Journal of Pediatric Surgery 49 (2014) 1767–1770
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pulmonary hypertension in giant omphalocele infants Emily A. Partridge a, Brian D. Hanna b, Howard B. Panitch c, Natalie E. Rintoul d, William H. Peranteau a, Alan W. Flake a, N. Scott Adzick a, Holly L. Hedrick a,⁎ a
Department of Surgery, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States Division of Cardiology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 19104 Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States d Division of Neonatology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States b c
a r t i c l e
i n f o
Article history: Received 24 August 2014 Accepted 5 September 2014 Key words: Abdominal wall defects Pulmonary hypoplasia Pulmonary hypertension Reactive airway disease
a b s t r a c t Background: Pulmonary hypoplasia has been described in cases of giant omphalocele (GO), although pulmonary hypertension (PH) has not been extensively studied in this disorder. In the present study, we describe rates and severity of PH in GO survivors who underwent standardized prenatal and postnatal care at our institution. Methods: A retrospective chart review was performed for all patients in our pulmonary hypoplasia program with a diagnosis of GO. Statistical significance was calculated using Fisher's exact test and Mann–Whitney test (p b 0.05). Results: Fifty-four patients with GO were studied, with PH diagnosed in twenty (37%). No significant differences in gender, gestational ages, birth weight, or Apgar scores were associated with PH. Patients diagnosed with PH were managed with interventions, including high frequency oscillatory ventilation, and nitric oxide. Nine patients required long-term pulmonary vasodilator therapy. PH was associated with increased length of hospital stay (p b 0.001), duration of mechanical ventilation (p = 0.008), and requirement for tracheostomy (p = 0.0032). Overall survival was high (94%), with significantly increased mortality in GO patients with PH (p = 0.0460). Prenatal imaging demonstrating herniation of the stomach into the defect was significantly associated with PH (p = 0.0322), with a positive predictive value of 52%. Conclusions: In this series, PH was observed in 37% of GO patients. PH represents a significant complication of GO, and management of pulmonary dysfunction is a critical consideration in improving clinical outcomes in these patients. © 2014 Elsevier Inc. All rights reserved.
Omphalocele is a midline ventral abdominal wall defect occurring at an incidence of 1 in 6000 live births [1], resulting in herniation of the abdominal viscera into a membrane-covered sac composed of an inner layer of peritoneum and an outer layer of amnion. Omphalocele may be classified as small, ruptured or giant according to the contents and integrity of the sac, with giant omphalocele (GO) defined as a large central sac-covered defect containing most of the liver [2]. Respiratory insufficiency is frequently observed in infants with giant abdominal wall defects including GO. Respiratory failure in these patients has been ascribed to increased intraabdominal pressure and upward displacement of the diaphragm following closure [3], though surgical techniques to minimize intraabdominal pressure following closure have demonstrated prolonged respiratory insufficiency in a subset of patients, implicating underlying pulmonary maldevelopment in this disorder [4]. Abnormal pulmonary development in infants with GO has been attributed to narrow chest wall deformities in addition to pulmonary hypoplasia. Pulmonary hypoplasia was described in a series of 114 patients with abdominal wall defects, with markedly decreased lung weight to body ratios in a subset of infants examined at ⁎ Corresponding author at: The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Division of General, Thoracic and Fetal Surgery, Philadelphia PA, 19104, United States. Tel.: +1 215 590 2733; fax: +1 215 590 2447. E-mail address: [email protected] (H.L. Hedrick). http://dx.doi.org/10.1016/j.jpedsurg.2014.09.016 0022-3468/© 2014 Elsevier Inc. All rights reserved.
autopsy [5]. Abnormal pulmonary vascular tone is frequently implicated in pulmonary hypoplasia, and represents a significant limitation to survival and long-term functional outcomes in patients with lung maldevelopment secondary to space-occupying lesions of the thorax including congenital diaphragmatic hernia [6]. In 2004, an interdisciplinary program was established for all infants seen at our institution with a diagnosis of pulmonary hypoplasia, including infants with GO. This prospective program follows patients with comprehensive evaluation, including assessment and management of pulmonary hypertension. We sought to describe the incidence and course of pulmonary hypertension in GO patients who underwent standardized prenatal and postnatal care at our institution. 1. Methods With approval by the Children's Hospital of Philadelphia Institutional Review Board, the records of all GO patients treated at our institution and enrolled in the interdisciplinary Pulmonary Hypoplasia Program between January 2004 and December 2012 were retrospectively analyzed. Recorded data on patient demographics, prenatal course and imaging, delivery information, neonatal care, surgical repair, and respiratory support requirements were analyzed. Inclusion criteria included a diagnosis of GO, as defined by a midline abdominal wall defect with a membranous sac containing most (N75%) of the liver.
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E.A. Partridge et al. / Journal of Pediatric Surgery 49 (2014) 1767–1770
Exclusion criteria included patients with abdominal wall defects not meeting the definition of GO, as pulmonary hypoplasia is not an established complication of these defects, as well as those patients managed by palliative care at birth. Respiratory support requirements were reviewed for all included patients. When mechanical ventilation was required, lung preservation strategies were used as previously described [7]. Ventilation support was aimed to maintain preductal oxygen saturations above 85%, with high-frequency oscillatory ventilation (HFOV) reserved for patients with refractory hypercapnia. Echocardiography was performed as clinically indicated to assess right ventricular pressures, with PH defined according to standard criteria (right ventricular systolic pressure estimate [RVSPE] ≥ 27 mm Hg, or qualitative features including right ventricular dilation/enlargement/hypertrophy, and septal flattening). PH was diagnosed based upon calculated RVSPE in those patients with sufficient tricuspid regurgitation (TR) to permit this measurement, with flows ≥27 mm Hg considered diagnostic of PH. In those patients with insufficient TR to permit calculation of RVSPE, the presence of two or more qualitative features of PH was considered diagnostic of PH. Directionality of flow through the ductus arteriosus was not considered in the diagnosis of PH. Echocardiograms were performed in the first week of life in all patients and were repeated approximately once weekly in patients with clinical or radiographic evidence of PH, with increased frequency if clinically indicated such as worsening shunting, increasing ventilation requirements, or other signs of clinical deterioration. Pulmonary vasodilator therapy, including inhaled nitric oxide and the phosphodiesterase type 5-inhibitor sildenafil, was administered in patients with clinically severe PH, as evidenced by requirement for maximal ventilator support with refractory hypoxia and shunting. Abdominal wall closure was performed by either staged Schuster repair [8] or delayed closure following silver sulfadiazine cream as described previously [9]. Gastroesophageal reflux disease (GERD) was defined by a requirement for H2 receptor antagonist and/or proton pump inhibitor therapy at the time of discharge from the NICU. All patients enrolled in our Pulmonary Hypoplasia Program undergo regular follow-up, and are assessed by our multidisciplinary team including general surgery, pulmonary, cardiology and gastroenterology. Statistical analysis was performed using Fisher's exact test for categorical variables and Mann–Whitney test for continuous variables, with p-values b0.05 considered significant. All data analyses were conducted using GraphPad Prism 6.0 (La Jolla, CA).
2. Results From January 2004 through December 2012, 56 neonates with GO were enrolled in the Pulmonary Hypoplasia Program. Parents of one infant with GO born during the study period declined enrollment. Two patients were excluded from further study because of management by palliative care from the time of birth, with prenatal diagnoses including GO complicated by Trisomy 18 and encephalocele, respectively. Of the remaining 54 patients, 34 (63%) patients did not demonstrate evidence of elevated pulmonary pressures, while 20 (37%) demonstrated echocardiographic findings meeting the criteria for a diagnosis of PH. Of the 20 patients diagnosed with PH, 13 were managed with nitric oxide therapy, and 9 of these patients went on to require long-term pulmonary vasodilator therapy with sildenafil. A total of 7 patients with echocardiographic evidence of PH were not treated with nitric oxide; one patient expired prior to surgical intervention, while 6 had mild PH which resolved following staged abdominal wall closure. Table 1 provides a description of the clinical parameters of the entire patient cohort stratified according to PH. Most patients were born near term, with no observed association between PH and gender, birth weight, gestational age or APGAR scores. Prenatal diagnosis of GO was made in all patients, with delivery by cesarean section in all cases. GO is commonly complicated by additional congenital anomalies, and in
Table 1 Baseline characteristics of patients.
Gender (male) Associated congenital anomaliesa TEF Duodenal atresia L-CDH R CDHb Morgagni hernia Pentalogy of Cantrell Prenatal pleural effusion Dextrocardia Coarctation of the aorta ASDc,d VSDc AV canal defect Vertebral anomalyc Rib anomaly Tetralogy of Fallot Bronchopulmonary sequestration Genetic syndrome Unilateral kidney Left-sided superior vena cava Dolichocephaly Plagiocephaly Hemifacial microsomiab Communicating hydrocephalusd Gestational age at delivery (weeks) 1-min APGAR 5-min APGAR Birth weight a b c d
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
15 (44%) 10 (29%)
14 (70%) 14 (70%)
0.0919 0.0037
1 1 0 0 0 0 0 0 0 0 1 1 1 1 1 1
0 1 1 1 1 3 1 1 1 2 1 0 2 0 0 0
2 1 0
0 0 1
0 0 0 0
1 1 1 1
35.9 ± 2.8
35.4 ± 2.8
0.5750
7.0 ± 1.8 7.9 ± 1.4 2555.2 ± 660.5
6.2 ± 2.2 7.9 ± 1.3 2557.2 ± 700.8
0.1170 0.6849 0.9916
Indicates parameters found to be statistically significant (p ≤ 0.05). Dual diagnosis of Right CDH and hemifacial microsomia in one patient. Multiple anomalies including ASD, VSD and vertebral anomalies in one patient. Dual diagnosis of ASD and communicating hydrocephalus in one patient.
this series, the presence of other anomalies was significantly associated with PH (p = 0.0037). Table 2 provides a description of the clinical course of the study population stratified according to PH. No significant differences were observed with respect to patients undergoing staged Schuster procedure compared to delayed abdominal closure. PH was found to be significantly associated with a number of endpoints related to pulmonary insufficiency, including duration of mechanical ventilation (p = 0.0008), requirement for HFOV (p = 0.0281) and tracheostomy (p = 0.0032), reliance on supplemental oxygen at the time of NICU discharge (p = 0.0004) and the diagnosis of reactive airway disease requiring chronic bronchodilator therapy (p = 0.0230). Gastroesophageal reflux disease was diagnosed in the majority of patients in both cohorts, with a requirement for long-term acid suppression therapy in 73.5% and 95% of patients respectively. A subset of patients ultimately required Nissen fundoplication, with a trend towards significantly increased rates in patients with PH (p = 0.0572). Reliance on tube feeding at the time of NICU discharge was significantly increased in the PH cohort (p = 0.0243). Fetal MRI and ultrasonography were reviewed for contents of the sac-covered defect in all patients, with results summarized in Table 3. Herniation of the liver was observed in all cases, and bowel loops were also contained within the sac in the majority of patients (76.5% and 90% respectively, p = 0.2912). Herniation of the stomach into the defect was observed less frequently and was significantly associated with the subsequent development of PH (p = 0.0322), with an odds ratio of 4.8462 (95% confidence 1.2865 to 18.2552).
E.A. Partridge et al. / Journal of Pediatric Surgery 49 (2014) 1767–1770 Table 2 Clinical outcomes.
NICU length of staya Staged closure Duration of mechanical ventilationa Requirement for HFOVa Requirement for tracheostomya Requirement for home oxygena Reactive airway diseasea Gastroesophageal reflux Requirement for feeding tube at time of NICU dischargea Nissen fundoplication Nitric oxide therapya Chronic pulmonary vasodilator therapya Survivala a
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
57.3 ± 35.2 22 (64.7%) 16.5 ± 14.9 3 (8.8%) 2 (5.9%) 5 (14.7%) 13 (38.2%) 25 (73.5%) 15 (44.1%)
152.3 ± 97.4 11 (55%) 45.3 ± 28.9 7 (35%) 8 (40%) 12 (60%) 15 (75%) 19 (95%) 16 (80%)
b0.0001 0.3934 0.0008 0.0281 0.0032 0.0004 0.0239 0.1308 0.0243
1 (2.9%) 0 (0%) 0 (0%)
4 (20%) 13 (65%) 9 (45%)
0.0572 b0.0001 b0.0001
34 (100%)
17 (85.0%)
0.0460
Indicates parameters found to be statistically significant (p ≤ 0.05).
3. Discussion In this study, we analyzed the incidence and management of pulmonary hypertension in GO patients who underwent standardized care at a single high-volume institution. We have observed PH in over one third of GO patients, demonstrating a significant and underreported complication of this disorder and emphasizing the importance of early regular assessment by echocardiography in surviving patients. Infants with GO complicated by PH had increased respiratory support requirements as evidenced by significant increases in duration of mechanical ventilation, requirement for high-frequency oscillatory ventilation and tracheostomy, and dependence on home oxygen therapy following hospital discharge. A spectrum of severity of PH was observed in this study, with a proportion of patients managed by conventional ventilatory support with spontaneous resolution of PH following abdominal wall closure (6/20, or 30%). The majority of PH patients required inhaled nitric oxide therapy (13/20, or 65%), and a subset of these patients went on to require long-term pulmonary vasodilator therapy (9/20, or 45%). Furthermore, our findings suggest that abnormal pulmonary vascular tone in children with GO does not necessarily resolve following surgical repair, as 9 patients required long-term pulmonary vasodilator therapy with sildenafil. Our study is strengthened by the large sample size of study participants and standardized treatment of patients, suggesting generalizability of our findings to this patient population. Several studies have previously reported pulmonary hypoplasia in children with abdominal wall defects [4,10,11]. The observed association of PH with herniation of the stomach suggests a direct relationship between the size of the defect and resulting degree of abdominal viscera herniation with the severity of pulmonary insufficiency, though further studies will be necessary to determine the mechanism of pulmonary hypoplasia in these patients. We observed high rates of reactive airway disease in GO survivors, and this was significantly associated with PH in our series. Whether
Table 3 Prenatal imaging features predict pulmonary hypertension.
Contents of hernia sac: liver Contents of hernia sac: bowel Contents of hernia sac: stomacha a
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
34 (100%) 32 (94.1%) 13 (38.2%)
20 (100%) 19 (95%) 12 (60%)
1.0000 1.0000 0.0322
Indicates parameters found to be statistically significant (p ≤ 0.05).
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this is an innate characteristic of the airways of infants with pulmonary hypoplasia caused by GO versus increased respiratory support requirements and sequalae of mechanical ventilation remains unclear. Pulmonary function abnormalities have been described in GO survivors from our center and include reduced mean forced vital capacity and forced expiratory volume on pulmonary function testing, with significant bronchodilator responsiveness in almost half of all patients studied [12]. Similar observations have been made among survivors of congenital diaphragmatic hernia [13] and bronchopulmonary dysplasia [14], suggesting that underlying pulmonary hypoplasia may predispose infants to the development of reactive airway disease. The high rates of GERD observed in this study support previous reports indicating increased predisposition to reflux disease in infants with congenital abdominal wall defects [15,16]. The etiology of GERD in patients with abdominal wall defects has been hypothesized to be attributable to increased intraabdominal pressure after closure of the abdominal wall [17], while motility disturbance of the upper gastrointestinal tract may also play a role [18]. In this study, severity of GERD as evidenced by requirement for Nissen fundoplication was significantly increased in PH patients, as was a reliance on tube feeding at the time of hospital discharge. The observed association of stomach herniation with PH and severe GERD requiring Nissen fundoplication might reflect a direct impact on upper gastrointestinal motility disorders. The results of this single-center retrospective study demonstrate a high incidence of PH in GO survivors, and identify prenatal imaging features which may predict abnormal vascular tone in these patients. It is expected that the findings of this large series of patients are applicable to the population of infants diagnosed with GO, suggesting that approximately one third of GO patients will develop pulmonary hypertension. Screening for PH should be performed within the first week of life, with echocardiography performed at regular intervals in patients with clinical or radiologic evidence of PH. In this series, patients with evidence of elevated pulmonary pressures were assessed by echocardiography approximately once weekly until demonstrable stabilization or resolution of PH. Following hospital discharge, all patients enrolled in our multidisciplinary Pulmonary Hypoplasia Program undergo regular follow-up in outpatient surgery, cardiology and pulmonology clinics, with electrocardiography, echocardiography and pulmonary function testing to reassess cardiopulmonary function as indicated. The observed association of PH with herniation of the stomach suggests a direct relationship between the size of the defect and frequency of abnormal pulmonary vascular tone, though further study is required to investigate the underlying mechanisms of PH and pulmonary hypoplasia in this patient population. These findings support a role for focused postnatal screening for PH in all GO survivors, and may assist in the management of these patients to optimize clinical outcomes.
References [1] Barisic I, Clementi M, Hausler M, et al. Evaluation of prenatal ultrasound diagnosis of fetal abdominal wall defects by 19 European registries. Ultrasound Obstet Gynecol 2001;18:309–16. [2] Danzer E, Gerdes M, D'Agostino JA, et al. Prospective, interdisciplinary follow-up of children with prenatally diagnosed giant omphalocele: short-term neurodevelopmental outcome. J Pediatr Surg 2010;45:718–23. [3] Schwaitzberg SD, Pokorny WJ, McGill CW, et al. Gastroschisis and omphalocele. Am J Surg 1982;144:650–4. [4] Hershenson MR, Brouillette RT, Lm Klemka, et al. Respiratory insufficiency in newborns with abdominal wall defects. J Pediatr Surg 1985;20:348–53. [5] Argyle JC. Pulmonary hypoplasia in infants with giant abdominal wall defects. Pediatr Pathol 1989;9:43–55. [6] Keijzer R, Puri P. Congenital diaphragmatic hernia. Semin Pediatr Surg 2010;19: 180–5. [7] Kays D, Langham Jr MR, Ledbetter D, et al. Detrimental effects of standard medical therapy in congenital diaphragmatic hernia. Ann Surg 1999;230:340–8. [8] Schuster SR. A new method for the staged repair of large omphaloceles. Surg Gynecol Obstet 1967;125:837–50. [9] Ein HS, Langer JC. Delayed management of giant omphalocele using silver sulfadiazine cream: an 18-year experience. J Pediatr Surg 2012;47:494–500.
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[10] Dimitriou G, Greenough A, Giffin F, et al. Temporary impairment of lung function in infants with abdominal wall defects who have undergone surgery. J Pediatr Surg 1996;31:670–2. [11] Thompson PJ, Greenough A, Dykes E, et al. Impaired respiratory function in infants with anterior abdominal wall defects. J Pediatr Surg 1993;28: 664–6. [12] Danzer E, Hedrick HL, Rintoul NE, et al. Assessment of early pulmonary function abnormalities in giant omphalocele survivors. J Pediatr Surg 2012; 47:1811–20. [13] Trachsel D, Selvadurai H, Bohn D, et al. Long-term pulmonary morbidity in survivors of congenital diaphragmatic hernia. Pediatr Pulmonol 2005;39:433–9.
[14] Northway WH, Moss RB, Carlisle KB, et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990;323:1793–9. [15] Koivusalo A, Rintala R, Lindahl H. Gastroesophageal reflux disease in children with a congenital abdominal wall defect. J Pediatr Surg 1999;34:1127–9. [16] Beaudoin S, Kieffer G, Sapin E, et al. Gastroesophageal reflux in neonates with congenital abdominal wall defect. Eur J Pediatr Surg 1995;5:323–6. [17] Qi B, Diez-Pardo JA, Soto C, et al. Transdiaphragmatic pressure gradients and lower esophageal sphincter after tight abdominal wall plication in the rat. J Pediatr Surg 1996;31:1666–9. [18] Jolley SG, Tunell WP, Thomas S, et al. The significance of gastric emptying in children with intestinal malformation. J Pediatr Surg 1985;20:627–31.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pulmonary hypertension in giant omphalocele infants Emily A. Partridge a, Brian D. Hanna b, Howard B. Panitch c, Natalie E. Rintoul d, William H. Peranteau a, Alan W. Flake a, N. Scott Adzick a, Holly L. Hedrick a,⁎ a
Department of Surgery, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States Division of Cardiology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 19104 Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States d Division of Neonatology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States b c
a r t i c l e
i n f o
Article history: Received 24 August 2014 Accepted 5 September 2014 Key words: Abdominal wall defects Pulmonary hypoplasia Pulmonary hypertension Reactive airway disease
a b s t r a c t Background: Pulmonary hypoplasia has been described in cases of giant omphalocele (GO), although pulmonary hypertension (PH) has not been extensively studied in this disorder. In the present study, we describe rates and severity of PH in GO survivors who underwent standardized prenatal and postnatal care at our institution. Methods: A retrospective chart review was performed for all patients in our pulmonary hypoplasia program with a diagnosis of GO. Statistical significance was calculated using Fisher's exact test and Mann–Whitney test (p b 0.05). Results: Fifty-four patients with GO were studied, with PH diagnosed in twenty (37%). No significant differences in gender, gestational ages, birth weight, or Apgar scores were associated with PH. Patients diagnosed with PH were managed with interventions, including high frequency oscillatory ventilation, and nitric oxide. Nine patients required long-term pulmonary vasodilator therapy. PH was associated with increased length of hospital stay (p b 0.001), duration of mechanical ventilation (p = 0.008), and requirement for tracheostomy (p = 0.0032). Overall survival was high (94%), with significantly increased mortality in GO patients with PH (p = 0.0460). Prenatal imaging demonstrating herniation of the stomach into the defect was significantly associated with PH (p = 0.0322), with a positive predictive value of 52%. Conclusions: In this series, PH was observed in 37% of GO patients. PH represents a significant complication of GO, and management of pulmonary dysfunction is a critical consideration in improving clinical outcomes in these patients. © 2014 Elsevier Inc. All rights reserved.
Omphalocele is a midline ventral abdominal wall defect occurring at an incidence of 1 in 6000 live births [1], resulting in herniation of the abdominal viscera into a membrane-covered sac composed of an inner layer of peritoneum and an outer layer of amnion. Omphalocele may be classified as small, ruptured or giant according to the contents and integrity of the sac, with giant omphalocele (GO) defined as a large central sac-covered defect containing most of the liver [2]. Respiratory insufficiency is frequently observed in infants with giant abdominal wall defects including GO. Respiratory failure in these patients has been ascribed to increased intraabdominal pressure and upward displacement of the diaphragm following closure [3], though surgical techniques to minimize intraabdominal pressure following closure have demonstrated prolonged respiratory insufficiency in a subset of patients, implicating underlying pulmonary maldevelopment in this disorder [4]. Abnormal pulmonary development in infants with GO has been attributed to narrow chest wall deformities in addition to pulmonary hypoplasia. Pulmonary hypoplasia was described in a series of 114 patients with abdominal wall defects, with markedly decreased lung weight to body ratios in a subset of infants examined at ⁎ Corresponding author at: The Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia, Division of General, Thoracic and Fetal Surgery, Philadelphia PA, 19104, United States. Tel.: +1 215 590 2733; fax: +1 215 590 2447. E-mail address: [email protected] (H.L. Hedrick). http://dx.doi.org/10.1016/j.jpedsurg.2014.09.016 0022-3468/© 2014 Elsevier Inc. All rights reserved.
autopsy [5]. Abnormal pulmonary vascular tone is frequently implicated in pulmonary hypoplasia, and represents a significant limitation to survival and long-term functional outcomes in patients with lung maldevelopment secondary to space-occupying lesions of the thorax including congenital diaphragmatic hernia [6]. In 2004, an interdisciplinary program was established for all infants seen at our institution with a diagnosis of pulmonary hypoplasia, including infants with GO. This prospective program follows patients with comprehensive evaluation, including assessment and management of pulmonary hypertension. We sought to describe the incidence and course of pulmonary hypertension in GO patients who underwent standardized prenatal and postnatal care at our institution. 1. Methods With approval by the Children's Hospital of Philadelphia Institutional Review Board, the records of all GO patients treated at our institution and enrolled in the interdisciplinary Pulmonary Hypoplasia Program between January 2004 and December 2012 were retrospectively analyzed. Recorded data on patient demographics, prenatal course and imaging, delivery information, neonatal care, surgical repair, and respiratory support requirements were analyzed. Inclusion criteria included a diagnosis of GO, as defined by a midline abdominal wall defect with a membranous sac containing most (N75%) of the liver.
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Exclusion criteria included patients with abdominal wall defects not meeting the definition of GO, as pulmonary hypoplasia is not an established complication of these defects, as well as those patients managed by palliative care at birth. Respiratory support requirements were reviewed for all included patients. When mechanical ventilation was required, lung preservation strategies were used as previously described [7]. Ventilation support was aimed to maintain preductal oxygen saturations above 85%, with high-frequency oscillatory ventilation (HFOV) reserved for patients with refractory hypercapnia. Echocardiography was performed as clinically indicated to assess right ventricular pressures, with PH defined according to standard criteria (right ventricular systolic pressure estimate [RVSPE] ≥ 27 mm Hg, or qualitative features including right ventricular dilation/enlargement/hypertrophy, and septal flattening). PH was diagnosed based upon calculated RVSPE in those patients with sufficient tricuspid regurgitation (TR) to permit this measurement, with flows ≥27 mm Hg considered diagnostic of PH. In those patients with insufficient TR to permit calculation of RVSPE, the presence of two or more qualitative features of PH was considered diagnostic of PH. Directionality of flow through the ductus arteriosus was not considered in the diagnosis of PH. Echocardiograms were performed in the first week of life in all patients and were repeated approximately once weekly in patients with clinical or radiographic evidence of PH, with increased frequency if clinically indicated such as worsening shunting, increasing ventilation requirements, or other signs of clinical deterioration. Pulmonary vasodilator therapy, including inhaled nitric oxide and the phosphodiesterase type 5-inhibitor sildenafil, was administered in patients with clinically severe PH, as evidenced by requirement for maximal ventilator support with refractory hypoxia and shunting. Abdominal wall closure was performed by either staged Schuster repair [8] or delayed closure following silver sulfadiazine cream as described previously [9]. Gastroesophageal reflux disease (GERD) was defined by a requirement for H2 receptor antagonist and/or proton pump inhibitor therapy at the time of discharge from the NICU. All patients enrolled in our Pulmonary Hypoplasia Program undergo regular follow-up, and are assessed by our multidisciplinary team including general surgery, pulmonary, cardiology and gastroenterology. Statistical analysis was performed using Fisher's exact test for categorical variables and Mann–Whitney test for continuous variables, with p-values b0.05 considered significant. All data analyses were conducted using GraphPad Prism 6.0 (La Jolla, CA).
2. Results From January 2004 through December 2012, 56 neonates with GO were enrolled in the Pulmonary Hypoplasia Program. Parents of one infant with GO born during the study period declined enrollment. Two patients were excluded from further study because of management by palliative care from the time of birth, with prenatal diagnoses including GO complicated by Trisomy 18 and encephalocele, respectively. Of the remaining 54 patients, 34 (63%) patients did not demonstrate evidence of elevated pulmonary pressures, while 20 (37%) demonstrated echocardiographic findings meeting the criteria for a diagnosis of PH. Of the 20 patients diagnosed with PH, 13 were managed with nitric oxide therapy, and 9 of these patients went on to require long-term pulmonary vasodilator therapy with sildenafil. A total of 7 patients with echocardiographic evidence of PH were not treated with nitric oxide; one patient expired prior to surgical intervention, while 6 had mild PH which resolved following staged abdominal wall closure. Table 1 provides a description of the clinical parameters of the entire patient cohort stratified according to PH. Most patients were born near term, with no observed association between PH and gender, birth weight, gestational age or APGAR scores. Prenatal diagnosis of GO was made in all patients, with delivery by cesarean section in all cases. GO is commonly complicated by additional congenital anomalies, and in
Table 1 Baseline characteristics of patients.
Gender (male) Associated congenital anomaliesa TEF Duodenal atresia L-CDH R CDHb Morgagni hernia Pentalogy of Cantrell Prenatal pleural effusion Dextrocardia Coarctation of the aorta ASDc,d VSDc AV canal defect Vertebral anomalyc Rib anomaly Tetralogy of Fallot Bronchopulmonary sequestration Genetic syndrome Unilateral kidney Left-sided superior vena cava Dolichocephaly Plagiocephaly Hemifacial microsomiab Communicating hydrocephalusd Gestational age at delivery (weeks) 1-min APGAR 5-min APGAR Birth weight a b c d
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
15 (44%) 10 (29%)
14 (70%) 14 (70%)
0.0919 0.0037
1 1 0 0 0 0 0 0 0 0 1 1 1 1 1 1
0 1 1 1 1 3 1 1 1 2 1 0 2 0 0 0
2 1 0
0 0 1
0 0 0 0
1 1 1 1
35.9 ± 2.8
35.4 ± 2.8
0.5750
7.0 ± 1.8 7.9 ± 1.4 2555.2 ± 660.5
6.2 ± 2.2 7.9 ± 1.3 2557.2 ± 700.8
0.1170 0.6849 0.9916
Indicates parameters found to be statistically significant (p ≤ 0.05). Dual diagnosis of Right CDH and hemifacial microsomia in one patient. Multiple anomalies including ASD, VSD and vertebral anomalies in one patient. Dual diagnosis of ASD and communicating hydrocephalus in one patient.
this series, the presence of other anomalies was significantly associated with PH (p = 0.0037). Table 2 provides a description of the clinical course of the study population stratified according to PH. No significant differences were observed with respect to patients undergoing staged Schuster procedure compared to delayed abdominal closure. PH was found to be significantly associated with a number of endpoints related to pulmonary insufficiency, including duration of mechanical ventilation (p = 0.0008), requirement for HFOV (p = 0.0281) and tracheostomy (p = 0.0032), reliance on supplemental oxygen at the time of NICU discharge (p = 0.0004) and the diagnosis of reactive airway disease requiring chronic bronchodilator therapy (p = 0.0230). Gastroesophageal reflux disease was diagnosed in the majority of patients in both cohorts, with a requirement for long-term acid suppression therapy in 73.5% and 95% of patients respectively. A subset of patients ultimately required Nissen fundoplication, with a trend towards significantly increased rates in patients with PH (p = 0.0572). Reliance on tube feeding at the time of NICU discharge was significantly increased in the PH cohort (p = 0.0243). Fetal MRI and ultrasonography were reviewed for contents of the sac-covered defect in all patients, with results summarized in Table 3. Herniation of the liver was observed in all cases, and bowel loops were also contained within the sac in the majority of patients (76.5% and 90% respectively, p = 0.2912). Herniation of the stomach into the defect was observed less frequently and was significantly associated with the subsequent development of PH (p = 0.0322), with an odds ratio of 4.8462 (95% confidence 1.2865 to 18.2552).
E.A. Partridge et al. / Journal of Pediatric Surgery 49 (2014) 1767–1770 Table 2 Clinical outcomes.
NICU length of staya Staged closure Duration of mechanical ventilationa Requirement for HFOVa Requirement for tracheostomya Requirement for home oxygena Reactive airway diseasea Gastroesophageal reflux Requirement for feeding tube at time of NICU dischargea Nissen fundoplication Nitric oxide therapya Chronic pulmonary vasodilator therapya Survivala a
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
57.3 ± 35.2 22 (64.7%) 16.5 ± 14.9 3 (8.8%) 2 (5.9%) 5 (14.7%) 13 (38.2%) 25 (73.5%) 15 (44.1%)
152.3 ± 97.4 11 (55%) 45.3 ± 28.9 7 (35%) 8 (40%) 12 (60%) 15 (75%) 19 (95%) 16 (80%)
b0.0001 0.3934 0.0008 0.0281 0.0032 0.0004 0.0239 0.1308 0.0243
1 (2.9%) 0 (0%) 0 (0%)
4 (20%) 13 (65%) 9 (45%)
0.0572 b0.0001 b0.0001
34 (100%)
17 (85.0%)
0.0460
Indicates parameters found to be statistically significant (p ≤ 0.05).
3. Discussion In this study, we analyzed the incidence and management of pulmonary hypertension in GO patients who underwent standardized care at a single high-volume institution. We have observed PH in over one third of GO patients, demonstrating a significant and underreported complication of this disorder and emphasizing the importance of early regular assessment by echocardiography in surviving patients. Infants with GO complicated by PH had increased respiratory support requirements as evidenced by significant increases in duration of mechanical ventilation, requirement for high-frequency oscillatory ventilation and tracheostomy, and dependence on home oxygen therapy following hospital discharge. A spectrum of severity of PH was observed in this study, with a proportion of patients managed by conventional ventilatory support with spontaneous resolution of PH following abdominal wall closure (6/20, or 30%). The majority of PH patients required inhaled nitric oxide therapy (13/20, or 65%), and a subset of these patients went on to require long-term pulmonary vasodilator therapy (9/20, or 45%). Furthermore, our findings suggest that abnormal pulmonary vascular tone in children with GO does not necessarily resolve following surgical repair, as 9 patients required long-term pulmonary vasodilator therapy with sildenafil. Our study is strengthened by the large sample size of study participants and standardized treatment of patients, suggesting generalizability of our findings to this patient population. Several studies have previously reported pulmonary hypoplasia in children with abdominal wall defects [4,10,11]. The observed association of PH with herniation of the stomach suggests a direct relationship between the size of the defect and resulting degree of abdominal viscera herniation with the severity of pulmonary insufficiency, though further studies will be necessary to determine the mechanism of pulmonary hypoplasia in these patients. We observed high rates of reactive airway disease in GO survivors, and this was significantly associated with PH in our series. Whether
Table 3 Prenatal imaging features predict pulmonary hypertension.
Contents of hernia sac: liver Contents of hernia sac: bowel Contents of hernia sac: stomacha a
No pulmonary hypertension (n = 34)
Pulmonary hypertension (n = 20)
p Value
34 (100%) 32 (94.1%) 13 (38.2%)
20 (100%) 19 (95%) 12 (60%)
1.0000 1.0000 0.0322
Indicates parameters found to be statistically significant (p ≤ 0.05).
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this is an innate characteristic of the airways of infants with pulmonary hypoplasia caused by GO versus increased respiratory support requirements and sequalae of mechanical ventilation remains unclear. Pulmonary function abnormalities have been described in GO survivors from our center and include reduced mean forced vital capacity and forced expiratory volume on pulmonary function testing, with significant bronchodilator responsiveness in almost half of all patients studied [12]. Similar observations have been made among survivors of congenital diaphragmatic hernia [13] and bronchopulmonary dysplasia [14], suggesting that underlying pulmonary hypoplasia may predispose infants to the development of reactive airway disease. The high rates of GERD observed in this study support previous reports indicating increased predisposition to reflux disease in infants with congenital abdominal wall defects [15,16]. The etiology of GERD in patients with abdominal wall defects has been hypothesized to be attributable to increased intraabdominal pressure after closure of the abdominal wall [17], while motility disturbance of the upper gastrointestinal tract may also play a role [18]. In this study, severity of GERD as evidenced by requirement for Nissen fundoplication was significantly increased in PH patients, as was a reliance on tube feeding at the time of hospital discharge. The observed association of stomach herniation with PH and severe GERD requiring Nissen fundoplication might reflect a direct impact on upper gastrointestinal motility disorders. The results of this single-center retrospective study demonstrate a high incidence of PH in GO survivors, and identify prenatal imaging features which may predict abnormal vascular tone in these patients. It is expected that the findings of this large series of patients are applicable to the population of infants diagnosed with GO, suggesting that approximately one third of GO patients will develop pulmonary hypertension. Screening for PH should be performed within the first week of life, with echocardiography performed at regular intervals in patients with clinical or radiologic evidence of PH. In this series, patients with evidence of elevated pulmonary pressures were assessed by echocardiography approximately once weekly until demonstrable stabilization or resolution of PH. Following hospital discharge, all patients enrolled in our multidisciplinary Pulmonary Hypoplasia Program undergo regular follow-up in outpatient surgery, cardiology and pulmonology clinics, with electrocardiography, echocardiography and pulmonary function testing to reassess cardiopulmonary function as indicated. The observed association of PH with herniation of the stomach suggests a direct relationship between the size of the defect and frequency of abnormal pulmonary vascular tone, though further study is required to investigate the underlying mechanisms of PH and pulmonary hypoplasia in this patient population. These findings support a role for focused postnatal screening for PH in all GO survivors, and may assist in the management of these patients to optimize clinical outcomes.
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