PREVIOUS ISSUES - JANUARY 2004
January 2004 Volume 1 Issue 5
COURSE DIRECTORS
Edward E. Lawson, M.D.
Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine
Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine
Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine
Lorraine A. Harbold, R.N., M.S.
The Johns Hopkins Hospital;
NICU Education Coordinator
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In this issue... Volume 1, Number 5

Our focus this month is on Congenital Diaphragmatic Hernia (CDH). Despite generalized improvements in neonatal mortality over the last decade, the mortality of infants with CDH has remained frustratingly consistent (1). The primary limitation to survival is the degree of pulmonary hypoplasia that is associated with the diaphragmatic defect.

Are outcomes predetermined in patients with congenital diaphragmatic hernia? This month we review investigations into the three main areas of research in this field:
  • measures that predict outcome
  • therapeutic interventions to alter outcome, and
  • efforts to understand the mechanisms of the defect.
Reviews
Tami Hutton Garmany, MD

Commentary
Aaron Hamvas, M.D.
Commentary
Our guest editor opinion
INVESTIGATING THE PATHOPHYSIOLOGY OF CDH
PREDICTING OUTCOMES
TREATMENT: EARLY VERSUS LATE TERM DELIVERY
CHALLENGING CONVENTIONAL TREATMENT THEORY: THE FLORIDA EXPERIENCE
CHALLENGING CONVENTIONAL TREATMENT THEORY: THE COLUMBIA EXPERIENCE
TREATMENT: FETAL SURGERY TECHNIQUE
REFERENCES AND ADDITIONAL SOURCES OF INFORMATION
Guest Editors of the Month
Tami Hutton Garmany, M.D.
Newborn Medicine Fellow
Division of Newborn Medicine
Washington University
St. Louis Children's Hospital
Aaron Hamvas, M.D.
Professor of Pediatrics
Division of Newborn Medicine
Washington University
St. Louis Children's Hospital

Guest Faculty Disclosures

Tami Hutton Garmany, MD
Faculty Disclosure: Dr. Garmany receives support from the National Institutes of Health.

Aaron Hamvas, M.D.
Faculty Disclosure: Dr Hamvas receives grant and research support from the National Institutes of Health.

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COMMENTARY
The ability to quantify the extent of the hypoplasia and predict the outcomes has remained elusive, whether by ultrasonographic measurements or indices of gas exchange. While these indices may permit some stratification for clinical research purposes, they fail to be either sensitive or specific enough to permit directed care.

Two interventions have received significant attention. "Permissive hypercapnea" challenges the dogma of treating the associated pulmonary hypertension with hyperventilation and attempts to minimize ventilator induced lung injury. While survival rates of 70-80% provide optimism and indicate that this strategy is probably not harmful, we need to interpret these studies cautiously. First, they have been primarily retrospective and focus on the changes in respiratory management over time, often neglecting parallel improvements in newborn care, such as aggressive nutritional intervention. Second, 60-70% of the mortality occurs within the first 24-48 hours after birth, a timeframe in which ventilator-induced lung injury is unlikely to be the operative explanation for improved survival. Fetal intervention, while showing promise in animals with experimentally induced CDH, has been disappointing in human trials. Attempts to repair the diaphragmatic defect or occlude the trachea to improve lung growth have been successful from a technical standpoint, but have resulted in premature birth, which masks the effectiveness of the interventions (2).

These trials illustrate some important points. First, the factors that determine pulmonary outcome of CDH apparently play a role much earlier in gestation than can be addressed by intervention at 22 weeks gestation or beyond. Second, these observations suggest that the animal models, while simulating the mechanical features of CDH, do not adequately recapitulate the basic embryologic defect(s). Jesudason, et al, through their series of studies examining the roles of growth factors in lung development, raise the critical question: which comes first, a disruption of lung development with subsequent disruption of diaphragm development, or vice-versa? (3) It is likely that these disparate mechanisms are responsible for the disparate pulmonary outcomes of these infants.

Continuing collaboration between the basic, surgical, neonatal, and nursing sciences will be necessary to understand the genetic, developmental, and environmental factors that cause CDH, and to improve the care and outcomes of these infants.

INVESTIGATING THE PATHOPHYSIOLOGY OF CDH 
Jesudason, EC. Challenging embryological theories on congenital diaphragmatic hernia: future therapeutic implications for paediatric surgery. Ann R Coll Surg Engl 2002;84: 252-259.

A series of animal experiments challenges the theory that lung hypoplasia results from extrinsic compression in diaphragmatic hernia.
These experiments used the pesticide nitrofen to induce CDH and lung hypoplasia in rats. At the equivalent of 4.5 weeks human gestation and prior to diaphragmatic herniation, nitrofen-exposed lung primordia already had fewer terminal buds than normal lungs.

In subsequent experiments, terminal bud counts were recorded daily and lung epithelia were evaluated. Both normal and nitrofen-exposed lungs increased in size and branching, but the nitrofen-exposed lungs had reduced lung area, lung perimeter and terminal bud count. There were morphological differences between the two groups as well.

The third and fourth experiments involved the impact of growth factors on lung development. FGF1 binds FGFR2IIIb while FGF2 essentially does not. Binding of the FGFR2IIIb receptor is essential for lung branching morphogenesis. Heparin modulates FGF kinetics. Normal lungs responded to FGF1+heparin with increased terminal bud counts, lung epithelial area and lung perimeter while nitrofen-exposed lungs did not. FGF2 alone had minor effects on normal lungs and FGF2+heparin was inhibitory. Nitrofen-exposed lungs with FGF2 alone had increases in lung area and reductions in terminal bud count while FGF2+heparin transiently and modestly altered lung morphogenesis.

In the fourth experiment, epidermal growth factor (EGF) was cultured with embryonic lung explants. In normal lungs, EGF produced minor inhibitory changes in morphological development while in nitrofen-exposed lungs, EGF yielded moderate morphological changes.

The author concluded that lung hypoplasia begins during embryogenesis and prior to the diaphragmatic defect. A 36% incidence of stunted nitrofen-exposed lungs correlates well with the 30-40% incidence of CDH subsequently seen in these animals and supports the theory that lung hypoplasia occured before the hernia. Secondly, nitrofen-exposed lungs respond abnormally when cultured with heparin and/or certain FGFs. Growth factor signaling may be perturbed in the hypoplastic lung.
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PREDICTING OUTCOMES
Lipshutz GS, Albanese CT, Feldstein VA, Jennings RW, Housley HT, Beech R, Farrell JA, Harrison MR. Prospective Analysis of Lung-to-Head Ratio Predicts Survival for Patients With Prenatally Diagnosed Congenital Diaphragmatic Hernia. J Ped Surg 1997; 32(11): 1634-1636.

Accurate prediction of outcome for fetuses with CDH is difficult. This prospective study measured lung-to head ratios (LHR) in fetuses with left-sided diaphragmatic hernias and correlated these ratios to outcome.
Fifteen patients with sonographically identified left-sided CDH were prospectively referred to the UCSF Fetal Treatment Center for evaluation. Sonography was repeated by one of four experienced sonographers and fetal lung-to-head ratio (LHR) was determined between 24-26 weeks estimated gestational age. Postnatal care took place at UCSF or another tertiary care facility.

The principal outcome variable was survival at 60 days after optimal postnatal care, including high frequency ventilation, inhaled nitric oxide, and ECMO if necessary. Need for ECMO support was a secondary outcome. Overall survival rate was 47% with pulmonary insufficiency responsible for all mortality. Survivors had a LHR of 1.4 ± 0.33 and non-survivors had LHR of 1.05 ± 0.3 (P < .05). All fetuses with a LHR of less than 1.0 died and all fetuses with a LHR greater than 1.4 survived. ECMO support was needed for all patients with a LHR < 1.0, seventy-five percent of patients with a LHR between 1.0 and 1.4, but only one of four patients with LHR > 1.4.

The authors conclude that LHR can be a reliable measure used as an adjunct in predicting postnatal survival with conventional therapy or ECMO support, although it is dependent on sonographic technique and gestational age.
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TREATMENT: EARLY VERSUS LATE TERM DELIVERY
Stevens TP, Chess PR, McConnochie KM, Sinkin RA, Guillet R, Maniscalco WM, Fisher SG. Survival in Early- and Late-Term Infants With Congenital Diaphragmatic Hernia Treated With Extracorporeal Membrane Oxygenation. Pediatrics Sept 2002; 110 (3), Sept 2002: 590-596

The optimal gestational age for delivery of infants with CDH is unknown. This study compared outcomes in infants born early-term versus those born late-term.
Data from the Extracorporeal Life Support Organization Registry for infants with CDH treated with ECMO were obtained retrospectively from four time periods: Era 1: April 1976-1985; Era 2: 1986-1990; Era 3: 1991-1995; and Era 4: 1996-June 2001. Within each era, infants born at early-term (38 0/7 to 39 6/7 weeks) were compared to those born at late-term (40 0/7 to 41 6/7 weeks).

The relative survival rate for late-term infants was almost 20% greater than for early-term infants. Early-term infants who survived ECMO were on ECMO longer and had longer hospital stays than late-term infants. Gestational age did not independently predict survival but was correlated with birth weight, which was associated with improved survival.

Patient data associated with survival was analyzed by era to identify trends in characteristics of infants treated with ECMO over time. The percentage of infants born early-term increased (40% in Era 1 to 57% in Era 4) as did the percentage of prenatal diagnoses (4% to 51%). In Era 4, early-term infants were more likely to suffer a renal, neurologic, and hemorrhagic complication than were late-term infants (50% vs 40%). The respiratory severity parameters (PIP ≥ 40 and PaO2/FiO2 < 0.4) at initiation of ECMO decreased over the 4 eras and there were no significant differences in the incidences of low arterial pH (<7.2) or elevated pCO2 (>50 torr) between the early- and late-term infants over the 4 eras.

With greater birth weight having a protective effect against complications on ECMO, the trend toward earlier delivery and at lower birth weights may contribute to higher complication rates on ECMO. The authors conclude that for the approximately 50% percent of infants with CDH that are treated with ECMO, clinical outcomes may be improved by delay of elective delivery until 40 weeks completed gestation.
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CHALLENGING CONVENTIONAL TREATMENT THEORY: THE FLORIDA EXPERIENCE
Kays DW, Langham MR, Ledbetter DJ, Talbert JL. Detrimental Effects of Standard Medical Therapy in Congenital Diaphragmatic Hernia Annals of Surgery September 1999; 230 (3): 340-351

This study, from the University of Florida demonstrated improved survival with permissive hypercapnea, gentle ventilation and delayed surgical repair in infants with CDH.
This retrospective cohort study grouped patients into 3 eras based on treatment strategies.
  • Era 1 included 12 infants treated with paralysis, hyperventilation, alkalization, hyperoxia, and surgical repair within the first 24 hours. ECMO was not available.


  • Era 2 included 14 patients treated with paralysis, hyperventilation, alkalization, and ECMO if needed. Ventilator pressures were moderated and hyperoxia was used less vigorously. Surgery was delayed for >24 hours in most patients.


  • Era 3 included 53 infants treated with low pressure ventilation and sedation but not paralysis. Bicarbonate was given if the arterial pH was below 7.20. Inhaled NO and ECMO were used if necessary. Surgery was delayed for at least 24 hours or until the patient was stable.
Survival rates were 17% in era 1, 50% in era 2, and 89% in era 3. Birth weight, gestational age, Apgar score at 1 and 5 minutes, and the incidence of serious but nonlethal anomalies were similar in all three groups. The number of infants with liver and or stomach herniated into the chest was similar in all groups. The number of prenatally diagnosed hernias rose significantly from era 1 to 2 to 3 (from 0 to 36% to 41%). In eras 1 and 2, hyperventilation was successful in decreasing PaCO2 initially but was not sustainable. The incidence of pneumothorax decreased throughout the eras. The addition of NO did not improve survival or decrease the need for ECMO. The need for ECMO did not change between eras 2 and 3. ECMO survival increased significantly in era 3 (29% in era 2 and 83% in era 3).

The authors concluded that hyperventilation and alkalization had detrimental effects on infants with CDH. Abandoning these treatment modalities, along with the use of gentle ventilation, improved survival with and without ECMO.
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CHALLENGING CONVENTIONAL TREATMENT THEORY: THE COLUMBIA EXPERIENCE
Boloker J, Bateman DA, Wung JT, Stolar CJH. Congenital Diaphragmatic Hernia in 120 Infants Treated Consecutively With Permissive Hypercapnea/Spontaneous Respiration/Elective Repair J of Ped Surgery March 2002; 37 (3).

The results of this large retrospective study indicate that conventional treatments may increase the incidence of iatrogenic lung injury and thereby reduce survival
Data from 120 infants with CDH were collected retrospectively. All infants were placed on conventional "low-rate" ventilation. If this protocol was not adequate, the infant was changed to high frequency positive pressure ventilation (HFPPV) and then to HFOV if necessary. PIP was kept <25 if possible. Oxygen was given to maintain preductal saturations 90-95% and was weaned to keep delivery at a minimum. Hyperventilation and muscle relaxants were not used. Sedation was used sparingly with no continuous infusions. Inhaled NO and ECMO were initiated if necessary. Surgery was delayed until the ductal saturation gradient subsided, echocardiography showed minimal evidence of pulmonary hypertension, and ventilator support was minimized. No infant had surgical repair before 36 hours of life. No prophylactic chest tubes were placed.

No survivors required a PIP >25, while 58% of non-survivors required PIP >25. 50% of survivors required HFPPV to ventilate, while 78.2% of non-survivors were treated with HFPPV. ECMO was used in 8.9% of patients. Non-survivors had lower pH and higher PaCO2 values at all times despite using higher PIP values. Survivors exhibited decreasing FiO2 requirements and an average PaCO2 of 47.4 ± 9.3 over the first day of life. Only a moderate increase in ventilator management was needed postoperatively. No patient required ECMO postoperatively if not required preoperatively. The survival rate was 75.8%, excluding lethal anomalies, pre-ECMO neurological complications and lethal lung hypoplasia.

The authors conclude that preventing iatrogenic lung injury, thus decreasing the need for ECMO, improves survival. They postulate that intraoperative chest tube placement causes hyperinflation of the hypoplastic lung, leading to increased pulmonary vascular resistance, lung damage and cardiopulmonary instability. Finally, the study demonstrated that delayed surgical repair was associated with decreased ECMO need and improved survival rate, leading the authors to conclude that a more stable infant is better able to tolerate the decreased compliance following surgery.
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TREATMENT: FETAL SURGERY TECHNIQUE
Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA, Albanese CT. A Randomized Trial of Fetal Endoscopic Tracheal Occlusion for Severe Fetal Congenital Diaphragmatic Hernia N Engl J Med Nov 13, 2003; 349 (20): 1916-1924

Occlusion of the trachea was shown to stimulate lung growth in a number of animal models. Initial studies also suggested improved survival in human fetuses with severe CDH. This is the first randomized, controlled trial in humans to evaluate this technique
Twenty-four women carrying fetuses 22-27 weeks gestation with left-sided CDH were randomized to fetal endoscopic tracheal occlusion (n=11) or standard care (n=13). Eligibility requirements included liver herniation, no preterm labor, and LHR <1.4, determined previously by these authors to correspond to a survival rate of approximately 20%. Randomization was stratified according to LHRs. The primary outcome was survival at 90 days of life.

Infants in both groups were intubated in the delivery room and given pancuronium and sedatives. Conventional ventilation was used with the goal of maintaining pCO2 45-60 mmHg and preductal oxygen saturations >90%. If ventilation and oxygenation were inadequate, HFOV, iNO, and ECMO were used. Surgery was performed when the infant's respiratory status had stabilized.

Morbidity in the intervention group included preterm premature rupture of membranes in all women and chorioamnionic separation in 64% of the women. Infants in the intervention group were delivered at a mean gestational age of 30.8 ± 2.0 weeks, while the mean in the control group was 37.0 ± 1.5 weeks. There was no difference in survival between the two groups of infants (77% of controls vs. 73% of intervention). Overall, there was a direct association between higher LHR and increased survival. There were no differences in the rates of respiratory, gastrointestinal, or neurologic complications and no differences in the ages at time of repair, extubation, or discharge, or in the proportion of infants requiring supplemental oxygen at discharge.

Enrollment in the study was terminated early due to the absence of a significant difference in outcome between the two groups of infants as well as a higher than expected survival rate in the standard care group. The authors concluded that fetal tracheal occlusion did not improve outcome for fetuses with severe CDH over standard care. They postulate that the benefits of improved lung growth due to fetal tracheal occlusion may be outweighed by the adverse effects of premature delivery caused by the intervention.
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REFERENCES AND ADDITIONAL SOURCES OF INFORMATION:
(For non-journal subscribers, an additional fee may apply for full text article)

1. Stege G, Fenton A, Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatrics 2003; 112:532-535
 view journal abstract  view full article  back to top

2. Sydorak RM, Harrison MR. Congenital diaphragmatic hernia: advances in prenatal therapy. Clin Perinatol 2003; 30:465-479.
 view journal abstract    back to top

3. Jesudason EC. Challenging embryological theories on congenital diaphragmatic hernia: future therapeutic implications for paediatric surgery. Ann R Coll Surg Engl 2002; 84:252-259.
 view journal abstract  view full article  back to top
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