Extracorporeal Membrane Oxygenation for Congenital Diaphragmatic Hernia: A Single Center Experience in Turkey

Objective: Extracorporeal membrane oxygenation is a temporary life-support modality offered for stabilizing neonates with congenital diaphragmatic hernia who are in a critical condition and unresponsive to optimal medical therapy. The aim of this study was to examine our institutional outcomes of early congenital diaphragmatic hernia repair on extracorporeal membrane oxygenation. Materials and Methods: A total of 17 extracorporeal membrane oxygenation-supported patients with congenital diaphragmatic hernia were evaluated and the demographic, diagnostic, laboratory, clinical data, complications and outcome of the patients were reported. Results: The study consisted of 7 females and 10 males. Mean birth weight was 3107 g (range, 2360–3840 g). Median age of extracorporeal membrane oxygenation initiation was 2.1 days. In total four patients received venovenous extracorporeal membrane oxygenation. Other patients received venoarterial extracorporeal membrane oxygenation via aortic and right atrial cannulation. The mean duration of extracorporeal membrane oxygenation was 25 days (range: 1-140 days). Six patients (35.2%) could be weaned from extracorporeal membrane oxygenation. The most common extracorporeal membrane oxygenation related complications were hemorrhage, disseminated intravascular coagulation and limb ischemia (64.7%, 41.1% and 29.4%, respectively). Diaphragmatic defect was repaired via a subcostal incision in 12 of 13 patients. In 88.2% of patients diaphragmatic repair was performed with polytetrafluoroethylene patch. In 77% of patients early congenital diaphragmatic hernia repair was performed concomitantly with extracorporeal membrane oxygenation insertion. The survival rate was 17.6%. Conclusion: Early repair of congenital diaphragmatic hernia in neonates on extracorporeal membrane oxygenation can be associated with high rates of morbidity and mortality. However, extracorporeal membrane oxygenation may be considered a life-saving measure for patients with congenital diaphragmatic hernia who would have otherwise not been salvageable.


INTRODUCTION
Congenital diaphragmatic hernia (CDH) is a severe and complex congenital anomaly occurs approximately 1 in every 2500 to 3000 live births [1]. Despite the advances in medical and surgical techniques and neonatal care capabilities overall survival rate for CDH is still high. Both pulmonary hypoplasia and persistent pulmonary hypertension are considered to be the principal factors determining the survival. was determined from the date of the last follow-up. The neonates were admitted to the neonatal intensive care unit after delivery. Patients with hemodynamic compromise and respiratory distress were stabilized using usual medical therapy and ventilation support. Indication for ECMO in CDH patients was failure of conventional medical management strategies. Patients with life-threatening congenital anomalies, uncontrolled bleeding, and irreversible brain damage were excluded. ECMO cannulations were performed by pediatric cardiovascular surgeons in the operation room. Hernia repair was performed by pediatric surgeons either concomitantly with or several days after the ECMO cannulation. In our institution, the preferred ECMO strategy and cannulation method for neonates with CDH were venoarterial (VA) ECMO and central cannulation through the ascending aorta and right atrium, respectively. The ECMO circuit included a centrifugal pump and a hollow-fiber membrane oxygenator with an integrated heat exchanger. Statistical analysis was performed using SPSS 21 for Windows (SPSS Inc., Chicago, IL, USA). The demographic and clinical findings of the patients were described with rates and percentages, mean, and median values.
Consequently, a considerable amount of neonates with CDH and persistent pulmonary hypertension may necessitate additional support to provide sufficient tissue oxygenation and perfusion [2,3]. In such patients who have unstable hemodynamic parameters and low saturations despite optimal medical management and ventilation support, extracorporeal membrane oxygenation (ECMO), which is a temporary and modified form of cardiopulmonary bypass, should be considered as a bridging strategy until patient stabilization [4,5]. Although management with ECMO has been proven to be associated with better overall survival in patients with CDH, it carries a mortality rate reaching up to 50% primarily due to the systemic anticoagulation-related risk of bleeding [6][7][8].
Most reports regarding the use of ECMO in CDH neonates are from the USA. There are fewer papers reported in Asia and Europe [9][10][11]. In recent years, the use of ECMO reported in Turkey has been involving adult patients primarily. Despite pediatric ECMO applications have been increasing in Turkey, there is only one study mentioning the use of ECMO in CDH to our knowledge [12]. The purpose of our study is to report our experience with the use of ECMO in CDH patients and its outcomes. We are not aware of any previous report emphasizing the results of ECMO usage in patients with CDH in Turkey.

MATERIALS and METHODS
Data of 17 neonates who were operated for CDH were analyzed. In addition to patient characteristics, data were collected including the following variables: Associated cardiac comorbidity, results of preoperative arterial blood gas analysis, right ventricular systolic pressure values, ventilator management, ECMO timing, cannulation site, duration, and complications, surgical technique preference for hernia repair, application of post ECMO stem-cell therapy and in-hospital mortality.

DISCUSSION
CDH is a developmental failure of the diaphragm due to incomplete fusion of elements structuring the diaphragm. It occurs most frequently in the left side and associated with the herniation of the abdominal viscera into the chest cavity. Decreased surface area of the alveoli and the vascular bed (lung hypoplasia), the development of the abnormal pulmonary vasculature, which is more prone to developing resistance and activation of thromboxane synthetase pathways lead to persistent pulmonary hypertension and respiratory failure, subsequently [5,13,14]. Management of the respiratory failure in CDH is complicated and includes both ventilation and pharmacological methods. The initiation of high-frequency oscillatory ventilation (HFOV), is pivotal. Inhaled nitric oxide (iNO) and administration of surfactant may improve oxygenation. Parallel to the advancements of these strategies worldwide uses of ECMO for neonatal acute hypoxic respiratory failure reduced in the last decades [15][16][17]. Nevertheless, ECMO is considered the only intervention for infants who continue to demonstrate respiratory or cardiac failure despite optimal medical and/or ventilation support [18]. The first successful use of ECMO in a newborn with cardiopulmonary failure was reported by Bartlett et al. in 1975 [19]. Nowadays, the frequency of ECMO usage for CDH ranges between 0% to 61%, with mortality rates of 30% to 40% [2,18,20]. Although ECMO can be a life-saving intervention and improves survival in newborns with CDH, it embraces substantial complications including major bleeding, intracranial infarct or bleed, seizures, and infection. The rate of these complications increase primarily with prolonged ECMO usage and relevant mortality may reach up to 50% [5,21]. Thus, it is critical to give the decision of ECMO initiation with a multidisciplinary approach. In our study, the decision for all ECMO initiations was made by a multidisciplinary approach with the primary initiative of the intensive care physicians.  [25]. Mortality rate was considerably high in our study (82.4%). DIC, hemorrhage and sepsis, which all are associated with ECMO usage, were the potential causes of mortality. Besides, the average duration of ECMO run (25 days) is high in the present study which undoubtedly plays a role in adverse outcomes and complications. In the light of these results, we think that ECMO usage in patients with CDH is debatable. Estimation of overall outcome is very difficult due to variations of individual responses. Thus, the decision of ECMO initiation should be individualized and considered primarily based on the reversibility of the respiratory problem. We also believe that survival rate could be increased with growing experience, advancements in ECMO technology and application of novel tissue engineering strategies such as stem cell therapy.

LIMITATIONS OF THE STUDY
This is a retrospective study based on a single-institute experience. The study population is very small and there is no control group. Thus, our findings may only reflect the preliminary results of a learning period.

CONCLUSION
ECMO has high morbidity and mortality rates in neonates with CDH and its survival benefit is unclear. Therefore, further prospective studies with larger patient samples are warranted to evaluate its applicability in patients with CDH. In the meantime, ECMO may be considered a life-saving measure for patients with CDH who would have otherwise not been salvageable.

CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.