White matter brain impairment after cardiopulmonary bypass circulation in the neonate

Background:

We observed that 50 % of neonates with congenital heart defects (CHD) subjected to surgery with cardio-pulmonary bypass (CPB) developed white matter brain abnormality following CPB. Exposure to cell-free hemoglobin (hb) during CPB was associated with increased circulating levels of the brain damage marker Tau and with white matter brain impairment as determined by MRI.

Exposure to cell-free Hb during CPB was solely determined by cell-free Hb content in the prime solution. We hypothesise that exposure to cell-free hb is causal in white matter impairment. Secondly we hypothesise that this exposure is associated with alterations in brain hemodynamics which may contribute to white matter impairment.

Aims:

To, in a clinical study including neonates born with severe CHD, describe brain hemodynamics during CPB, and the correlation to postoperative white matter integrity as determined by MRI.

To, in a piglet bypass model, delineate the impact of controlled exposure to circulating cell-free hb and hyperoxemia on brain hemodynamics.

To, in a piglet bypass model, define the influence of controlled exposure to circulating cell-free hb and hyperoxemia on neuroinflammation and brain parenchymal redox status

To, in a piglet bypass model, explore novel pharmaceutical and extra-corporal scavenger strategies to find a feasible therapeutic option for the mitigation of cell-free hb toxicity and oxidative stress. Work plan:

The clinical study will recruit 50 infants with severe CHD requiring surgery with CPB. Pre- and postop brain MRI. Intraoperative monitoring of brain perfusion with a) continuous NIRS/diffuse correlation spectroscopy and with b) intermittent ultra-fast multi-planar Doppler combined with photo-acoustics. Circulating levels of cell-free hb.

Newborn piglet model of CPB. Controlled exposure to varied circulating levels of cell-free hb. Monitoring of brain hemodynamics as in clinical study. Assessment of brain parenchymal and cerebro-spinal fluid inflammation and oxidative stress.

Evaluation of treatment strategies in the piglet model directed towards reducing exposure to cell-free hb by a) pharmacological scavenging and b) extracorporal filtration based on molecular imprinting technology. Importance:

By enhancing our understanding of mechanisms leading to brain impairment during CPB in newborns with CHD we aim to develop specific preventive strategies. This is of utmost value to the individual, their family and to society as a whole.