Surgical Complications in Children with CDH: A Multivariate Analysis

Multivariate logistic regression analyses were performed to evaluate the association of the hypothesized risk factors with the outcomes of surgical haemorrhage and chylothorax. The hypothesized potential risk factors were prenatal diagnosis of CHD (yes/no), side of CDH (left/right/bilateral), liver-up and left-side hernia, because this is often described as severe (yes/no), pulmonary hypertension (yes/no), treatment with inhaled nitric oxide (iNO) (yes/no), ECMO use (yes/no), repair with diaphragmatic patch (yes/no), and abdominal patch after CDH repair (yes/no). The odds ratios (OR) with 95% confidence intervals (CI) were first estimated for the separate potential risk factors, and thereafter an adjusted model was used including all potential risk factors. For the outcome recurrence of CDH within 1 year, a Cox regression analyses were used accounting for time to recurrence, calculating hazard ratios (HR) and 95% CI in a crude and adjusted model for the risk factors. Only patients who were surgically repaired were included in these analyses. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics Data Editor software program version 22.

Two hundred and fifteen patients were included in this study, of whom 58% were born in our centre. Eleven patients born in this period were excluded for several reasons such as diagnosis at a later age (three patients) or dying directly after birth (four patients). All included patients had a follow-up period of at least 1 year, which was the endpoint of follow-up of this study. They had a 1-year survival rate of 73%. After 1 year, ten patients were lost to follow-up for several reasons, but were contacted to ask whether they preferred follow-up by this centre or by contact with their peripheral centre [14]. ECMO was used in 31% of the patients (n = 66). All except one were treated with VA-ECMO. The mean ECMO run duration was 8.6 days (SD 3.6). Of the 66 ECMO patients, 38 patients did not survive up to the age of one. The mortality rate after 1 year was higher in patients requiring ECMO compared to those who did not (58% vs. 14%, p < 0.001). Of the 20 patients who did not survive and did not receive ECMO treatment, two patients had a chromosomal anomaly and five a cardiac anomaly. The diaphragm defects of fifteen of these patients were not repaired at all.

Of all 215 patients, the defects of 197 patients were surgically repaired. The approach to repair was performed by a subcostal incision in most patients (89%), 3% by thoracotomy while the remainder (8%) was repaired in a minimally invasive fashion (four laparoscopic and twelve by thoracoscopy). Demographics of these 197 patients are displayed in Table 1, with specifics of the missing data presented below the table. Most patients were male (62%) and more than half of the patients was prenatally diagnosed (54%). Patch repair was required in 78 (40%) of the patients. A more detailed description of surgical repair of these patients can be found in a previous overview article on this cohort [15].

Almost one third of the surgically repaired patients were cannulated on ECMO (63 patients). ECMO patients more often required a patch compared to the non-ECMO patients (49 patients (64%) vs. 14 patients (12%), p < 0.001). Mortality after 1 year was significantly higher in patch repaired patients compared to primary repaired patients (34/78 vs. 6/119, p < 0.001).

In total, 60 patients developed one of the three primary outcomes, such as a chylothorax, haemorrhage or recurrence within 1 year. Of these patients with complications, 23 patients (38%) did not survive compared to 17 (12%) of the patients without complications (p < 0.001). Patients with complications required surgery more often within the first year of life than those without complications (median 3 (range 1–12) vs. 1 (range 1–11), p < 0.001).

As expected, our data show that ECMO is associated with the development of surgical haemorrhage. This can partly be explained by the fact that these patients are treated with anticoagulation medication (for example, heparin), which makes these neonates more vulnerable to bleeding complications [16]. Patients who required both ECMO and a patch had the highest chance of developing surgical haemorrhage. However, after adjusting for other risk factors, patch repair on its own did not seem to be associated with this outcome. Remarkably, inhaled nitric oxide seemed to raise the chance of haemorrhage, while pulmonary hypertension itself did not. Nitric oxide is a vasodilator and is used in cases of severe respiratory failure. However, side effects are decreased platelet aggregation, surfactant dysfunction and an increased risk of bleeding [17]. There has been a lot of discussion on the role of iNO treatment in CDH patients and its use is highly variable among centres all over the world [18]. Some suggest that iNO does not influence outcomes such as bleeding complications [19]. However, a multicentre study (2016) of the CDH registry stated that iNO use worldwide is highly variable and does not seem to be beneficial and may even be associated with an increased mortality rate [18]. Our study adds evidence that it may raise the rate of surgical haemorrhage and the indications in favour of using it during surgery should be well thought out.

It has been previously described that ECMO or patch repair in CDH patients both increase the incidence of chylothorax [20, 21]. In this study, patients with both ECMO and patch repair had the highest chance of developing this complication, but independently they did not increase the risk for chylothorax. There are different hypotheses on why CDH patients develop a chylothorax such as rupture of the lymph vessels peri-operatively during CDH repair or due to a high pressure of abdominal organs intra-thoracically (so more damage to lymph vessels), which could also explain the relationship with patch repair, in which the large defect enables more organs to protrude into the thoracic cavity [22]. The association between ECMO and chylothorax has also been described, and it was hypothesized that the pressure in the ductus thoracicus becomes too high causing chylus [22]. Previously, timing of repair was also associated with the odds of developing chylothorax, as only the patients repaired before ECMO did not show an increased risk on chylothorax [21]. None of the patients in this cohort were repaired before ECMO cannulation, but still no correlation could be found.

Recurrence in this group was not significantly associated with ECMO treatment or patch repair. Moreover, the combination of these two treatments did not seem to influence the incidence of short term recurrences. There was no significant difference in primary versus patch repaired patients, which could be due to technical factors such as the manner of patch implementation and avoidance of tension on sutures, which seem to have an influence on developing a recurrence [7, 23]. In our analysis, an abdominal patch, however, seemed to be associated with recurrences (OR 95% CI 11.3 (1.5–84.4)), because almost half of patients with recurrences (42%) initially required an abdominal patch. Delayed abdominal closure after initial requirement of an abdominal patch is more likely when patients are repaired while cannulated on ECMO [24]. The use of abdominal patches has been described as a predictor of mortality, and these patients are more likely to require a higher amount of blood transfusions while on ECMO [24, 25]. In our cohort, mortality rate after 1 year was high as well (57%) where an abdominal patch was needed. However, a clear association with development of recurrences has not yet been described before. One of the causes could be the severity of the disease in these neonates, because an abdominal patch is used mainly in patients with larger defects; however, half of the defect sizes were unknown in the patients with recurrence. Another cause could be the closure of the abdomen in patients with large defects, which gives an increased intra-abdominal volume but may still give a relatively higher intra-abdominal pressure as well during and after surgery. This could lead to a recurrence of the defect due to the high pressure on the diaphragm. Another predictor for recurrence in our study was the presence of pulmonary hypertension during initial hospitalization. This could be due to the underlying pathology, or due to the treatment of the pulmonary hypertension, although we did not find an independent association with the use of iNO. Moreover, there is only a small number of recurrences in this cohort which could possibly be of influence on the significance of these risk factors. A longer follow-up in a larger cohort and prospective data gathering could give more insight into the causes of the recurrence in children with pulmonary hypertension. However, a previous study on the long term outcomes of this research group did not show significantly more recurrences (three after the age of 1 year of age) in the longer follow-up, although ten patients did not complete the long-term follow-up [14].

As this study shows, several factors are associated with different types of surgical complications. Due to its retrospective nature, this data collection may be less reliable. Therefore, our findings will need to be confirmed prospectively. However, the incidence of surgical complications is influenced by multiple factors and these factors could influence surgical timing and peri-operative management to improve surgical outcome. Further steps for possible prevention of these complications are required and need to be prospectively evaluated.