Maayke Hunfeld

241 General discussion During CA the brain is injured directly as a result of loss of blood flow (no-flow time) and the suboptimal flow that depends on the quality of CPR. Secondary neurological injury in which hyperoxia is a common feature, has also been described due to reperfusion after successful resuscitation. The neuronal injury cascade leading to cell death is a complex process, including excitotoxicity, disrupted calcium homeostasis, free radical formation, pathological protease cascades, and activation of cell death signaling pathways (46, 47). The areas which are most vulnerable to ischemia are the cerebral cortex, watershed areas, subcortical white matter, vascular end zones, hippocampus, cerebellar Purkinje cells and basal ganglia (46, 48-52). In our cohort, intelligence scores 2 years post-OHCA were lower than normative data. Previous studies have shown that intellectual outcome is dependent on the age at which brain injury was acquired. In young children, acquired brain injury causes diffuse deficits, whereas in older children more specific deficits are found (53, 54). The median age of our OHCA cohort was relatively low at 48 months. Young children with brain injury have to learn new skills with impaired basal functions, causing a more negative effect on intelligence at long-term (55, 56). White matter injury is often seen after prolonged ischemia (46). The integrity of the white matter is correlated with full scale IQ and performance IQ (57). There is a parallel with children with TBI, in which white matter is also implicated; Tractography on DTI has revealed abnormal organization of the structural connectome in children with moderate and children with severe TBI. This abnormal organization was associated with lower intelligence (24) . Executive functions such as attention and cognitive flexibility were also affected in our cohort. These are functions that are controlled by the frontal lobes of the brain, which are often injured after hypoperfusion and hypoxia (58). Besides, damage to other brain areas connected to the frontal lobes can also impair executive functions. The hippocampus is another brain structure sensitive for hypoxia, and this sensitivity might also explain attention deficits (51). Unfortunately, we could not correlate neuropsychological findings with MRI results, because only few children had received both MRI during PICU admission and neuropsychological assessment during follow-up. Standard brain MRI at follow-up is not included in our clinical follow- up protocol. Because there is rarely a clinical indication for follow-up brain MRI, relating neuropsychological findings with MRI results is feasible only in the context of a research project beyond routine clinical care. The current literature does not yet contain studies on the association of MRI findings and neuropsychological functioning. Obviously, other factors also contribute to neurocognitive outcome: 1) underlying disease and genetic factors (59); 2) socioeconomic status (SES) of the patient and parents (in our patients, SES was significantly lower than that of the general Dutch population, which may have influenced neurocognitive outcome) (60); and 3) treatment post-OHCA (administration of sedatives, inadequate analgesia, number 8