- Email: [email protected]
The Fetal Heart in Diaphragmatic Hernia
CONGENITAL DIAPHRAGMATIC HERNIA
0095-5108/96 $0.00 + .20
THE FETAL HEART IN DIAPHRAGMATIC HERNIA Lindsey D. Allan, MD, Michael S. Irish, MD, and Philip L. Glick, MD
Despite optimal perinatal care of infants born with congenital diaphragmatic hernia (CDH), the mortality of the patients remains exceedingly high. This as yet unexplained mortality, or "hidden mortality" as coined by Harrison et al 8 in 1994, has recently led us to suggest the possible role of cardiac maldevelopment as "a missing link" in the high mortality of infants with CDH. 16 It has also been suggested that leftventricular disproportion may be used as a predictor of fetal outcome. Although a number of prenatal prognostic indicators for CDH have been proposed (fetal age at the time of diagnosis, the presence of fetal bowel within the chest, mediastinal shift), none have correlated well with postnatal morbidity and mortality. 6• 9• 10• 17 Sharland et al, 26 however, in a retrospective review of 55 cases of CDH diagnosed prenatally, demonstrated the relative prognostic indicators of gestational age at the time of diagnosis, ratios of aortic to pulmonary artery (Ao/PA) diameters, and of left-to-right ventricular maximum width ratios obtained on fetal ultrasound. In their series, reduced left-to-right ventricular ratios and Ao/PA ratios, and diagnoses before 25 weeks' gestation each correlated with a higher mortality when cases of elective termination and congenital heart disease were excluded. The pulmonary hemodynamic pathophysiology of CDH has been well documented. Hypoplastic pulmonary arteries and increased pulmonary artery muscle mass, along with pulmonary hypoplasia, derange-
From the Division of Pediatric Cardiology, Babies Hospital 2N, Columbia Presbyterian Medical Center, New York (LDA); and the Departments of Pediatric Surgery (MSI, PLC) and Pediatrics (PLC), The Buffalo Institute of Fetal Therapy, The Children's Hospital of Buffalo, Buffalo, New York
CLINICS IN PERINATOLOGY VOLUME 23 • NUMBER 4 • DECEMBER 1996
795
796
ALLAN et al
Table 1. TOTAL AND COMPONENT HEART WEIGHTS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMBS*
Group
Right and Left Atria
Right Ventricle
Left Ventricle
Interventricular Septum
Total Heart
CDH (n=7) Control (n = 7)
0.68±0.06t 1.14±0.15
1.26±0.07 1.57 ± 0.17
1.65±0.11t 2.15±0.19
1.25±0.11t 1.99±0.21
4.88±0.25t 6.75±0.49
'Data expressed as g/kg lamb, mean ± standard error. tP < 0.05 for CDH versus control littermates.
ments in gas exchange, and delayed closure of the ductus arteriosus, all lead to pulmonary hypertension in the neonate with CDH. It has been suggested that a primary cardiac abnormality in isolated CDH may contribute pathogenetically despite these alterations in pulmonary circulation.7 Seibert et al,25 in a human autopsy study, found that newborns with left-sided CDH had smaller left ventricles, interventricular septums, and atria as compared with age-matched controls. Similar observations have been made sonographically, demonstrating a significantly lower left-ventricular mass index in patients with left-sided CDH compared with a control group of patients with other causes of pulmonary hypertension. 24 A lower left-ventricular mass index was also observed in CDH patients who required ECMO and in nonsurvivors. In a study utilizing the fetal lamb model of CDH, Karamanoukian et al1 4 demonstrated that total heart weight and left ventricular, septal, and atrial weights are significantly decreased when compared to littermate controls3 (Table 1). They also found identical DNA to protein ratios of the left ventricles of both CDH and controls, implying that the decreased weight of the left ventricle in CDH is caused by hypoplasia (Table 2). Interestingly, although in utero surgical repair of CDH in lambs corrects these cardiac morphometric abnormalities, in utero tracheal ligation does not. 18 Presumably, although the enlarged lungs resulting from tracheal ligation cause reduction of the herniated abdominal viscera, they also act as an intrathoracic, space-occupying mass and prevent normal cardiac development. Furthermore, when Ao/PA root ratios were evaluated, the authors found no difference in the aortic root Table 2. DNA AND PROTEIN ANALYSIS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMB HEARTS*
Group
Aortic (Ao) Root
Pulmonary Artery (PA) Root
Ductus Arteriosus
Ao/PA Ratio
CDH (N=8) CDH (N=5)
0.37±0.01 0.37±0.01
0.47±0.01t 0.38±0.01
0.35±0.01t 0.22±0.02
0.81±0.01 t 1.00±0.03
*Data expressed in centimeters, mean ± standard error. tP<0.005 for CDH versus control littermates.
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
797
Table 3. AORTIC (Ao), PULMONARY ARTERY (PA), AND DUCTUS ARTERIOSUS (DUCTUS) DIAMETERS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMBS* Groupt
Protein
DNA
DNA/Protein
Hydroxyproline
Elastin
CDH RV CDH LV CONTROL RV CONTROL LV
98±12 80±20 95±27 109±38
1.37±0.38 2.00±0.59 1.60±0.48 1.70±0.33
0.011 ±0.003 0.015 ± 0.004 0.013±0.005 0.015 ± 0.006
0.519±0.03 0.586±0.05 0.538±0.04 0.514±0.99
0.45±0.36 0.61 ±0.12 0.69±0.34 0.61 ±0.18
RV = right ventricle; LV = left ventricle. *Data expressed as mg/kg heart weight, mean ± standard error. tN = 10 for each group.
diameters between CDH and controls, suggesting that the observed decrease in Ao/PA root ratio was caused by an increase in PA diameter. Ductus arteriosus diameters were also significantly greater in CDH animals (Table 3). Their observations were supported by earlier sonographic data on human fetuses with CDH. 26 The authors hypothesized that left-ventricular hypoplasia may result from in utero increased left atrial pressure (from compression of the herniated abdominal viscera), decreased right-left shunting through the foramen ovale, and increased PA pressures and flow, thus increasing both PA and ductus arteriosus diameters. 14 Although lung hypoplasia seems to relate to morbidity and mortality, it is difficult to quantify this technically. Karamanoukian et al1 7 have gone on to demonstrate a predictive correlation between heart weight and lung weight in the neonatal lamb with surgically created CDH (Fig. 1). They speculate that similar data, obtained from prenatal echocardiographic parameters of cardiac volume and mass, may be helpful in identifying fetuses with lethal pulmonary hypoplasia. Thus, the status of the fetal heart in CDH may well be the "missing link" in predicting outcome as well as a useful criterion for those fetuses that should be considered for in utero intervention. BACKGROUND AND PERSONAL EXPERIENCE (DR. ALLAN)
Over the last 16 years, the fetal heart of just over 100 cases of diaphragmatic hernia has been studied in two centers: Guy's Hospital in London during a 13-year period, and Columbia Presbyterian Medical Center (CPMC) in New York over a 3-year period. In both series, the population seen has been selected for referral to tertiary centers, so it is not entirely representative of the whole spectrum of this disease. This is reflected in the rate of chromosomal anomalies, which was 6 of 38 cases (16%) in the series reported by Adzick,1 4% in the Guy's series of 72 cases, and none of 21 cases seen at CPMC. In the Guy's series, patients were referred for a cardiac scan as part of the primary evaluation, whereas in the CPMC series, in most cases, the heart was evaluated as
798
ALLAN et al
200-
.-..
150-
s
-
"
Lung wt= ·0.004 x Heart wt+ 135
"" " "
.c
Cl
·a; 3::
100
Cl
c:
0
:I
..J
50- Lungwt -- 0 ·69 x Heart wt + 37
0 0
I 10
0 0
0
n
0 CID
0100
I 20
0
0
0 u
0
I 30
I 40
I 50
Heart weight (g) Figure 1. Regression analysis of the relationship between lung weight (in grams) to heart weight (in grams) in CDH lambs (circle) and control lambs (triangle). Analysis of variance, F= 182.75; P< 0.001. CDH =congenital diaphragmatic hernia.
part of a presurgical work-up. As a result, more than 50% of patients in the Guy's series were seen prior to 24 weeks' gestation as compared with only 14% at CPMC. In many cases presenting to CPMC, however, the diagnosis had been made earlier in pregnancy, but patients were seen by us only when they transferred to our center for late prenatal care and delivery with a view to surgery.
THE FETAL CARDIAC EXAMINATION
Three aspects of fetal cardiac examination are important in the assessment of a fetus with a diaphragmatic hernia. In the normal fetus, the heart and lungs comfortably occupy the space the thorax provides in a state of mutual synergism. The intrusion into the thoracic cavity of any portion of abdominal contents necessarily alters this and produces mechanical effects on the heart as well as the lungs. Second, the "insult" in embryologic or early fetal life that caused the diaphragmatic defect can also damage the concurrently developing heart. There is therefore an increased incidence of structural cardiac malformations. Finally, the normal characteristics of cardiac physiology are altered in the presence of a thoracic mass, and the evaluation of some of these parameters may help in predicting the severity of lung hypoplasia or the outcome of neonatal surgery.
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
799
MECHANICAL EFFECTS OF A DIAPHRAGMATIC HERNIA ON THE FETAL HEART
Basically, any space-occupying lesion within the confines of the thorax can displace heart or lung tissue from their normal positions. It seems clear that the site and size of the diaphragmatic defect will influence the volume of abdominal contents that herniate into the chest. In addition, the timing during pregnancy at which herniation occurs appears to vary. 2 These variations will influence the cardiac findings. In the common left-sided defect, the heart is shifted into the right chest with varying degrees of severity. Similarly, in the more rare right-sided hernia, the liver displaces the heart further to the left than normal. These signs are seen in the four-chamber view of the heart. In the normal fetus, the right lung lies between the right atrium and part of the right ventricle, and the lateral chest wall (Fig. 2). Most of the heart, comprising half of the left atrium, the left ventricle, and most of the right ventricle, lies in the left half of the chest. The interventricular septum is at an angle of about 40 degrees to the midline, although this shows some variation ( + 20 degrees) in normals. 27 An example of a diaphragmatic hernia is seen in Figure 3. Both right atrium and right ventricle are in apposition to the right chest wall, and the whole heart
Figure 2. In this normal four chamber view of the heart, there is lung tissue between the right atrium and part of the right ventricle and the right chest wall. If the thorax is divided equally in two from the spine, most of the heart lies in the left chest with the interventricular septum at an angle of about 40° to the midline. RA= right atrium, LA= left atrium, LV =left ventricle, RV= right ventricle.
800
ALLAN et al
Figure 3. In this fetus with a diaphragmatic hernia, the heart lies completely in the right chest, with the right atrium and right ventricle directly against the thoracic wall. The interventricular septum is almost parallel to the midline. The stomach position is related to the left ventricle. The left atrium is small and the left ventricle smaller than the right. ST=stomach, RA= right atrium, LV=left ventricle, RV=right ventricle.
lies in the right chest. The ventricular septum is oriented almost parallel to the midline of the thorax. The stomach is varied in its position relative to the heart, and it is also variously dilated, although this is likely to be dynamic (Figs. 4 and 5). In the majority of fetuses with left-sided diaphragmatic lesions, the left heart is smaller than the right. This has been described in a previous publication. 26 The left ventricle/right ventricle (LV /RV) ratios found previously are similar to the results shown in Figure 6 in a smaller, recent series of 21 cases. In about a third of cases, even the absolute cardiac size is smaller than normal, as shown by the cardiothoracic ratio compared with normal (Fig. 7). As can be seen from the graphs, however, neither of these measurable parameters appear to have a clear relationship to the outcome. The size or growth of the cardiac chambers and vessels in part depends on the blood flow they receive. Normally, the left ventricle receives about 45% of the combined cardiac output, falling to about 40% in the last 10 weeks of pregnancy. 22 In the human fetus, about 20% of the combined cardiac output goes to the lungs and then returns to the left atrium in the pulmonary veins. 28 A further 25% of combined cardiac output, falling to 20% in later pregnancy, reaches the left ventricle through the foramen ovale. This jet of blood is a well-oxygenated stream derived from the ductus venosus, which passes through the inferior
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
801
Figure 4. In this fetus with a diaphragmatic hernia, the stomach lies behind the heart in the right chest. The left atrium is small and the left ventricle mildly smaller than the right ventricle. ST= stomach; RA= right atrium; LV =left ventricle; RV= right ventricle.
Figure 5. In this fetus with a diaphragmatic hernia, the stomach is dilated and close to the left ventricle. The left atrium is small and the left ventricle smaller than the right ventricle. ST= stomach; RA= right atrium; LA= left atrium; RV= right ventricle; LV =left ventricle.
802
ALLAN et al
1.2 1.1 1.0 0.9 0.8 0
:;::; ca
0.7
>
0.6
>
0.5
a: a:
....J
ot*
0.4 0.3 0.2
t* Termination of pregnancy 0.1
t
Died
0 14
16
18
20
22
24
26
28
30
32
34
36
38
40
Gestation Figure 6. The left ventricle to right ventricle (LV/RV) ratio is plotted for the fetuses with diaphragmatic hernia. The ratio value fell below the fifth centile in the majority of patients. The fetus with a ratio above the normal range had a right-sided hernia. The lines represent sequential studies in the same patient. Two patients elected to interrupt the pregnancy. There were three deaths in the continuing left-sided lesions. The fetus with the abnormally high LV/RV ratio who died had a right-sided hernia. 111 = 95th centile; ..6. = normal centile; o = fifth centile; o = patient values.
vena cava to the foramen. The mechanism of the relative underdevelopment of the left heart is probably a combination of decreased pulmonary venous return because of diminished lung mass and a decrease in the interatrial shunt. The latter is evidenced by the documentation of left to right shunting at the foramen ovale in the affected fetus. The relative diminution of left heart blood flow results in the left heart (affecting the left ventricle, aorta, and aortic arch) being smaller than normal at delivery. This has been associated with a poorer outlook for corrective surgery, but the association is not clear-cut. 25 ' 26' 29 The absolute size of the left ventricle may be related to the position of the stomach relative to the left atrium, the pressure within the stomach, or the timing during pregnancy of the passage of the stomach into the chest. Alternatively, it may be that a smaller left ventricle simply reflects a larger mass of abdominal contents within the thorax and therefore smaller lung volume, which would in turn negatively influence the outcome.
803
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
0.60 0.55 0.50
0
0
ot*
0.45
0
0.40
ot*
0 0.35 :;::; II!
0:: 0.30
I.....
u
0.25 0.20 0.15 0.10
t* Termination of pregnancy 0.05
t
Died
0 14
16
18
20
22
24
26
28
30
32
34
36
38
40
Gestation Figure 7. The cardiothoracic (CIT) ratio is plotted for the fetuses with diaphragmatic hernia. The ratio value fell below the fifth centile in the some of the patients. The lines represent sequential studies in the same patient. Two patients elected to interrupt the pregnancy. There were three deaths of the continuing left-sided lesions. There is no clear relationship between absolute heart size and outcome. A = 95th centile; 11 = normal centile; 111 = fifth centile; o = patient values at first visit; o = patient values at follow-up visit.
It has been suggested that the small left ventricle at delivery may be less compliant and less able to maintain the systemic circulation, but this is not proved. In an analogous situation in total anomalous pulmonary venous drainage, the left ventricle is small and underdeveloped, sometimes into the range associated with the hypoplastic left heart syndrome, but circulatory effects are related to the obstructed pulmonary veins and not to left ventricular failure. In this setting, and in diaphragmatic hernia, after successful surgical repair the left ventricle quickly recovers and "catches up" to a normal size. There have been two examples of a right-sided hernia seen in our series. In this setting, liver tissue herniates through the diaphragmatic defect into the right thorax. In both cases, the heart was displaced further to the left than normal (Fig. 8), and the right heart may be slightly smaller than normal. This may be due to an increase in the interatrial shunt to the left in fetal life, although this cannot be proved.
804
ALLAN et al
Figure 8. The heart is seen in a four chamber view. It is displaced further to the left than normal by the liver in the right thorax. There is only a trivial portion of left lung and no right lung visible. RV= right ventricle; LV =left ventricle.
Both patients proved impossible to ventilate adequately and died soon after birth. CARDIAC MALFORMATIONS IN ASSOCIATION WITH DIAPHRAGMATIC HERNIA
There were 12 examples of congenital heart malformation seen in 72 cases in the Guy's series (20%) and 2 of 21 cases in the CPMC series (10%). This may reflect selection of fetuses with a cardiac defect referred to a fetal cardiac center in the early series and de-selection of affected fetuses (by termination of pregnancy) referred to CPMC for surgery. The types of malformation that have been seen in our series are listed in Table 4. There is much discussion on the timing of the "insult" that
Table 4. CARDIAC MALFORMATIONS ASSOCIATED WITH CONGENITAL DIAPHRAGMATIC HERNIA Ventricular septa! defect Ventricular septa! defect with pulmonary stenosis Atrioventricular septa! defect Tetralogy of Fallo! Hypoplastic left heart syndrome ? Coarctation of the aorta (suspected, no autopsy)
4 1 3 3 2 1
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
805
produces diaphragmatic hernia. The preponderance of ventricular-septal defect suggests that the insult is after 6 weeks of postconceptional life rather than before, because the ventricular septum is one of the last parts of the heart to complete its formation. The association of two cases of true hypoplastic left heart syndrome (with mitral and aortic atresia) may reflect very severe and early (less than 15 weeks) lack of left-heart blood flow, a more extreme form of the diminution of left heart flow that is seen in the later fetus, but it is probably more likely to be a primary cardiac malformation. The presence of diaphragmatic hernia with congenital heart disease indicates a poor prognosis, there being no survivors of 14 cases with this combination in our series; however, the pregnancy was interrupted in four cases, and there was a chromosomal anomaly in a further two cases. There is no reason why a small ventricular septal defect should affect the immediate postnatal course, and particularly in at least one recent case, it may have been coincidental to the outcome. There was one case in which a coarctation lesion was suspected postnatally, but the neonate died soon after birth and there was no autopsy. This is a diagnosis that is difficult to make prenatally and particularly so in the setting of diaphragmatic hernia. The signs of coarctation include the left ventricle smaller than right, the aorta smaller than the pulmonary artery, hypoplasia of the transverse arch, and reversal of the interatrial shunt. These are "normal" findings in the presence of a diaphragmatic hernia. It is probable that when the diagnosis of diaphragmatic hernia is made prior to 24 weeks' gestation, the heart is severely displaced and the left ventricle is significantly smaller than the right, particularly if CHD is suspected in addition, most obstetricians recommend termination of pregnancy. This may be appropriate advice but it should be made with caution. Two cases in our recent series were referred from experienced ultrasonographers with a false-positive diagnosis of a severe heart malformation. Furthermore, it is clear from both series that survival after surgery, despite early diagnosis and an abnormal LV /RV ratio, is possible. In our recent series, an 83% survival has been achieved in the continuing left-sided lesions. Admittedly, detailed information on the proportion diagnosed prior to 24 weeks' gestation, which would influence the results, 8 is not currently available. CHANGES IN CARDIAC PHYSIOLOGY IN DIAPHRAGMATIC HERNIA
In spite of severe cardiac displacement, there is normally no disturbance of systemic venous return to the right atrium. The hepatic vein flow profile is normal, reflecting normal right atrial pressures. As described earlier, left to right interatrial flow, a reversal of normal, can be documented by color flow mapping of the foramen ovale. This indicates that the left atrial pressure, at least at some times in the cardiac cycle, must be higher than right atrial pressure. This alteration in pressure cannot be marked because the pulmonary venous flow tracing, when it
806
ALLAN et al
can be obtained, shows a pattern that is within the normal range. This change in left atrial pressure may be related to the presence of the stomach close behind it, or it may be related to intrathoracic pressure per se. It is possible to estimate the right- and left-heart output using a Doppler velocity tracing of the pulmonary and aortic flow. This will show an increase of right-heart flow relative to the left as evidenced by the differences in ventricular sizes; however, this is not helpful in predicting the outcome, which is currently our greatest challenge. It has been suggested that alterations in branch pulmonary artery Doppler tracings can indicate "downstream" resistance and may reflect the degree of lung hypoplasia4; however, preliminary results in our recent series show an abnormal pattern of flow in cases of diaphragmatic hernia but with no clear difference between survivors and nonsurvivors (Figs. 9 and 10). This idea needs further study. In addition, it may be possible to gain a crude estimate of pulmonary blood flow by calculating flow from the Doppler profile in the pulmonary trunk and the duct and subtracting the latter from the former. This may correlate with lung volume and therefore postnatal course. This also merits further study. POSTNATAL CARDIAC CARE
Postnatally, infants who develop or maintain severe respiratory and cardiovascular distress have persistence of fetal circulation: elevated
Figure 9. A, The right pulmonary artery (RPA) flow in a normal fetus at 24 weeks gestation is seen. The systolic (SYST) and diastolic (DIAS) phases of the flow are marked. There is a notch at the end of systole as the pulmonary valve closes and forward flow in diastole. Illustration continued on opposite page
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
807
Figure 9 (Continued). B, The right pulmonary artery flow in a normal fetus at 29 weeks' gestation is seen. The systolic and diastolic phases of the flow are marked. There is forward flow in diastole. C, The right pulmonary artery flow in a normal fetus at 36 weeks gestation is seen. The systolic and diastolic phases of the flow are marked. There is forward flow in diastole.
808
ALLAN et al
Figure 10. A, The right pulmonary artery (RPA) flow in a fetus with diaphragmatic hernia at 23 weeks gestation is seen. The systolic (SYS) and diastolic (DIAS) phases of the flow are marked. There is reversal of flow in diastole. This is suggestive of a high resistance in the lung fields, but the pregnancy was interrupted so this could not be verified. Illustration continued on opposite page
pulmonary artery pressures, increased pulmonary vascular resistance, and right-to-left shunting (at the level of the foramen ovale, at the ductus arteriosus, and within the lung vasculature). A vicious circle of hypercarbia, acidosis, and progressive hypoxemia results. Upon delivery, the prenatally diagnosed infant with CDH should be transported to the neonatal intensive care unit, anticipating the need for urgent cardiorespiratory support. Appropriate monitoring should include preand postductal pulse oximetry, and arteriovenous access. A urinary catheter is placed to monitor fluid resuscitation, and a nasogastric tube is inserted to avoid visceral distension, which would lead to further intrathoracic and mediastinal compression and compromise. An echocardiogram is obtained as early as possible to assess for structural abnormalities, pulmonary hypertension, and extrapulmonary (foramen ovale and ductal) shunting. If pulmonary hypertension or systemic hypotension exist, ionotropic agents such as dopamine (2-20 µg/kg/min), epinephrine (0.1 µg/kg/ min), or dobutamine (2-20 µg/kg/min) should be used in an effort to raise the systemic above pulmonary arterial pressure. This will minimize right-to-left shunting and optimize left ventricular output. Measures to correct or prevent factors associated with an elevated pulmonary vascular resistance (hypoxia, hypercarbia, acidosis, and hypothermia) should be implemented. Because pulmonary artery catheters are not practical
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
809
Figure 10 (Continued). B, The right pulmonary artery flow in a fetus with diaphragmatic hernia at 34 weeks gestation is seen. The flow profile is clearly abnormal with only a small spike of forward flow in diastole. This neonate had an uncomplicated postnatal course with good repair of the diaphragmatic defect and no extra-corporeal membrane oxygenation requirement. C, The right pulmonary artery flow in a fetus with diaphragmatic hernia at 34 weeks gestation is seen. The flow pattern is similar to that in the fetus illustrated in B. This neonate died, however, within 3 hours of delivery despite all efforts.
810
ALLAN et al
in the neonate, frequent echocardiograms are helpful to assess pulmonary and systemic hemodynamics and left and right ventricular function. Recently, the selective pulmonary vasodilator nitric oxide (NO) has been studied and used clinically in treating infants with persistent pulmonary hypertension associated with CDH.5, n-13, 15 In contrast to infants with CDH, those with persistent pulmonary hypertension of the newborn (PPHN) respond dramatically to inhaled N0. 19, 23 In addition, it has been shown in infants with CDH that short-term NO inhalation is effective only after decannulation from ECM0. 15 These disparities in response to inhaled NO have been attributed to the unique pathophysiology of surfactant deficiency in CDH. Inhaled NO alone does not improve pH, pC02 , p0 2, nor does it change pulmonary hemodynamics in the fetal lamb model of CDH. 12 Inhaled NO does, however, decrease pulmonary artery pressure in the CDH lamb pretreated with exogenous surfactant. 12 By opening atelectatic terminal lung units, surfactant synergistically enhances the delivery and effect of inhaled NO as well as decreases pulmonary vascular resistance and increases pulmonary blood flow. 20 ' 21
SUMMARY
Cardiac evaluation is an important part of the investigation of a fetus with a diaphragmatic hernia. The heart is displaced by the physical presence of the abdominal contents in the chest, and the flow dynamics within the heart are altered. This can produce secondary diminution of chamber growth, particularly of the left heart. Structural heart malformation is also a frequently associated finding. Evaluation of cardiovascular flow profiles may give us further understanding of the pathophysiology of this lesion and may help to predict those fetuses that might benefit from intrauterine therapy.
References 1. Adzick NS, Vacanti JP, Lillehei CW, et al: Fetal diaphragmatic hernia: Ultrasound diagnosis and clinical outcome in 38 cases. J Pediatr Surg 24:654-657, 1989 2. Bronshtein M, Lewit N, Sujov PO, et al: Prenatal diagnosis of congenital diaphragmatic hernia: Timing of visceral herniation and outcome. Prenat Diagn 5:695-698, 1995 3. de Lorimier AA, Tierney DF, Parker HR: Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 62:12-17, 1967 4. Emerson DS, Cartier MS: The fetal pulmonary circulation. In Copel JA, Reed KL (eds): Doppler Ultrasound in Obstetrics and Gynecology. New York, Raven Press, 1995, p 307-323 5. Frostell CG, Lonnqvist PA, Sonesson SE, et al: Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia: Successful use of inhaled nitric oxide. Anaesthesia 48:679-683, 1993 6. Glick PL, Leach CL, Besner GE, et al: Pathophysiology of congenital diaphragmatic
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
7. 8. 9. 10. 11.
12.
13.
14. 15.
16. 17.
18. 19. 20. 21.
22.
23. 24. 25. 26. 27. 28.
811
hernia: III. Exogenous surfactant therapy for the high-risk neonate with CDH. J Pediatr Surg 27:866-869, 1992 Haller A: Discussion. In Dibbins AW, Wiener ES: Mortality from neonatal diaphragmatic hernia. J Pediatr Surg 9:661, 1974 Harrison MR, Adzick NS, Estes JM, et al: A prospective study of the outcome for fetuses with diaphragmatic hernia. JAMA 271:382-384, 1994 Harrison MR, Adzick NS, Flake AW, et al: Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg 28:1411-1418, 1993 Harrison MR, Langer JC, Adzick NS, et al: Correction of congenital diaphragmatic hernia in utero: V. Initial clinical experience. J Pediatr Surg 25:47-55; discussion 56-47, 1990 Henneberg SW, Jepsen S, Andersen PK, et al: Inhalation of nitric oxide as a treatment of pulmonary hypertension in congenital diaphragmatic hernia. J Pediatr Surg 30:853855, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: VIII. Inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia. J Pediatr Surg 30:1-4, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia. X: Localization of nitric oxide synthase in the intima of pulmonary artery trunks of lambs with surgically created congenital diaphragmatic hernia. J Pediatr Surg 30:5-9, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: XI. Anatomic and biochemical characterization of the heart in the fetal lamb CDH model. J Pediatr Surg 30:925-928; discussion 929, 1995 Karamanoukian HL, Glick PL, Zayek M, et al: Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics 94:715-718, 1994 Karamanoukian HL, Wilcox DT, Glick PL: The "missing link" in congenital diaphragmatic hernia [letter]. J Pediatr Surg 29:954-955, 1994 Karamanoukian HL, O'Toole SJ, Rossman JR, et al: Can cardiac weight predict lung weight in patients with congenital diaphragmatic hernia? J Pediatr Surg 31:823-825, 1996 Karamanoukian HL, O'Toole SJ, Rossman JR, et al: Fetal surgical interventions and the development of the heart in congenital diaphragmatic hernia. J Surg Res, in press Kinsella JP, Neish SR, Ivy DD, et al: Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide [see comments]. J Pediatr 123:103-108, 1993 O'Toole SJ, Karamanoukian HL, Irish MS, et al: In utero lung distension decreases surfactant protein gene expression. Am J Respir Crit Care Med 153:A641, 1996 O'Toole SJ, Karamanoukian HL, Rossman JE, et al: In utero mechanical forces, lung compliance, and collagen deposition: A study in the fetal lamb model of congenital diaphragmatic hernia. Am J Respir Crit Care Med 153:A552, 1996 Rasanen J, Wood DC, Weiner S, et al: The role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Circulation 94:1068-1073, 1996 Roberts JD, Polaner DM, Lang P, et al: Inhaled nitric oxide in persistent pulmonary hypertension of the newborn [see comments]. Lancet 340:818-819, 1992 Schwartz SM, Vermilion RP, Hirschi RB: Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia. J Pediatr 125:447-451, 1994 Seibert JR, Haas JE, Beckwith JB: Left ventricular hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 19:567, 1984 Sharland GK, Lockhart SM, Heward AJ, et al: Prognosis in fetal diaphragmatic hernia. Am J Obstet Gynecol 166:9-13, 1991 Smith RS, Comstock CH, Kirk JS, et al: Ultrasound left cardiac axis deviation, a marker for fetal anormalies. Obstet Gynecol 85:187-191, 1995 Sutton MS, Groves A, MacNeill A, et al: Assessment of changes in blood flow through the lungs and foramen ovale in the normal human fetus with gestational age: A prospective Doppler echocardiographic study. Br Heart J 71:232-237, 1994
812
ALLAN et al
29. Swartz SM, Vermilion RP, Hirsch! RB: Evaluation of left ventricular mass in children with left sided congenital diaphragmatic hernia. Pediatr Res 33:235A, 1993
Address reprint requests to Lindsey D. Allan, MD Division of Pediatric Cardiology Babies Hospital 2N Columbia Presbyterian Medical Center 3959 Broadway New York, NY 10032 e-mail: [email protected]
0095-5108/96 $0.00 + .20
THE FETAL HEART IN DIAPHRAGMATIC HERNIA Lindsey D. Allan, MD, Michael S. Irish, MD, and Philip L. Glick, MD
Despite optimal perinatal care of infants born with congenital diaphragmatic hernia (CDH), the mortality of the patients remains exceedingly high. This as yet unexplained mortality, or "hidden mortality" as coined by Harrison et al 8 in 1994, has recently led us to suggest the possible role of cardiac maldevelopment as "a missing link" in the high mortality of infants with CDH. 16 It has also been suggested that leftventricular disproportion may be used as a predictor of fetal outcome. Although a number of prenatal prognostic indicators for CDH have been proposed (fetal age at the time of diagnosis, the presence of fetal bowel within the chest, mediastinal shift), none have correlated well with postnatal morbidity and mortality. 6• 9• 10• 17 Sharland et al, 26 however, in a retrospective review of 55 cases of CDH diagnosed prenatally, demonstrated the relative prognostic indicators of gestational age at the time of diagnosis, ratios of aortic to pulmonary artery (Ao/PA) diameters, and of left-to-right ventricular maximum width ratios obtained on fetal ultrasound. In their series, reduced left-to-right ventricular ratios and Ao/PA ratios, and diagnoses before 25 weeks' gestation each correlated with a higher mortality when cases of elective termination and congenital heart disease were excluded. The pulmonary hemodynamic pathophysiology of CDH has been well documented. Hypoplastic pulmonary arteries and increased pulmonary artery muscle mass, along with pulmonary hypoplasia, derange-
From the Division of Pediatric Cardiology, Babies Hospital 2N, Columbia Presbyterian Medical Center, New York (LDA); and the Departments of Pediatric Surgery (MSI, PLC) and Pediatrics (PLC), The Buffalo Institute of Fetal Therapy, The Children's Hospital of Buffalo, Buffalo, New York
CLINICS IN PERINATOLOGY VOLUME 23 • NUMBER 4 • DECEMBER 1996
795
796
ALLAN et al
Table 1. TOTAL AND COMPONENT HEART WEIGHTS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMBS*
Group
Right and Left Atria
Right Ventricle
Left Ventricle
Interventricular Septum
Total Heart
CDH (n=7) Control (n = 7)
0.68±0.06t 1.14±0.15
1.26±0.07 1.57 ± 0.17
1.65±0.11t 2.15±0.19
1.25±0.11t 1.99±0.21
4.88±0.25t 6.75±0.49
'Data expressed as g/kg lamb, mean ± standard error. tP < 0.05 for CDH versus control littermates.
ments in gas exchange, and delayed closure of the ductus arteriosus, all lead to pulmonary hypertension in the neonate with CDH. It has been suggested that a primary cardiac abnormality in isolated CDH may contribute pathogenetically despite these alterations in pulmonary circulation.7 Seibert et al,25 in a human autopsy study, found that newborns with left-sided CDH had smaller left ventricles, interventricular septums, and atria as compared with age-matched controls. Similar observations have been made sonographically, demonstrating a significantly lower left-ventricular mass index in patients with left-sided CDH compared with a control group of patients with other causes of pulmonary hypertension. 24 A lower left-ventricular mass index was also observed in CDH patients who required ECMO and in nonsurvivors. In a study utilizing the fetal lamb model of CDH, Karamanoukian et al1 4 demonstrated that total heart weight and left ventricular, septal, and atrial weights are significantly decreased when compared to littermate controls3 (Table 1). They also found identical DNA to protein ratios of the left ventricles of both CDH and controls, implying that the decreased weight of the left ventricle in CDH is caused by hypoplasia (Table 2). Interestingly, although in utero surgical repair of CDH in lambs corrects these cardiac morphometric abnormalities, in utero tracheal ligation does not. 18 Presumably, although the enlarged lungs resulting from tracheal ligation cause reduction of the herniated abdominal viscera, they also act as an intrathoracic, space-occupying mass and prevent normal cardiac development. Furthermore, when Ao/PA root ratios were evaluated, the authors found no difference in the aortic root Table 2. DNA AND PROTEIN ANALYSIS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMB HEARTS*
Group
Aortic (Ao) Root
Pulmonary Artery (PA) Root
Ductus Arteriosus
Ao/PA Ratio
CDH (N=8) CDH (N=5)
0.37±0.01 0.37±0.01
0.47±0.01t 0.38±0.01
0.35±0.01t 0.22±0.02
0.81±0.01 t 1.00±0.03
*Data expressed in centimeters, mean ± standard error. tP<0.005 for CDH versus control littermates.
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
797
Table 3. AORTIC (Ao), PULMONARY ARTERY (PA), AND DUCTUS ARTERIOSUS (DUCTUS) DIAMETERS OF FETAL CONGENITAL DIAPHRAGMATIC HERNIA (CDH) AND CONTROL LAMBS* Groupt
Protein
DNA
DNA/Protein
Hydroxyproline
Elastin
CDH RV CDH LV CONTROL RV CONTROL LV
98±12 80±20 95±27 109±38
1.37±0.38 2.00±0.59 1.60±0.48 1.70±0.33
0.011 ±0.003 0.015 ± 0.004 0.013±0.005 0.015 ± 0.006
0.519±0.03 0.586±0.05 0.538±0.04 0.514±0.99
0.45±0.36 0.61 ±0.12 0.69±0.34 0.61 ±0.18
RV = right ventricle; LV = left ventricle. *Data expressed as mg/kg heart weight, mean ± standard error. tN = 10 for each group.
diameters between CDH and controls, suggesting that the observed decrease in Ao/PA root ratio was caused by an increase in PA diameter. Ductus arteriosus diameters were also significantly greater in CDH animals (Table 3). Their observations were supported by earlier sonographic data on human fetuses with CDH. 26 The authors hypothesized that left-ventricular hypoplasia may result from in utero increased left atrial pressure (from compression of the herniated abdominal viscera), decreased right-left shunting through the foramen ovale, and increased PA pressures and flow, thus increasing both PA and ductus arteriosus diameters. 14 Although lung hypoplasia seems to relate to morbidity and mortality, it is difficult to quantify this technically. Karamanoukian et al1 7 have gone on to demonstrate a predictive correlation between heart weight and lung weight in the neonatal lamb with surgically created CDH (Fig. 1). They speculate that similar data, obtained from prenatal echocardiographic parameters of cardiac volume and mass, may be helpful in identifying fetuses with lethal pulmonary hypoplasia. Thus, the status of the fetal heart in CDH may well be the "missing link" in predicting outcome as well as a useful criterion for those fetuses that should be considered for in utero intervention. BACKGROUND AND PERSONAL EXPERIENCE (DR. ALLAN)
Over the last 16 years, the fetal heart of just over 100 cases of diaphragmatic hernia has been studied in two centers: Guy's Hospital in London during a 13-year period, and Columbia Presbyterian Medical Center (CPMC) in New York over a 3-year period. In both series, the population seen has been selected for referral to tertiary centers, so it is not entirely representative of the whole spectrum of this disease. This is reflected in the rate of chromosomal anomalies, which was 6 of 38 cases (16%) in the series reported by Adzick,1 4% in the Guy's series of 72 cases, and none of 21 cases seen at CPMC. In the Guy's series, patients were referred for a cardiac scan as part of the primary evaluation, whereas in the CPMC series, in most cases, the heart was evaluated as
798
ALLAN et al
200-
.-..
150-
s
-
"
Lung wt= ·0.004 x Heart wt+ 135
"" " "
.c
Cl
·a; 3::
100
Cl
c:
0
:I
..J
50- Lungwt -- 0 ·69 x Heart wt + 37
0 0
I 10
0 0
0
n
0 CID
0100
I 20
0
0
0 u
0
I 30
I 40
I 50
Heart weight (g) Figure 1. Regression analysis of the relationship between lung weight (in grams) to heart weight (in grams) in CDH lambs (circle) and control lambs (triangle). Analysis of variance, F= 182.75; P< 0.001. CDH =congenital diaphragmatic hernia.
part of a presurgical work-up. As a result, more than 50% of patients in the Guy's series were seen prior to 24 weeks' gestation as compared with only 14% at CPMC. In many cases presenting to CPMC, however, the diagnosis had been made earlier in pregnancy, but patients were seen by us only when they transferred to our center for late prenatal care and delivery with a view to surgery.
THE FETAL CARDIAC EXAMINATION
Three aspects of fetal cardiac examination are important in the assessment of a fetus with a diaphragmatic hernia. In the normal fetus, the heart and lungs comfortably occupy the space the thorax provides in a state of mutual synergism. The intrusion into the thoracic cavity of any portion of abdominal contents necessarily alters this and produces mechanical effects on the heart as well as the lungs. Second, the "insult" in embryologic or early fetal life that caused the diaphragmatic defect can also damage the concurrently developing heart. There is therefore an increased incidence of structural cardiac malformations. Finally, the normal characteristics of cardiac physiology are altered in the presence of a thoracic mass, and the evaluation of some of these parameters may help in predicting the severity of lung hypoplasia or the outcome of neonatal surgery.
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
799
MECHANICAL EFFECTS OF A DIAPHRAGMATIC HERNIA ON THE FETAL HEART
Basically, any space-occupying lesion within the confines of the thorax can displace heart or lung tissue from their normal positions. It seems clear that the site and size of the diaphragmatic defect will influence the volume of abdominal contents that herniate into the chest. In addition, the timing during pregnancy at which herniation occurs appears to vary. 2 These variations will influence the cardiac findings. In the common left-sided defect, the heart is shifted into the right chest with varying degrees of severity. Similarly, in the more rare right-sided hernia, the liver displaces the heart further to the left than normal. These signs are seen in the four-chamber view of the heart. In the normal fetus, the right lung lies between the right atrium and part of the right ventricle, and the lateral chest wall (Fig. 2). Most of the heart, comprising half of the left atrium, the left ventricle, and most of the right ventricle, lies in the left half of the chest. The interventricular septum is at an angle of about 40 degrees to the midline, although this shows some variation ( + 20 degrees) in normals. 27 An example of a diaphragmatic hernia is seen in Figure 3. Both right atrium and right ventricle are in apposition to the right chest wall, and the whole heart
Figure 2. In this normal four chamber view of the heart, there is lung tissue between the right atrium and part of the right ventricle and the right chest wall. If the thorax is divided equally in two from the spine, most of the heart lies in the left chest with the interventricular septum at an angle of about 40° to the midline. RA= right atrium, LA= left atrium, LV =left ventricle, RV= right ventricle.
800
ALLAN et al
Figure 3. In this fetus with a diaphragmatic hernia, the heart lies completely in the right chest, with the right atrium and right ventricle directly against the thoracic wall. The interventricular septum is almost parallel to the midline. The stomach position is related to the left ventricle. The left atrium is small and the left ventricle smaller than the right. ST=stomach, RA= right atrium, LV=left ventricle, RV=right ventricle.
lies in the right chest. The ventricular septum is oriented almost parallel to the midline of the thorax. The stomach is varied in its position relative to the heart, and it is also variously dilated, although this is likely to be dynamic (Figs. 4 and 5). In the majority of fetuses with left-sided diaphragmatic lesions, the left heart is smaller than the right. This has been described in a previous publication. 26 The left ventricle/right ventricle (LV /RV) ratios found previously are similar to the results shown in Figure 6 in a smaller, recent series of 21 cases. In about a third of cases, even the absolute cardiac size is smaller than normal, as shown by the cardiothoracic ratio compared with normal (Fig. 7). As can be seen from the graphs, however, neither of these measurable parameters appear to have a clear relationship to the outcome. The size or growth of the cardiac chambers and vessels in part depends on the blood flow they receive. Normally, the left ventricle receives about 45% of the combined cardiac output, falling to about 40% in the last 10 weeks of pregnancy. 22 In the human fetus, about 20% of the combined cardiac output goes to the lungs and then returns to the left atrium in the pulmonary veins. 28 A further 25% of combined cardiac output, falling to 20% in later pregnancy, reaches the left ventricle through the foramen ovale. This jet of blood is a well-oxygenated stream derived from the ductus venosus, which passes through the inferior
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
801
Figure 4. In this fetus with a diaphragmatic hernia, the stomach lies behind the heart in the right chest. The left atrium is small and the left ventricle mildly smaller than the right ventricle. ST= stomach; RA= right atrium; LV =left ventricle; RV= right ventricle.
Figure 5. In this fetus with a diaphragmatic hernia, the stomach is dilated and close to the left ventricle. The left atrium is small and the left ventricle smaller than the right ventricle. ST= stomach; RA= right atrium; LA= left atrium; RV= right ventricle; LV =left ventricle.
802
ALLAN et al
1.2 1.1 1.0 0.9 0.8 0
:;::; ca
0.7
>
0.6
>
0.5
a: a:
....J
ot*
0.4 0.3 0.2
t* Termination of pregnancy 0.1
t
Died
0 14
16
18
20
22
24
26
28
30
32
34
36
38
40
Gestation Figure 6. The left ventricle to right ventricle (LV/RV) ratio is plotted for the fetuses with diaphragmatic hernia. The ratio value fell below the fifth centile in the majority of patients. The fetus with a ratio above the normal range had a right-sided hernia. The lines represent sequential studies in the same patient. Two patients elected to interrupt the pregnancy. There were three deaths in the continuing left-sided lesions. The fetus with the abnormally high LV/RV ratio who died had a right-sided hernia. 111 = 95th centile; ..6. = normal centile; o = fifth centile; o = patient values.
vena cava to the foramen. The mechanism of the relative underdevelopment of the left heart is probably a combination of decreased pulmonary venous return because of diminished lung mass and a decrease in the interatrial shunt. The latter is evidenced by the documentation of left to right shunting at the foramen ovale in the affected fetus. The relative diminution of left heart blood flow results in the left heart (affecting the left ventricle, aorta, and aortic arch) being smaller than normal at delivery. This has been associated with a poorer outlook for corrective surgery, but the association is not clear-cut. 25 ' 26' 29 The absolute size of the left ventricle may be related to the position of the stomach relative to the left atrium, the pressure within the stomach, or the timing during pregnancy of the passage of the stomach into the chest. Alternatively, it may be that a smaller left ventricle simply reflects a larger mass of abdominal contents within the thorax and therefore smaller lung volume, which would in turn negatively influence the outcome.
803
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
0.60 0.55 0.50
0
0
ot*
0.45
0
0.40
ot*
0 0.35 :;::; II!
0:: 0.30
I.....
u
0.25 0.20 0.15 0.10
t* Termination of pregnancy 0.05
t
Died
0 14
16
18
20
22
24
26
28
30
32
34
36
38
40
Gestation Figure 7. The cardiothoracic (CIT) ratio is plotted for the fetuses with diaphragmatic hernia. The ratio value fell below the fifth centile in the some of the patients. The lines represent sequential studies in the same patient. Two patients elected to interrupt the pregnancy. There were three deaths of the continuing left-sided lesions. There is no clear relationship between absolute heart size and outcome. A = 95th centile; 11 = normal centile; 111 = fifth centile; o = patient values at first visit; o = patient values at follow-up visit.
It has been suggested that the small left ventricle at delivery may be less compliant and less able to maintain the systemic circulation, but this is not proved. In an analogous situation in total anomalous pulmonary venous drainage, the left ventricle is small and underdeveloped, sometimes into the range associated with the hypoplastic left heart syndrome, but circulatory effects are related to the obstructed pulmonary veins and not to left ventricular failure. In this setting, and in diaphragmatic hernia, after successful surgical repair the left ventricle quickly recovers and "catches up" to a normal size. There have been two examples of a right-sided hernia seen in our series. In this setting, liver tissue herniates through the diaphragmatic defect into the right thorax. In both cases, the heart was displaced further to the left than normal (Fig. 8), and the right heart may be slightly smaller than normal. This may be due to an increase in the interatrial shunt to the left in fetal life, although this cannot be proved.
804
ALLAN et al
Figure 8. The heart is seen in a four chamber view. It is displaced further to the left than normal by the liver in the right thorax. There is only a trivial portion of left lung and no right lung visible. RV= right ventricle; LV =left ventricle.
Both patients proved impossible to ventilate adequately and died soon after birth. CARDIAC MALFORMATIONS IN ASSOCIATION WITH DIAPHRAGMATIC HERNIA
There were 12 examples of congenital heart malformation seen in 72 cases in the Guy's series (20%) and 2 of 21 cases in the CPMC series (10%). This may reflect selection of fetuses with a cardiac defect referred to a fetal cardiac center in the early series and de-selection of affected fetuses (by termination of pregnancy) referred to CPMC for surgery. The types of malformation that have been seen in our series are listed in Table 4. There is much discussion on the timing of the "insult" that
Table 4. CARDIAC MALFORMATIONS ASSOCIATED WITH CONGENITAL DIAPHRAGMATIC HERNIA Ventricular septa! defect Ventricular septa! defect with pulmonary stenosis Atrioventricular septa! defect Tetralogy of Fallo! Hypoplastic left heart syndrome ? Coarctation of the aorta (suspected, no autopsy)
4 1 3 3 2 1
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
805
produces diaphragmatic hernia. The preponderance of ventricular-septal defect suggests that the insult is after 6 weeks of postconceptional life rather than before, because the ventricular septum is one of the last parts of the heart to complete its formation. The association of two cases of true hypoplastic left heart syndrome (with mitral and aortic atresia) may reflect very severe and early (less than 15 weeks) lack of left-heart blood flow, a more extreme form of the diminution of left heart flow that is seen in the later fetus, but it is probably more likely to be a primary cardiac malformation. The presence of diaphragmatic hernia with congenital heart disease indicates a poor prognosis, there being no survivors of 14 cases with this combination in our series; however, the pregnancy was interrupted in four cases, and there was a chromosomal anomaly in a further two cases. There is no reason why a small ventricular septal defect should affect the immediate postnatal course, and particularly in at least one recent case, it may have been coincidental to the outcome. There was one case in which a coarctation lesion was suspected postnatally, but the neonate died soon after birth and there was no autopsy. This is a diagnosis that is difficult to make prenatally and particularly so in the setting of diaphragmatic hernia. The signs of coarctation include the left ventricle smaller than right, the aorta smaller than the pulmonary artery, hypoplasia of the transverse arch, and reversal of the interatrial shunt. These are "normal" findings in the presence of a diaphragmatic hernia. It is probable that when the diagnosis of diaphragmatic hernia is made prior to 24 weeks' gestation, the heart is severely displaced and the left ventricle is significantly smaller than the right, particularly if CHD is suspected in addition, most obstetricians recommend termination of pregnancy. This may be appropriate advice but it should be made with caution. Two cases in our recent series were referred from experienced ultrasonographers with a false-positive diagnosis of a severe heart malformation. Furthermore, it is clear from both series that survival after surgery, despite early diagnosis and an abnormal LV /RV ratio, is possible. In our recent series, an 83% survival has been achieved in the continuing left-sided lesions. Admittedly, detailed information on the proportion diagnosed prior to 24 weeks' gestation, which would influence the results, 8 is not currently available. CHANGES IN CARDIAC PHYSIOLOGY IN DIAPHRAGMATIC HERNIA
In spite of severe cardiac displacement, there is normally no disturbance of systemic venous return to the right atrium. The hepatic vein flow profile is normal, reflecting normal right atrial pressures. As described earlier, left to right interatrial flow, a reversal of normal, can be documented by color flow mapping of the foramen ovale. This indicates that the left atrial pressure, at least at some times in the cardiac cycle, must be higher than right atrial pressure. This alteration in pressure cannot be marked because the pulmonary venous flow tracing, when it
806
ALLAN et al
can be obtained, shows a pattern that is within the normal range. This change in left atrial pressure may be related to the presence of the stomach close behind it, or it may be related to intrathoracic pressure per se. It is possible to estimate the right- and left-heart output using a Doppler velocity tracing of the pulmonary and aortic flow. This will show an increase of right-heart flow relative to the left as evidenced by the differences in ventricular sizes; however, this is not helpful in predicting the outcome, which is currently our greatest challenge. It has been suggested that alterations in branch pulmonary artery Doppler tracings can indicate "downstream" resistance and may reflect the degree of lung hypoplasia4; however, preliminary results in our recent series show an abnormal pattern of flow in cases of diaphragmatic hernia but with no clear difference between survivors and nonsurvivors (Figs. 9 and 10). This idea needs further study. In addition, it may be possible to gain a crude estimate of pulmonary blood flow by calculating flow from the Doppler profile in the pulmonary trunk and the duct and subtracting the latter from the former. This may correlate with lung volume and therefore postnatal course. This also merits further study. POSTNATAL CARDIAC CARE
Postnatally, infants who develop or maintain severe respiratory and cardiovascular distress have persistence of fetal circulation: elevated
Figure 9. A, The right pulmonary artery (RPA) flow in a normal fetus at 24 weeks gestation is seen. The systolic (SYST) and diastolic (DIAS) phases of the flow are marked. There is a notch at the end of systole as the pulmonary valve closes and forward flow in diastole. Illustration continued on opposite page
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
807
Figure 9 (Continued). B, The right pulmonary artery flow in a normal fetus at 29 weeks' gestation is seen. The systolic and diastolic phases of the flow are marked. There is forward flow in diastole. C, The right pulmonary artery flow in a normal fetus at 36 weeks gestation is seen. The systolic and diastolic phases of the flow are marked. There is forward flow in diastole.
808
ALLAN et al
Figure 10. A, The right pulmonary artery (RPA) flow in a fetus with diaphragmatic hernia at 23 weeks gestation is seen. The systolic (SYS) and diastolic (DIAS) phases of the flow are marked. There is reversal of flow in diastole. This is suggestive of a high resistance in the lung fields, but the pregnancy was interrupted so this could not be verified. Illustration continued on opposite page
pulmonary artery pressures, increased pulmonary vascular resistance, and right-to-left shunting (at the level of the foramen ovale, at the ductus arteriosus, and within the lung vasculature). A vicious circle of hypercarbia, acidosis, and progressive hypoxemia results. Upon delivery, the prenatally diagnosed infant with CDH should be transported to the neonatal intensive care unit, anticipating the need for urgent cardiorespiratory support. Appropriate monitoring should include preand postductal pulse oximetry, and arteriovenous access. A urinary catheter is placed to monitor fluid resuscitation, and a nasogastric tube is inserted to avoid visceral distension, which would lead to further intrathoracic and mediastinal compression and compromise. An echocardiogram is obtained as early as possible to assess for structural abnormalities, pulmonary hypertension, and extrapulmonary (foramen ovale and ductal) shunting. If pulmonary hypertension or systemic hypotension exist, ionotropic agents such as dopamine (2-20 µg/kg/min), epinephrine (0.1 µg/kg/ min), or dobutamine (2-20 µg/kg/min) should be used in an effort to raise the systemic above pulmonary arterial pressure. This will minimize right-to-left shunting and optimize left ventricular output. Measures to correct or prevent factors associated with an elevated pulmonary vascular resistance (hypoxia, hypercarbia, acidosis, and hypothermia) should be implemented. Because pulmonary artery catheters are not practical
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
809
Figure 10 (Continued). B, The right pulmonary artery flow in a fetus with diaphragmatic hernia at 34 weeks gestation is seen. The flow profile is clearly abnormal with only a small spike of forward flow in diastole. This neonate had an uncomplicated postnatal course with good repair of the diaphragmatic defect and no extra-corporeal membrane oxygenation requirement. C, The right pulmonary artery flow in a fetus with diaphragmatic hernia at 34 weeks gestation is seen. The flow pattern is similar to that in the fetus illustrated in B. This neonate died, however, within 3 hours of delivery despite all efforts.
810
ALLAN et al
in the neonate, frequent echocardiograms are helpful to assess pulmonary and systemic hemodynamics and left and right ventricular function. Recently, the selective pulmonary vasodilator nitric oxide (NO) has been studied and used clinically in treating infants with persistent pulmonary hypertension associated with CDH.5, n-13, 15 In contrast to infants with CDH, those with persistent pulmonary hypertension of the newborn (PPHN) respond dramatically to inhaled N0. 19, 23 In addition, it has been shown in infants with CDH that short-term NO inhalation is effective only after decannulation from ECM0. 15 These disparities in response to inhaled NO have been attributed to the unique pathophysiology of surfactant deficiency in CDH. Inhaled NO alone does not improve pH, pC02 , p0 2, nor does it change pulmonary hemodynamics in the fetal lamb model of CDH. 12 Inhaled NO does, however, decrease pulmonary artery pressure in the CDH lamb pretreated with exogenous surfactant. 12 By opening atelectatic terminal lung units, surfactant synergistically enhances the delivery and effect of inhaled NO as well as decreases pulmonary vascular resistance and increases pulmonary blood flow. 20 ' 21
SUMMARY
Cardiac evaluation is an important part of the investigation of a fetus with a diaphragmatic hernia. The heart is displaced by the physical presence of the abdominal contents in the chest, and the flow dynamics within the heart are altered. This can produce secondary diminution of chamber growth, particularly of the left heart. Structural heart malformation is also a frequently associated finding. Evaluation of cardiovascular flow profiles may give us further understanding of the pathophysiology of this lesion and may help to predict those fetuses that might benefit from intrauterine therapy.
References 1. Adzick NS, Vacanti JP, Lillehei CW, et al: Fetal diaphragmatic hernia: Ultrasound diagnosis and clinical outcome in 38 cases. J Pediatr Surg 24:654-657, 1989 2. Bronshtein M, Lewit N, Sujov PO, et al: Prenatal diagnosis of congenital diaphragmatic hernia: Timing of visceral herniation and outcome. Prenat Diagn 5:695-698, 1995 3. de Lorimier AA, Tierney DF, Parker HR: Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 62:12-17, 1967 4. Emerson DS, Cartier MS: The fetal pulmonary circulation. In Copel JA, Reed KL (eds): Doppler Ultrasound in Obstetrics and Gynecology. New York, Raven Press, 1995, p 307-323 5. Frostell CG, Lonnqvist PA, Sonesson SE, et al: Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia: Successful use of inhaled nitric oxide. Anaesthesia 48:679-683, 1993 6. Glick PL, Leach CL, Besner GE, et al: Pathophysiology of congenital diaphragmatic
THE FETAL HEART IN DIAPHRAGMATIC HERNIA
7. 8. 9. 10. 11.
12.
13.
14. 15.
16. 17.
18. 19. 20. 21.
22.
23. 24. 25. 26. 27. 28.
811
hernia: III. Exogenous surfactant therapy for the high-risk neonate with CDH. J Pediatr Surg 27:866-869, 1992 Haller A: Discussion. In Dibbins AW, Wiener ES: Mortality from neonatal diaphragmatic hernia. J Pediatr Surg 9:661, 1974 Harrison MR, Adzick NS, Estes JM, et al: A prospective study of the outcome for fetuses with diaphragmatic hernia. JAMA 271:382-384, 1994 Harrison MR, Adzick NS, Flake AW, et al: Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg 28:1411-1418, 1993 Harrison MR, Langer JC, Adzick NS, et al: Correction of congenital diaphragmatic hernia in utero: V. Initial clinical experience. J Pediatr Surg 25:47-55; discussion 56-47, 1990 Henneberg SW, Jepsen S, Andersen PK, et al: Inhalation of nitric oxide as a treatment of pulmonary hypertension in congenital diaphragmatic hernia. J Pediatr Surg 30:853855, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: VIII. Inhaled nitric oxide requires exogenous surfactant therapy in the lamb model of congenital diaphragmatic hernia. J Pediatr Surg 30:1-4, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia. X: Localization of nitric oxide synthase in the intima of pulmonary artery trunks of lambs with surgically created congenital diaphragmatic hernia. J Pediatr Surg 30:5-9, 1995 Karamanoukian HL, Glick PL, Wilcox DT, et al: Pathophysiology of congenital diaphragmatic hernia: XI. Anatomic and biochemical characterization of the heart in the fetal lamb CDH model. J Pediatr Surg 30:925-928; discussion 929, 1995 Karamanoukian HL, Glick PL, Zayek M, et al: Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios. Pediatrics 94:715-718, 1994 Karamanoukian HL, Wilcox DT, Glick PL: The "missing link" in congenital diaphragmatic hernia [letter]. J Pediatr Surg 29:954-955, 1994 Karamanoukian HL, O'Toole SJ, Rossman JR, et al: Can cardiac weight predict lung weight in patients with congenital diaphragmatic hernia? J Pediatr Surg 31:823-825, 1996 Karamanoukian HL, O'Toole SJ, Rossman JR, et al: Fetal surgical interventions and the development of the heart in congenital diaphragmatic hernia. J Surg Res, in press Kinsella JP, Neish SR, Ivy DD, et al: Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide [see comments]. J Pediatr 123:103-108, 1993 O'Toole SJ, Karamanoukian HL, Irish MS, et al: In utero lung distension decreases surfactant protein gene expression. Am J Respir Crit Care Med 153:A641, 1996 O'Toole SJ, Karamanoukian HL, Rossman JE, et al: In utero mechanical forces, lung compliance, and collagen deposition: A study in the fetal lamb model of congenital diaphragmatic hernia. Am J Respir Crit Care Med 153:A552, 1996 Rasanen J, Wood DC, Weiner S, et al: The role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Circulation 94:1068-1073, 1996 Roberts JD, Polaner DM, Lang P, et al: Inhaled nitric oxide in persistent pulmonary hypertension of the newborn [see comments]. Lancet 340:818-819, 1992 Schwartz SM, Vermilion RP, Hirschi RB: Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia. J Pediatr 125:447-451, 1994 Seibert JR, Haas JE, Beckwith JB: Left ventricular hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 19:567, 1984 Sharland GK, Lockhart SM, Heward AJ, et al: Prognosis in fetal diaphragmatic hernia. Am J Obstet Gynecol 166:9-13, 1991 Smith RS, Comstock CH, Kirk JS, et al: Ultrasound left cardiac axis deviation, a marker for fetal anormalies. Obstet Gynecol 85:187-191, 1995 Sutton MS, Groves A, MacNeill A, et al: Assessment of changes in blood flow through the lungs and foramen ovale in the normal human fetus with gestational age: A prospective Doppler echocardiographic study. Br Heart J 71:232-237, 1994
812
ALLAN et al
29. Swartz SM, Vermilion RP, Hirsch! RB: Evaluation of left ventricular mass in children with left sided congenital diaphragmatic hernia. Pediatr Res 33:235A, 1993
Address reprint requests to Lindsey D. Allan, MD Division of Pediatric Cardiology Babies Hospital 2N Columbia Presbyterian Medical Center 3959 Broadway New York, NY 10032 e-mail: [email protected]