicenter studies.2,4 This low rate may be attributed partially
to overall respiratory care strategy as well as a higher
threshold for ECMO initiation. The higher threshold may
Table 3. Morbitity and Mortality Data
Inborn (n 67)
Survivors

Total
Code in delivery suite*
Preoperative chest tube
ECMO
Death 24 hours
Severe cardiac disease
Overall anomalies

44
1 (2%)
0
3 (7%)

2 (5%)
3 (7%)

Deaths

Outborn (n 53)
Survivors

23
47
4 (17%)
1 (2%)
11 (48%)
6 (13%)
3 (13%)
7 (15%)
14 (61%)

7 (30%)
1 (2%)
14 (61%)
6 (13%)

Deaths

6
1 (17%)
4 (67%)
3 (50%)
2 (33%)
0
0

NOTE. Percentages reported as percentages of the total number.


*Any infant requiring epinephrine during initial resuscitation.
Tube placement secondary to tension pneumothorax.

PERMISSIVE HYPERCAPNEA FOR CDH

derive from emphasis on preductal rather than postductal


measures of oxygenation.
The principal causes of CDH mortality can be divided
into 4 categories: associated lethal anomalies, overwhelming pulmonary hypoplasia, central nervous system
hemorrhage/injury, and iatrogenic barotrauma.6 In this
series, mortality in the first 2 categories accounted for
approximately 69.6% (16 of 23) of inborn deaths. When
these 2 categories of patients are eliminated from our
inborn data, inborn survival mirrors that of outborn patients
(86.3%, 44 of 51 v. 88.7%, 47 of 53, respectively). This
suggests that for patients without severe associated
anomalies or overwhelming pulmonary hypoplasia, improved survival rate may be achieved by preventing
iatrogenic lung injury and, in turn, decreasing the need
for ECMO with its potential for central nervous system
morbidity.
The practice of delayed surgery is widespread in the
management of CDH but not universal. The rate of early
repair (within 24 hours of birth) was 37.7% in one
multicenter report.3 Surgical repair decreases lung compliance, a decrease that could prove fatal in a patient
already compromised by pulmonary hypoplasia and
PPHN.11,12 Additionally, the postbirth transition of vascular and pulmonary function is prolonged in the CDH
infant, further complicating emergent early repair.16 Delayed surgery is theorized to provide additional time for
this remodeling, leading to a more stable infant, better
able to tolerate a postoperative decrease in compliance.
Improvement of survival has never been shown consistently with delayed repair,1,5,6,17-20 but in all cases, failure
to show improvement corresponded with a hyperventilation strategy.5,6,18 In this series, delayed surgery did not
lead to severe deterioration in respiratory status, neither
prerepair (while awaiting delayed surgery), nor immediately postrepair. In this series, delayed surgery was
associated with decreased ECMO need and improved
survival rate without increasing morbidity rate.1,5,6,17-20
Hyperventilation and muscle paralysis still is used
in the treatment of the PPHN associated with CDH in
some centers. Deliberate hyperventilation often requires
high rates and peak pressures, increasing the potential
for iatrogenic injury. In this series, less rigid parameters
for ventilation and oxygenation were used, helping to
limit exposure to high ventilator settings. The pCO2 range
was widened to accept moderate hypercapnea, whereas
oxyenation adequacy was monitored by preductal pulseoximetry alone. The evolution and time course of the
blood gas data delineate the spontaneously breathing
CDH infants inherently plastic early respiratory status
and support a strategy of accepting moderate permissive
hypercapnea. Similarly, preductal pulseoximetry, rather
than postductal PaO2 (or pulseoximetry), was used to
monitor oxygenation. This practice allowed for moderate

363

postductal oxygenation variability and eliminated ventilator adjustments designed to maintain an artifically
elevated postductal PaO2. Despite the frequent presence
of initial PPHN, abandoning more rigid parameters did
not prove problematic as evidenced by the steady improvement in oxygenation and ventilation over the first
36 hours of life in inborn survivors. Tolerance of acute
variability may prevent chronic iatrogenic lung damage
caused by aggressive ventilator manipulation in an attempt to create consistently ideal blood gas levels.
Hyperventilation often requires a PIP above 30 to
achieve CO2 levels in the desired alkalotic range. Animal
models have shown significant iatrogenic lung injury as
a result of both brief, high-volume manual inflations (6
bagged breaths) and prolonged moderate-pressure mechanical ventilation (PIP, 30).21,22 Both situations are
seen consistently during the resuscitation and ventilation
of the hyperventilated CDH patient. In the human, autopsy data have shown high rates of hyaline membrane
formation, parenchymal hemorrhage, bronchopneumonia, and pneumothoraces in the hyperventilated CDH
infant using high PIP.23 Avoiding hyperinflation of the
lung additionally helps minimize interference with systemic vascular return and decreases pulmonary vascular
resistance, helping to alleviate PPHN.24 In this study,
escalating ventilator PIP to high levels did not change
any inborn patients eventual outcome because no survivors were treated with a PIP greater than 25 (although
some did require HFOV). The use of high ventilator
pressures may have been further avoided by the use of
HFPPV, which allowed increases in minute ventilation
and alleviated paradoxial chest wall motion without
increasing PIP. Providing ample accommodation time
before making ventilator changes in anticipation of expected short-term variation in oxygenation (barring severe decompensation) may have similarly prevented PIP
escalation and additional morbidity and mortality.
Iatrogenic lung injury can result from other sources.
Ipsilateral prophylactic chest tube placement in the operating suite often is a routine part of CDH repair, with
76% of patients undergoing thoracostomy in a recent
review.3 The natural course of the potential space created
by hernia reduction; however, is to passively fill with
fluid, a process that is delayed by placement of the tube.
Additionally, the forces generated by this tubes negative
pressure can be potentially damaging. During expiration,
the suction of the chest tubes negative pressure prevents
ipsilateral lung deflation.11 This force is theorized to
cause the hypoplastic ipsilateral lung to grossly hyperinflate within the first 24 to 48 hours, potentially creating a
dangerous increase in pulmonary vascular resistance and
leading to avoidable pulmonary damage.11,25 The rapid
hyperinflation and resultant lung injury may cause cardiopulmonary instability. This potential for harm may

364

BOLOKER ET AL

have merit, because patients treated with prophylactic


thoracostomy had a significantly higher mortality rate
than their untreated counterparts in one large cohort
(29% v 11%; P .01).3 In our series, repair without
routine thoracostomy placement did not prove problematic and may have helped eliminate the need for postoperative ECMO potentially caused by chest tube induced
deterioration.
Identifying risk factors for CDH mortality in the gentle ventilation setting has proved elusive. The development of a tension pneumothorax despite a gentle ventilation strategy may indicate the presence of lethal
pulmonary hypoplasia. The use of high PIP in the CDH
infant should be avoided because it puts their vulnerable
lungs at risk for iatrogenic pneumothoraces (and further
morbidity and mortality). In our series, inborn infants
requiring emergent tube thoracostomy did not respond to
conservative management (conventional PIP 25 and
HFOV MAP 20), and a pneumothorax developed after
escalation of their respiratory care in response to inadequate oxygenation and ventilation. Emergent preoperative chest tube placement always preceded mortality in
the inborn population. Development of a tension pneumothorax in the outborn population, however, was not
highly correlated with mortality (40% death rate, 4 of 10
patients) and may reflect different pretransfer respiratory
care strategies. Outborn infants were not treated initially
with gentle ventilation and, thus, had early exposure to
high PIP. The resultant pneumothoraces (as well as
increased need for iNO and HFOV) may have reflected
aggressive respiratory management in patients with adequate but small lung volumes, rather than the presence

of extreme pulmonary hypoplasia. In the CDH infant


treated from birth with gentle ventilation, emergent tube
thoracostomy is an ominous sign.
The use of the OI, although easily manipulated, may
serve as another predictor of mortality and survival rates.
In inborn infants, a 6 hour OI greater than 20 indicated
patients with an increased risk of mortality (100% sensitivity, 80% specificity). In this inborn cohort, the overall oxygenation indices were low, reflecting the low
PIPs used with a gentle ventilation strategy and the
aggressive weaning of administered oxygen based on a
preductal saturation range, rather than a population of
infants with less severe disease. The infant treated with a
gentle ventilation strategy, therefore, requires analysis
using a lower range of oxygenation indices. In outborn
patients, the OI of 20 was not a useful tool, reflecting that
before transfer, infants often had been treated with other
strategies (including hyperventilation) in the first 6 hours
of life.
We speculate that treating patients with gentle ventilation, delayed surgery, and no chest tube during repair
may decrease mortality rate and ECMO need by lowering the incidence of iatrogenic pulmonary injury. With
this strategy, most infants without associated anomalies
(coexisting severe extrapulmonary defects or lethal lung
hypoplasia) can be treated with conventional ventilation
modes alone. Furthermore, the expected survival rate of
the patient with isolated CDH may be as high as 86.3%
to 88.7%. Although the 6-hour OI may have limited
prognostic value, tension pneumothorax in the gently
ventilated patient is a grave prognostic sign.

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Discussion
D. Kays (Gainesville, FL): Congratulations, Charlie,
for a superb series and presentation, and thank you for
asking me to review your manuscript. I must tell the
audience that I am a disciple of Dr Stolar and Dr Wung,
having trained at Babies Hospital from 1990 to 1992.
This allows me to both applaud you and to ask difficult
questions. I know you would do the same for me.
What we have heard is a very large consecutive
unselected series of CDH with a 76% survival rate from
the center that has defined gentle ventilation. This is a
remarkable achievement, and I congratulate you. The
central message that you have been teaching for 15 years,
that lung parenchyma must be preserved and not injured,
by the application of a strict pressure-limited ventilation
strategy, is crucial. What is equally important in this era
of high technology is that a new machine or a new drug
is not the answer. Application of high-frequency oscillatory ventilation, nitric oxide, and surfactant did not
affect survival rate appreciably. Lest the audience think
that these results are unique to Charlie Stolar and Jen
Wung and cannot be exported, we have been treating
patients similarly since 1992 and have reported 60 consecutive patients in the Annals of Surgery. We currently
have 80 consecutive patients with an 80% overall survival rate and 92% survival rate of inborn patients with
isolated CDH. I will limit myself to 2 questions.
First, what is the anatomic distribution of your
defects? How did patients with liver in the left chest
do? Your outstanding survival rate may help to define
the indications, or lack thereof, for prenatal surgical
interventions.
Two, why did you do a calculation of survival of a
subset of patients after removal of 10 patients with lethal
lung hypoplasia? Although I understand removing pa-

tients with other lethal anomalies, removing patients


from CDH survival statistics because of lung hypoplasia
is a very slippery slope and one I think we should avoid.
Charlie, I congratulate you on your presentation and
results. Your work is the single major reason that several
centers in the United States now report overall survival
rates of greater than 70%. We and the diaphragmatic
hernia population owe you a great debt of gratitude.
C.J.H. Stolar (response): The first question about the
lateralitythey were two thirds on the left and one third
on the right. That made no difference in outcome.
You asked about why I eliminated those 10 patients
that had overwhelming pulmonary hypoplasia. In 1984,
Peter Dillon and I published that report indicating those
selection criteria based on preductal oximetry, and to
some degree I regret ever having written that, because I
have been pilloried every time I have been in front of an
audience since, but we have been consistent about that
because I believe that some infants, albeit a minority,
who have overwhelming pulmonary hypoplasia. Extracorporeal life support, inhaled nitric oxide, surfactant,
whatever you want to treat with, are all treatments for
pulmonary hypertension or lung injury. They are not
treatments for pulmonary hypoplasia. Perhaps our fetal
intervention colleagues will figure out a way to successfully treat that small subset of infants with overwhelming
hypoplasia, but they remain an important subset, and I do
not think it is realistic to treat those patients with ECMO.
In fact, I think you hurt those children if you place them
on extracorporeal life support with no exit strategy. I
know you have been at our hospital, you know what that
situation can look like, and many people in this room
know what that looks like. So we have disciplined
ourselves not to get into treating these patients if we

366

cannot see a way to get out. As I showed you, it is only


8% of 120 patients we determined to have overwhelming
hypoplasia as proved by their autopsy findings, so I am
very comfortable with that. I do not think it is a slippery
slope at all.
K. Lally (Houston, TX): I appreciate you not asking
me to review your manuscript (laughter) and would
plead with you to come up with some type of objective
risk stratifications. I am not comfortable with the decision that it is an arbitrary, we dont think they are going
to survive. I question you, have you done any risk
stratification? Have you looked at how your patients
compare objectively? When we look at the registry data,
the high-risk patients range from 2% to 30% among
high-volume institutions, and that has a profound impact
on overall survival rate. Another question is, there is still
a 10% to 15% mortality rate in this group, and do you
have any other suggestions on what to do?
C.J.H. Stolar (response): I know it is very difficult to
do risk stratification because there is variability from
center to center in the way patients are managed. There
is variability within centers, so we can only look atit is
hard to have apples and apples. We sort of have apples
and figs, so it has been very difficult, but the prognostic
features that have been reliable for us have been the
preductal oximetry. I also should add that infants that
develop a spontaneous pneumothorax in the transitional
nursery, we have had 11 of those, none of whom have
survived, and a systematic approach that you are advocating through the registry I recommend and I applaud. It
is just difficult to get apples and apples to compare.

BOLOKER ET AL

A. Coran (Ann Arbor, MI): I just want to address one


of the issues you discussed, and that is the use or nonuse
of chest tubes. You used no chest tubes in any of the
patients. Were there any complications that were associated with that, such as a persistent pleural effusion or a
chylothorax?
C.J.H. Stolar (response): The pleural space is driven
to be obliterated. If there is not active bleeding and there
is no air leak, the pleural space will be filled by fluid. If
you put a chest tube in to drain it, you are just going to
drain that fluid, and it is another output to chase. We have
had no consequence the only circumstance in which
we place a chest tube is for active bleeding, all in the
ECMO patients, or an active air leak. Otherwise, we have
not placed it. We have had no chylothorax. It is really a
pneumothorax ex vacuo if you will. It does fill up with
fluid but not at the expense of lung volume.
C. Reyes (Pensacola, FL): During your selection of
patients for surgery, the timing of surgery, did you look
at the pulmonary artery pressures? Was that useful to you
for deciding the timing of surgery?
C.J.H. Stolar (response): The pulmonary pressures are
difficult to measure directly, but by duplex Doppler scan
you can look at the position of the ventricular septum, the
degree of mitral regurgitation, and you can look at the
acceleration index in the pulmonary artery and extrapolate a blood pressure, or at least a pulmonary vascular
resistance, and that combined with pre- and postductal
gradient is evidence that the pulmonary hypertension had
resolved. That is how we did it. You cannot actually
measure the number directly but you can interpret it.