Cerebral monitoring during neonatal surgery for non-cardiac congenital anomalies: a first step to improve outcome?

Infants with non-cardiac congenital anomalies, e.g. esophageal atresia,
duodenal atresia, anorectal malformation, abdominal wall defects, choanal
atresia, require major surgical interventions in the neonatal period. Concerns
have been raised about the potentially deleterious effects of surgery on
neonatal brain development. Surgery may be associated with stress, systemic
inflammation and respiratory, hemodynamic, and metabolic events that may result
in brain injury and subsequent neurodevelopmental impairment. Laboratory work
suggests that exposure to general anesthetic agents in critical periods of
brain development causes increased neuronal apoptosis and changes in the
morphology of dendritic spines in animals. Clinical implications of these
findings are, however, unclear. Outcome after neonatal cardiac surgery has been
well described; however, little is known about outcome after surgery for
non-cardiac congenital anomalies (NCCA).
One of the reasons for the lack of knowledge about brain injury and
neurodevelopmental outcome after surgery for NCCA is that infants with
congenital anomalies are usually excluded from studies. An association between
neonatal surgery and neurodevelopmental impairment has been reported in both
term and preterm infants. Furthermore, in recent years cases of severe brain
injury - even after relatively minor surgical procedures, such as inguinal
hernia repair - have come to our attention and have raised great concern
(nationally collected data, not published yet).

Neuroimaging (cranial ultrasound and cerebral magnetic resonance imaging (MRI))
has been integrated in standard neonatal intensive care practice for years and
has been of great importance for improving neonatal care. Neuroimaging has
shown to be useful in predicting outcome, clinical decision making and
initiating early neurodevelopmental intervention strategies in both term and
preterm infants. However, to date neuroimaging has not been implemented in
routine clinical care for infants undergoing neonatal surgery. The lack of
knowledge of neurodevelopmental outcome and cerebral monitoring in this
high-risk group of infants is reason for concern, but can be explained by the
lack of awareness in current medical practice and by the lack of coverage by
insurance companies. The incidence and severity of brain injury following
neonatal surgery is therefore unclear. It is however highly important to gain
insight into this matter, because comparable to very preterm infants and
asphyxiated neonates, infants undergoing neonatal surgery for congenital
anomalies are at risk for neonatal brain injury. Fortunately, we now have the
opportunity to extend standard clinical care in this vulnerable group of
infants by implementing neuroimaging and neuromonitoring in the routine care
process thanks to a grant from a Dutch insurance company.

Standard perioperative care involves monitoring of the infant*s respiratory,
metabolic and hemodynamic status by continuously or continually assessing
arterial oxygen saturation, arterial blood pressure, heart rate, end tidal CO2,
FiO2, respiration rate, blood sample analysis, serum glucose, etc. However,
none of these modalities provide the clinician with direct information about
perfusion, oxygenation, and functioning of the brain. In our hospital, standard
perioperative care is extended with amplitude-integrated
electro-encephalography (aEEG) for real time assessment of electrophysiological
functioning and cerebral near-infrared spectroscopy (NIRS) to provide
continuous and noninvasive monitoring of cerebral oxygen supply and extraction.

Biomarkers for oxidative stress, inflammation, and neuronal injury have been
used in clinical research settings to evaluate brain injury in asphyxiated
newborn infants. These biomarkers are measured at different time points after a
hypoxic-ischemic event to assess timing of neonatal brain injury.

The primary objective of the study is to assess (acute) brain injury in the
perioperative phase by cerebral MRI in infants with non-cardiac congenital
anomalies requiring surgery in the neonatal period.

This is a single-center observational prospective cohort study in the NICU and
PICU of the Wilhelmina Children*s Hospital, University Medical Center Utrecht
(UMCU), the Netherlands evaluating (acute) brain injury after surgery for
non-cardiac congenital anomalies in newborn infants.

There has been increasing concern about the potentially detrimental effects of
neonatal surgery on neurodevelopmental outcome, as an increasing number of
studies have shown an association between neurodevelopmental impairments and
neonatal surgery for NCCA. Moreover, distressing cases of newborn infants with
major brain injury even after minor surgery have come to our attention in
recent years. In our hospital the decision was therefore made to provide best
clinical care by adding neuromonitoring using MRI, cUS and perioperative aEEG
and NIRS to standard care for this vulnerable group of infants. In this way, we
will be informed about cerebral alterations that may occur in the perioperative
phase. In this study, we will evaluate the incidence and extent of potential
brain injury as a result from neonatal surgery for non-cardiac congenital
anomalies. We will also aim to identify risk factors and potential early
markers for brain injury. Moreover, we will aim to evaluate the impact of
perioperative brain injury on neurodevelopmental outcome.

The burden and potential risk of this research are considered to be negligible
and in proportion to the potential value of the study. This study involves the
combination of research procedures and routine clinical procedures. Collecting
urine samples and blood samples for measurements of biomarkers of oxidative
stress, neuronal injury and inflammation will be a research procedure.
Neuromonitoring using cerebral MRI, cUS, aEEG, and NIRS are part of routine
clinical care. Neurodevelopmental follow-up are also part of routine clinical
care.

There are no risks associated with collecting urine and blood samples. Blood
samples will be collected from indwelling arterial catheters and urine samples
will be collected from already inserted urinary catheters or from a gauze
placed in the infant*s diaper. Both urine and blood samples will only be
collected during clinical handling and no extra handling of the infant will be
performed.