Isoflurane-induced Neuroinflammation in Children With Hydrocephalus
Information source: Nationwide Children's Hospital
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Toxicity; Hydrocephalus
Intervention: Isoflurane (Drug); Dexmedetomidine (Drug)
Phase: Phase 3
Status: Enrolling by invitation
Sponsored by: Nationwide Children's Hospital Official(s) and/or principal investigator(s): Emmett Whitaker, M.D., Principal Investigator, Affiliation: Nationwide Children's Hospital
Summary
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.
Clinical Details
Official title: Isoflurane-induced Neuroinflammation in Children With Hydrocephalus: A Bench-to-bedside, Translational Study of Molecular Pathways and Therapeutic Approaches
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Primary outcome: Change in cerebrospinal fluid (CSF) cytokine levelsChange in cerebrospinal fluid (CSF) microRNA levels Change in serum cytokine levels Change in serum microRNA levels
Detailed description:
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.
Eligibility
Minimum age: N/A.
Maximum age: 5 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria (HC study patients):
- Pediatric patients, aged 6 months-less than 11 years, diagnosed with hydrocephalus
undergoing a primary surgical (non-bedside) shunting procedure with general
anesthesia.
- Participants must have a parent/guardian who is able to provide written informed
consent in accordance with human investigation committee guidelines.
- The shunting procedure must be an initial VPS placement (not a VPS revision).
Inclusion Criteria (MRI with general anesthesia: peripheral blood patients; anesthesia but
no surgery):
- Otherwise healthy pediatric patients, aged 6 months-less than 11 years, undergoing
MRI with general anesthesia for evaluation of non-neurologic, non-inflammatory
disease.
- Participants must have a parent/guardian who is able to provide written informed
consent in accordance with IRB guidelines.
Exclusion Criteria (HC study patients):
- Any active infection or infection within the last 14 days.
- Treatment in the last 48 hours with non-steroidal anti-inflammatory (NSAID) or
corticosteroid medications.
- Anticoagulant administration in the last 48 hours.
- Treatment with any drug known to induce or suppress inflammation.
- Clinically unstable patients.
- Patients that have an American Society of Anesthesiologists physical status ≥4
(severe, life-threatening disease).
- Infants born more than 4 weeks premature.
Exclusion Criteria (MRI with general anesthesia: peripheral blood patients; anesthesia but
no surgery):
- Known central nervous system disease.
- Treatment in the last 48 hours with non-steroidal anti-inflammatory (NSAID) or
corticosteroid medications.
- Treatment with any drug known to induce or suppress inflammation.
- Patients that have an American Society of Anesthesiologists (ASA) physical status ≥4
(severe, life-threatening disease).
- Infants born more than 4 weeks premature.
Locations and Contacts
Additional Information
Starting date: July 2015
Last updated: July 28, 2015
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