Hydrocephalus Clinical Trial
Official title:
Isoflurane-induced Neuroinflammation in Children With Hydrocephalus: A Bench-to-bedside, Translational Study of Molecular Pathways and Therapeutic Approaches
The investigators will quantify inflammatory biomarkers in cerebrospinal fluid (CSF) and serum of children with hydrocephalus who are undergoing ventriculoperitoneal shunt placement under isoflurane anesthesia.
Background & Significance. Each year, millions of children receive general anesthesia.
Isoflurane, a GABA type A (GABAA) receptor agonist is an inhaled anesthetic commonly used in
clinical anesthesia practice worldwide. Anesthetics traditionally have been assumed to be
safe as long as severe hypotension and hypoxia are avoided. Interfering with the balance of
excitatory and inhibitory neurotransmitters in the developing brain may interfere with the
formation of synaptic connections and enhance the normal apoptotic processes that lead to
neuronal pruning and may induce neuroinflammation. Such enhanced neuronal pruning and
neuroinflammation could lead to excessive neuronal loss at critical times during brain
development and consequently cause later learning disabilities. Recent reports of
neurotoxicity induced with isoflurane have triggered significant concern about the safety of
this agent.
Investigations into neuroinflammation and apoptosis after anesthetic exposure in human
children have been limited due to ethical and methodological concerns. Studies that have been
done have been largely retrospective, population-based studies. Results from these studies
have been mixed, some showing a decline in neurocognitive performance, some showing no
change. Further, the vast majority of prospective, hypothesis-driven research has been
undertaken in animal models. Developing a clinically relevant animal model and testing
resultant hypotheses in humans are critical steps in determining the underlying cause of
these changes as well as identifying possible therapeutic targets. The investigators
hypothesize that piglets exposed to commonly used anesthetics will exhibit increased
neuroinflammation when compared with controls. It is further hypothesized children undergoing
neurosurgery with isoflurane anesthesia will show evidence of increased central nervous
system inflammation. Finally, the investigators hypothesize that significantly less robust
inflammation will be seen in patients undergoing MRI with general anesthesia (no surgery),
indicating a role of surgical stress in the modulation of isoflurane-induced
neuroinflammation.
Clinical/Translational Investigation (NCH): Surgery Group. Patients aged 0-5 years undergoing
general anesthesia for ventriculoperitoneal shunt (VPS) repair will have CSF and serum
sampled at the beginning of surgery (after induction but before surgical incision) and at the
end of surgery (after closure but before emergence). Each of these patients will be
randomized to a standardized anesthetic. An additional CSF sample will be taken prior to post
anesthesia care unit (PACU) discharge. These samples will be analyzed as described above.
Control Group. Patients undergoing diagnostic MRI under general anesthesia for non-neurologic
pathology will receive a standardized anesthetic. Serum will be collected at the beginning
and end of the procedure and will be analyzed for inflammation as above.
Short term goals: Demonstrate that isoflurane has a role in modulation of neuroinflammation
in humans. Determine if surgical stress also has a role in modulation of this inflammation.
Develop a clinically relevant animal model for hypothesis-driven anesthetic neuroinflammation
research.
Long term goals: Identify which anesthetic regimens, if any, are safe for use in the
developing brain. Identify therapeutic targets for prevention or treatment of
anesthetic-induced neuroinflammation. Obtain independent federal funding for future research
and establish an experimental neuroscience program on the Nationwide Children's campus.
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