Summary of findings

We used a prospectively collected multi-centre dataset related to 3090 consecutive cardiac operations, and found 66 acute neurological events, providing an incidence rate of 2.1%. Only 14 acute neurological events were isolated post-operative complications, whereas the majority, 52, occurred alongside other types of complication, indicating a very challenging post-operative course. We found that children with acute neurological events were initially detected based on a range of methods (brain scan, electroencephalogram, and clinical assessment), often involving more than one of these at the point of diagnosis. This reflects the complex nature of acute neurological events, which may be clinically challenging to identify in critically ill children, requiring a range of diagnostic tools. Consideration of case complexity for interpretation of our findings was limited given the need to collapse variables (e.g. congenital heart diagnosis), into very broad categories because of small numbers of acute neurological event. Nonetheless, we were interested to note that the most important variables in our multiple risk factor analysis were surgical factors of longer cardiopulmonary bypass time and urgency of the operation. Given our study focuses on the prospective evaluation of post-operative acute neurological event, the specific flagging up of surgical risk factors as most important has face validity. Our study supports the inclusion of acute neurological event as a post-operative metric for paediatric cardiac surgery.

Results in context

There are relatively few studies that specifically explore post-operative acute neurological event as an entity, in part because there are so many other factors implicated in determining neurodevelopmental outcome for children with CHD. ^{Reference Mebius, Kooi, Bilardo and Bos1,Reference Snookes, Gunn and Eldridge13,Reference Sterken, Lemiere, Vanhorebeek, Van den Berghe and Mesotten14,Reference Brunetti, Gaynor and Retzloff26,Reference Ortinau, Smyser and Arthur27} In animal cardiopulmonary bypass models, brain injury was demonstrated with cardiopulmonary bypass-associated hypoxic/ischemic effects on oligodendrocyte precursor cells, and these impacts were worsened by preceding hypoxaemia as compared to normal oxygen levels. ^{Reference Agematsu, Korotcova, Scafidi, Gallo, Jonas and Ishibashi28,Reference Ishibashi, Scafidi and Murata29} These observations are in line with our observational findings in children after paediatric cardiac surgery given the strongest risk factors that we found were urgent heart surgery/longer bypass times. Furthermore, the findings of the Boston Circulatory Arrest Trial demonstrated that prolonged cardiopulmonary bypass times are linked to increased incidence of seizures and additional abnormalities in motor and speech function, as well as cognitive abilities supporting our findings and potentially indicating future sequelae of our patient group. ^{Reference Goldberg, Bove and Devaney30–Reference Gaynor, Nicolson and Jarvik35} In addition to the length of bypass time, the optimal bypass strategy in this patient group is an area of interest when considering measures to reduce post-operative complications. Tadphale et al, identified reduced rates of acute kidney injury with a higher cardiopulmonary bypass flow rate, higher haematocrit target on bypass, higher terminal haematocrit and no reduction in flow rate during hypothermia. ^{Reference Tadphale, Ramakrishnan and Spentzas36} A further study explored the relationship between this bypass strategy and neurological events, but did not find a link perhaps because of the low event rate (0.8%). ^{Reference Chakraborty, Ramakrishnan and Buyukgoz37}

The high proportion of children who had acute neurological events that also had other post-operative complications linked to low cardiac output syndrome (e.g. the need for extracorporeal life support and renal support, cardiac arrest, and necrotising enterocolitis) might imply that in some cases, low cardiac output syndrome could be on the causal pathway. This would be supported by data from the single ventricle reconstruction trial, which found that children who had low cardiac output syndrome associated events (extracorporeal life support and cardiac arrest) had worse neurodevelopmental outcomes after adjustment for other factors. ^{Reference Newburger, Sleeper and Bellinger38} A single centre study that reported electroencephalography amongst children who had extracorporeal life support reported that seizures were more common with low cardiac output syndrome. ^{Reference Lin, Banwell and Berg39} Low cardiac output syndrome is more likely with a poorer technical result from surgery and poorer technical results are also linked to worse neurodevelopmental outcome. ^{Reference Nathan, Karamichalis and Liu40,Reference Karamichalis, Barach, Nathan, Henaine, del Nido and Bacha41} Our dataset also demonstrated a 0.45% incidence of post-operative seizures which may be a significant marker for future neurodevelopment of these patients due to established links with poorer developmental outcomes. ^{Reference Goldberg, Bove and Devaney30–Reference Gaynor, Nicolson and Jarvik35,Reference Gaynor, Jarvik and Bernbaum42–Reference Marino, Lipkin and Newburger49} Strokes were observed in small proportion of our patients but is another key predictor of subsequent poor neurodevelopmental and reduced quality of life. ^{Reference Chen, Zimmerman and Jarvik52–Reference Chung, Guilliams and Wilson54}

Limitations

Assessment of the brain amongst children requiring cardiac surgery is most challenging in the youngest and sickest children since over and above the inherent difficulties in assessing very young children, they may be sedated and ventilated. In the setting of an imminent urgent cardiac operation, patient evaluation can take advantage of cerebral imaging and electroencephalogram, but none of these modalities is perfect. ^{Reference Brown, Agrawal and Kirschen55} Whilst we prospectively focussed on these assessment challenges, both pre- and post-operative evaluations are not standardised in the UK, hence the assessment will have been imperfect and could have confounded both the pre- and the post-operative evaluation. All participating teams used a dedicated research nurse and physician to assess children prospectively based on the same definition of acute neurological event; however, there was no prospective screening with either electroencephalogram or cross-sectional imaging in all children, in line with routine practice in the UK.

The rarity of acute neurological events and the small number of events in our study mean that the case-mix variables we considered were very broad, which is a particular barrier when trying to understand the inter-relationship between case complexity, the duration of an operation and the occurrence of acute neurological event. We note that children with more complex heart disease require more complex operations, which may require longer periods of cardiopulmonary bypass, and amongst the surgeries that had higher rates of acute neurological event, operations required at neonatal ages dominated. Neonatal operations with an above average rate of acute neurological events in our cohort included: arterial switch 5/85 (6%), complex arterial switch 2/12 (15%), Norwood operation 5/73 (7%), systemic to pulmonary arterial shunt 4/50 (8%), repair of TAPVC 3/43 (7%), and these mixed age operations featured, Rastelli 1/10 (10%), repair of pulmonary atresia 1/18 (6%), repair of anomalous coronary artery from the pulmonary artery 2/14 (14%), and repair of Cor triatriatum 1/10 (10%). The link between acute neurological events and the secondary outcomes of mortality and length of stay will have been influenced by case mix and also by the co-occurrence of other morbidities in 52 of 66 children affected.

Future directions

Our study supports the use of acute neurological event as a post-operative metric for paediatric cardiac surgery and we note that this metric is captured in the Society of Thoracic Surgery and the Paediatric Cardiac Critical Care Consortium (PC4). The definition and evaluation of patients for possible acute neurological events need to be carried out with utmost care and consistency. Additional monitoring methods such as routine use of electroencephalogram ^{Reference McDevitt, Gul, Jones, Scholefield, Seri and Drury56} might improve capture of events. Capture of in-hospital data on acute neurological events may contribute to wider efforts to study neurodevelopment in children with heart disease, including crucially, long-term clinical evaluation.