Our study showed that the survival rate of neonates with respiratory failure after receiving VV ECMO treatment was as high as 88% at hospital discharge, even higher than that (73%) of neonates with respiratory failure treated by ECMO according to ELSO registry report in January 2019 . The reason might be that the data of ELSO come from the mixed population of VA ECMO and VV ECMO, and the patients who received VA ECMO mostly had hemodynamic instability and needed cardiac support, thus reduce the survival rate. According to the ELSO database, the survival rate of VA ECMO in the treatment of neonatal respiratory failure between 2012 and 2017 was 70%, while that of VV ECMO was 80% .
Our results also showed that among the included studies, the mortality rate of patients in the Kkugdman et al’s  study was lowest, while that in the Chevalier et al’s  study was highest,. which was consistent with the ELSO database record. According to the ELSO database, neonates with MAS have the highest survival rate, with PPHN and CDH coming up next . On one hand, neonates with MAS enrolled in the Kkugdman et al’s study might have more stable respiratory status, plus some new treatment modalities (NO, HFV, surfactant) were used and the ECMO team was more experienced during this time, thus improve the survival rate. On another hand, in the Chevalier et al’s study, cannula applied on neonates was small, which means this group of neonates were small, and at that time ECMO equipment was not advanced, team of VV ECMO was not so experienced, these factors might result in the relatively high mortality of this study.
Since a double-lumen catheter was designed in 1989, VV ECMO was increasingly used in neonatal respiratory failure, and ligation of the carotid artery was avoided [2123–2224]. Over the years, many studies have reported the benefits of VV ECMO for neonatal respiratory failure. Roberts et al  in a single center study compared double-lumen venovenous extracorporeal membrane oxygenation with cephalic draining cannula (VVDL+V ECMO) with data as collected in the ELSO database, with survival rate of 89.1% and 68.7%, respectively. They concluded that VVDL+V approach was associated with improved survival and lower rates of complication as compared with the ELSO database. Fukuda et al  also compared VA with VV access in the cerebral circulation of newborn infants during extracorporeal membrane oxygenation, the results showed that neonates with severe pulmonary failure can be effectively supported by VV ECMO. In addition to stable hemodynamics of the brain compared with VA ECMO, it has advantages in myocardial and pulmonary vascular oxygenation, resulting in favorable cerebral hemodynamics. Moreover, many studies have showed that VV ECMO compared favorably to VA ECMO for cardiovascular support [2527–2628]. Several other previous studies have also showed that VV ECMO was associated to lower rates of neurologic complications as compared with VA ECMO [213,2729–2830]. Some potential advantages of VV ECMO over VA ECMO might explain the results. During VV ECMO, ligation of arteries was avoided, pulmonary circulation and coronary artery perfusion were maintained well, thus left ventricular afterload was reduced.
An overall survival of 88% was seen in the 347 neonates, higher than that of other age groups treated with VV perfusion according to the ELSO database. In addition to the baseline characteristics, many other factors could explain it. Firstly, the development of perinatology, such as intrapartum antimicrobial prophylaxis for Group B Strep (GBS)-colonized women, has greatly decreased the incidence of invasive early-onset GBS disease, contributing to the less severe status of the neonates . Secondly, as patients with MAS, RDS and PPHN have a good response to supplemental therapies such as pulmonary surfactant and iNO, their recovery process has been accelerated accordingly. For neonatal ECMO, the most common diagnoses are congenital diaphragmatic hernia (CDH), meconium aspiration syndrome (MAS), and persistent pulmonary hypertension (PPHN), accounting for almost 75% of all neonatal respiratory ECMO cases . Whilst for pediatric ECMO and adult ECMO, the most common diagnoses are pneumonia and ARDS . However, the above studies of neonatal ECMO were performed in the pre-ARDS era, in which ARDS was usually considered as neonatal RDS, and surfactant was therefore used repeatedly. So far no studies have shown the beneficial effects of surfactant for adult and pediatric ARDS. This might explain the lower survival rate of pediatric and adult ECMO for respiratory failure. In 2017, the international ARDS collaborative group provided the first consensus definition for neonatal ARDS . Actually, ARDS and RDS are two significant different diseases with different reactions to surfactant, and they should be therefore diagnosed and compared independently. Importantly, mortality rate is also associated with other factors like annual hospital ECMO volume for neonates and adults but not for pediatric cases .
In our study,However, a significant number of system-related complications, including mechanical complications, bleeding, pneumothorax, hypertension, seizure, renal failure, hemorrhage and so on, still occurred on patients during hospitalization, which had a deep impact on survival and long-term outcomes. According to ELSO registry data, the most common complication that occurred during ECLS for neonates with respiratory failure is mechanical complication, including clots in the ECMO circuit (oxygenator, bladder, hemofilter, or other), which is consistent with our study results. Bleeding and clots complications are multifactorial, and the rates of that during ECMO have increased since 2000. This trend can not be solely explained by the evolution of anticoagulation management strategies. Since some reports showed that ACT range of 180–220 was used by the majority of ECMO centers from 1996 to 2002, and this was unchanged until 2008 [32–34]. Both patients and circuit related factors might be the relative causes, such as the underlying patient pathophysiology could increase the risk of hemorrhage. Even though there exists a lack of research and evidence of an ideal test of anticoagulation for patients, continuous unfractionated heparin and close monitoring of anticoagulation are still required to reduce the risk of thrombosis and hemorrhage . In our study, the rates of Neurologic complications such as intracranial hemorrhage/infarction and seizure are high as well, with 6.6% and 14.9% respectively. When analyzing the ELSO registry report in 2016, neonates with ECMO have the highest rate of neurologic complications, with an IVH incidence of around 7.6% . Various pre-existing factors like low birth weight, acidosis, hypoxia, hypotension, and organ failure have been found to be associated with neurologic injury. Besides, some ECMO factors such as modality of ECMO used, hemorrhage, seizures, and development of new organ failure increase the risk of CNS injuries furtherly . So an understanding of risk factors associated with neonates undergoing ECMO and knowing how to deal with these factors are important to reduce complications. There exist some other complications as well, wWhether all these complications are definitely due to inadequate technology and equipment of ECMO, a lack of supportive care, or simply a critical condition that might be secondary to the underlying disease in the newborn remains unclear. However, along with evolving indications for ECMO, the monitoring technology and supportive therapies have dramatically changed during these years, especially when newer double lumen VV cannulas for respiratory failure have been introduced, the outcomes of patients have improved greatly. Further attempts, such as by improving the equipment of ECMO, or increasing the use of supportive treatments like vasoactive agents, are needed to determine whether such events can be reduced.
In this study, to minimize potential bias of observational study, we established inclusion and exclusion criteria strictly to provide accurate prevalence and incidence estimation, and we limited the minimum sample size of each study to 50 to reduce publication bias. Moreover, we excluded the studies published in the ELSO database to avoid data duplication and reduce selection bias, because only the selected medical centers had the chance to register in the ELSO database, which increased selection bias. InBy this way, detailed VV ECMO data of other medical centers other than the ELSO database were collected in this meta-analysis.