Isoflurane-induced Neuroinflammation in Children With Hydrocephalus

NCT ID: NCT02512809

Last Updated: 2018-12-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-31
• Study Completion Date: 2017-10-31

Brief 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.

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.

Conditions

Toxicity; Hydrocephalus

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Isoflurane Arm

Pediatric patients, aged 0-5 years, diagnosed with hydrocephalus undergoing a surgical (non-bedside) shunting procedure with general anesthesia. Pts will receive a standardized general anesthetic with isoflurane.

Group Type: EXPERIMENTAL

Isoflurane

Intervention Type: DRUG

Dexmedetomidine/remifentanil Arm

Pediatric patients, aged 0-5 years, diagnosed with hydrocephalus undergoing a surgical (non-bedside) shunting procedure with general anesthesia. Pts will receive a standardized general anesthetic with dexmedetomidine and remifentanil infusions..

Group Type: EXPERIMENTAL

Dexmedetomidine

Intervention Type: DRUG

MRI Control Arm

Otherwise healthy pediatric patients, aged 0-5 years, undergoing MRI with general anesthesia for evaluation of non-neurologic disease. Patients will receive a standardized general anesthetic with isoflurane.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Isoflurane

Intervention Type: DRUG

Dexmedetomidine

Intervention Type: DRUG

Other Intervention Names

Isosthesia, Forane; Precedex

Eligibility Criteria

Inclusion Criteria

• 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).

• 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

• 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.

• 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.

• Minimum Eligible Age: 1 Day
• Maximum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ohio State University

OTHER

Sponsor Role: collaborator

Nationwide Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Joseph D. Tobias

Chairman of Anesthesiology & Pain Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joseph Tobias, M.D.

Role: PRINCIPAL_INVESTIGATOR

Nationwide Children's Hospital

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB14-00625

Identifier Type: -

Identifier Source: org_study_id