Isoflurane-induced Neuroinflammation in Children With Hydrocephalus

• Sponsor: Nationwide Children's Hospital (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02512809
• Collaborator: Ohio State University (Other)
• Enrollment: 25
• Arms: 3
• Duration (Months): 28

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Toxicity; Hydrocephalus	Drug: Isoflurane; Drug: Dexmedetomidine	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Isoflurane-induced Neuroinflammation in Children With Hydrocephalus: A Bench-to-bedside, Translational Study of Molecular Pathways and Therapeutic Approaches
• Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Oct 31, 2017
• Actual Study Completion Date: Oct 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Isoflurane; Other Names: Isosthesia, Forane
Experimental: 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..	Drug: Dexmedetomidine; Other Names: Precedex
No Intervention: 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.

Outcome Measures

Primary Outcome Measures

1. Change in Serum Cytokine Levels [On the day of surgery or MRI from start of procedure to discharge from PACU (approx. 1-7 hrs.)]

   Surgery subjects will have blood collected once at the start of surgery, once at the end of surgery, and once in the PACU. MRI patients will have blood collected once prior to the start of the MRI and once at the completion of the MRI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Day to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Nationwide Children's Hospital
• Ohio State University

Investigators

• Principal Investigator: Joseph Tobias, M.D., Nationwide Children's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 31, 2017

More Information

Publications

None provided.

• Responsible Party: Joseph D. Tobias, Chairman of Anesthesiology & Pain Medicine, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT02512809
• Other Study ID Numbers: IRB14-00625
• First Posted: Jul 31, 2015
• Last Update Posted: Dec 13, 2018
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Hydrocephalus; Dexmedetomidine; Isoflurane

Study Results

Participant Flow

Pre-assignment Detail	There were no participants assigned to the "Isoflurane" and "Dexmedetomidine/Remifentanil Arm" Arms/Groups as only the MRI control arm completed enrollment prior to the original PI leaving the institution and there was no enrollment in the other 2 arms.

Arm/Group Title	MRI Control Arm
Arm/Group Description	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.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Isoflurane Arm	Dexmedetomidine/Remifentanil Arm	MRI Control Arm	Total
Arm/Group Description	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. Isoflurane	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.. Dexmedetomidine	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.	Total of all reporting groups
Overall Participants	0	0	25	25
Age (Count of Participants)
<=18 years	0 NaN	0 NaN	25 100%	25 100%
Between 18 and 65 years	0 NaN	0 NaN	0 0%	0 0%
>=65 years	0 NaN	0 NaN	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.73 (2.49)	3.73 (2.49)
Sex: Female, Male (Count of Participants)
Female	10 Infinity	10 Infinity
Male	15 Infinity	15 Infinity
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 NaN
Asian	3 Infinity	3 Infinity
Native Hawaiian or Other Pacific Islander	0 NaN	0 NaN
Black or African American	1 Infinity	1 Infinity
White	21 Infinity	21 Infinity
More than one race	0 NaN	0 NaN
Unknown or Not Reported	0 NaN	0 NaN
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	17.4 (8.3)	17.4 (8.3)
Anesthetic Time (minutes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [minutes]	54.7 (24.7)	54.7 (24.7)
Previous Anesthesia (Count of Participants)
Yes	12 Infinity	12 Infinity
No	13 Infinity	13 Infinity
American Society of Anesthesiologists (ASA) Physical Status classification (Count of Participants)
ASA 1	8 Infinity	8 Infinity
ASA 2	17 Infinity	17 Infinity

Outcome Measures

1. Primary Outcome

Title	Change in Serum Cytokine Levels
Description	Surgery subjects will have blood collected once at the start of surgery, once at the end of surgery, and once in the PACU. MRI patients will have blood collected once prior to the start of the MRI and once at the completion of the MRI.
Time Frame	On the day of surgery or MRI from start of procedure to discharge from PACU (approx. 1-7 hrs.)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MRI Control Arm
Arm/Group Description	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.
Measure Participants	25
IL-1β pre-isoflurane	25.97 (9.01)
IL-1β post-isoflurane	38.53 (16.56)
TNF-α pre-isoflurane	94.26 (18.07)
TNF-α post-isoflurane	85.84 (12.12)
IL-6 pre-isoflurane	2.28 (2.27)
IL-6 post-isoflurane	2.04 (2.15)

Adverse Events

Time Frame	1 day
Arm/Group Title	MRI Control Arm
Arm/Group Description	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.
All Cause Mortality
	MRI Control Arm
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	MRI Control Arm
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	MRI Control Arm
	Affected / at Risk (%)	# Events
Total	0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.