Patients with congenital diaphragmatic hernia (CDH) have significant morbidity and mortality. The leading cause of CDH related morbidity and mortality is respiratory failure resulting from pulmonary hypoplasia. The severity of CDH varies widely depending on the degree of pulmonary hypertension and pulmonary hypoplasia. The outcomes of CDH have been shown to improve by introducing high-frequency oscillatory ventilation (HFOV), inhaled nitric oxide (iNO), extracorporeal membrane oxygenation (ECMO), and fetal interventions. [1]

According to recent studies, ventilator-induced lung injury which clinically presents as pneumothoraces may worsen both the short-term [23] and long-term outcomes [45] of CDH patients. In order to avoid the harmful effects of barotrauma, ventilatory management of neonates with CDH has universally shifted to gentle ventilation strategies permitting hypercapnia and hypoxia [678910]. Nevertheless, the occurrence of pneumothorax has remained relatively high. In recent studies, the frequency of pneumothorax occurrence was reported in the range of 17.5% to 36.1% [11121314]. As a fatal preoperative and/or postoperative complication, the incidence of pneumothorax occurrence should be kept low and management strategies for CDH patients need to be elaborated more.

We reviewed neonates with CDH managed at a single center in order to determine the risk factors associated with the outcomes of neonates with CDH.

Up until the mid-1990s, the main purpose of ventilator care for CDH patients was to induce respiratory alkalosis by hyperventilation. Because respiratory alkalosis helps lower pulmonary vascular resistance and pulmonary artery pressure, resulting in reverse ductal shunting [15]. Recent studies have demonstrated that ventilator associated lung injury due to hyperventilation could have harmful effects on survival and long term pulmonary function [45].

A permissive hypercapnia strategy has been advocated for the management of infants with PPHN for more than 25 years [16] and has been adopted for CDH patients since the late 1990s. Several case series have indicated that preductal oxygenation is the most important step to improve outcome with a permitting airway pressure limitation and hypercapnia [678910]. Through taking advantage of iNO, pulmonary vascular resistance and pulmonary arterial pressure can both be selectively lowered. Therefore, the hyperventilation strategy could be substituted with the gentle ventilation strategy, which is the recent mainstay of ventilator care in infants with CDH.

This study clarified the association between overall mortality and the occurrence of pneumothorax. We assume that the use of gentle ventilation strategies helped prevent the occurrence of pneumothorax and therefore may have contributed to improved survival. According to several case series of CDH, gentle ventilation strategies which limit airway pressure and permit hypercapnia with enhancing preductal saturation are the most important factors for improved survival [678910]. However, some studies have indicated that underlying disease status representing the degree of hypoplasia itself is the main cause of pneumothorax occurrence [17]. These results suggest that most of occurrences of pneumothorax are inevitable, regardless of respiratory management.

Other significant risk factor was right-sided lesion. Right-sided CDH has been reported as an important risk factor in several studies [1819] and the relationship also reproduced in this study. Some studies reported that right-sided CDH was difficult to diagnose prenatally than left-sided CDH [2021]. Also, right-sided CDH patients required more ECMO support than left CDH patients [1819]. This reflects more severe of pulmonary hypertension and pulmonary hypoplasia in right-sided CDH patients and could be a reasonable assumption for poorer outcomes. In this study, the number of right-sided CDH patients was only 20, which lacks statistical power to derive any significant results. In order to describe unique characteristics of right-sided CDH patients, larger studies should be conducted with unified treatment protocol.

In this study, the mortality rate of recent 6 years (2009–2014) was lower than that of the earlier 14 years (1995–2008). When analyzed according to era divided into three periods, the recent era showed better survival rate than that of the intermediate era (2002–2008; 71% vs. 29%, p=0.006) and demonstrated a tendency of lower mortality than that of the early era (1995–2008; 71% vs 42%, p=0.062). Compared to the recent 6 years, there were more patients who were not able to undergo surgery in the intermediate era (91.7% vs. 47.6%, p=0.002, analyzed by fisher's exact test). In the period of 1995 to 2001, more patients seemed not to be able to underwent surgery but there was only statistical insignificant tendency (91.7% vs. 73.7%, p=0.212, analyzed by fisher's exact test). The reason why a CDH patient cannot undergo surgery is preoperative instablity. We assume that disease severity itself contributed most to the patient's instability via pulmonary hypoplasia and/or pulmonary hypertension. Under discussions with pediatric surgeons and neonatal intensivists, gentle ventilation strategies were emphasized more and HFOV was adopted at an early stage to reduce the occurrence of pneumothorax. We suggest the possibility that these approaches could have positively affected outcomes of recent era.

As well-known risk factors, karyotype abnormality, cardiac anomaly and non-cardiac anomaly were also reviewed. However, karyotyping was only analyzed in 15 patients and there were only 2 cases of reported karyotype abnormality, which is insufficient number to derive statistical power. Forty-six patients were checked for cardiac anomaly and there were 11 patients with cardiac anomalies. Forty-seven patients were checked for non-cardiac anomaly and there were 19 patients with the non-cardiac anomaly. However, most of patients who were not examined were more prevalent within the mortality group, 13 of 18 patients for cardiac anomaly and 13 of 17 patients for non-cardiac anomaly, respectively. Therefore, statistical analysis was not performed for the relationship between the mortality and the cardiac/non-cardiac anomaly due to possible substantial bias.

The most important limitation of this study is that it is based on retrospective review. In addition, the number of cases was only 64, which is an insufficient number to induce statistical significance. As described above, the treatment strategies for CDH patients were not established well and were decided by clinical decisions. Because this study has been conducted for a long period, the rationale for clinical decision have been changed in some degree. These minor changes in clinical decision could have produced heterogeneity in this study over periods and may have affected statistical analysis.

In the future, a more elaborate prospective study with more patients is needed to reveal any causal relationship between the occurrence of pneumothorax and overall mortality and to examine the risk factors which lack statistical power in this study.

In conclusion, the survival rate of neonates with CDH at our center has improved over the last 2 decades. We assume that the main cause of this improvement is the adoption of the gentle ventilation strategy with permissive hypercapnia and permissive hypoxia. The risk factors for mortality include the occurrence of pneumothorax and right-sided lesion. Therefore, it is vital to prevent the occurrence of pneumothorax in treating CDH patients.