PANDA (Pediatric Anesthesia & NeuroDevelopment Assessment) Study

Overview

The purpose of this study is to determine whether the use of anesthetic agents in infants and children have long term adverse effects on neurocognitive development. According to the National Hospital Discharge Survey, around 2.5 million children have surgical procedures requiring anesthesia each year in the US. Recent animal studies have suggested that the exposure of the immature organism to a variety of commonly used anesthetic agents may lead to neurobehavioral functional deficits in vivo and to neuronal apoptosis in vitro. While the relevance of these findings on children exposed to anesthetics remains to be determined, it is clearly critically important to public health that this issue is resolved quickly and clearly. Hypothesis: Exposure to anesthetic agents within the first three years of life will not significantly impair cognitive functions at ages 8 yr, 0 mo to 15 yr, 0 mo.

Full Title of Study: “Anesthesia Exposure and Neurodevelopment in Infants and Children: Pediatric Anesthesia & NeuroDevelopment (PANDA) Study”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Other
  • Study Primary Completion Date: April 2015

Detailed Description

The purpose of our study is to compare neurocognitive functions in sibling pairs: one of whom had exposure to anesthesia during surgery before 36 months of age (exposed sibling cohorts) and who would be from ages 8yr, 0 mo to15 yr, 0 mo at the time of the study; and the other who never had anesthesia or surgery less than 36 months of age, is from ages 8yr, 0mo to 15 yr, 0 mo at the time of the study, and is within 36 months of age range from the exposed sibling(unexposed sibling cohort). Neuropsychological assessments are administered to the sibling cohorts prospectively and parents of the siblings will complete parental interviews/questionnaires. We assess individually neurocognitive, behavioral and emotional function for both exposed and unexposed siblings. Family function will also be evaluated. We will also obtain complete medical history for each participant, including significant perinatal events and social history. We also review medical records when appropriate. All testing are performed during a one day site visit.

Interventions

  • Procedure: Inguinal hernia surgery
    • Non-experimental procedure
  • Procedure: General anesthesia
    • Non-experimental procedure/treatment

Arms, Groups and Cohorts

  • Exposed Cohort
    • Children who had inguinal hernia surgery and general anesthesia before 36 months of age (n=500). These children should be ages 8 yr, 0 mo to 15 yr, 0 mo at the time of the study period.
  • Unexposed Cohort
    • Children who are siblings of the exposed children (inguinal hernia surgery and general anesthesia) and differ in age from the exposed children by less than 36 months and have no history of surgery or exposure to volatile and intravenous anesthetics or sedatives including barbiturates, benzodiazepines and chloral hydrate less than 36 months of age. These children should also be ages 8 yr, 0 mo to 15 yr, 0 mo at the time of the study period.

Clinical Trial Outcome Measures

Primary Measures

  • Change in neurocognitive function
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Global cognitive function: verbal, performance and full IQ assessed by Wechsler Abbreviated Scale of Intelligence (WASI). These are one unit of measure for IQ.

Secondary Measures

  • Change in domain-specific function related to visual memory and learning
    • Time Frame: Varies; when the participant is 8-15 years of age
    • NEPSY II (A Developmental Neuropsychological Assessment) assesses visual memory learning
  • Change in domain-specific function related to verbal memory and learning
    • Time Frame: Varies; when the participant is 8-15 years of age
    • California Verbal Learning Test-Children (CVLT-C) assesses verbal memory and learning.
  • Change in domain-specific function related to receptive language
    • Time Frame: Varies; when the participant is 8-15 years of age
    • NEPSY II (A Developmental Neuropsychological Assessment) is used to assess receptive language and speeded naming.
  • Change in domain-specific function related to expressive language
    • Time Frame: Varies; when the participant is 8-15 years of age
    • WASI is used to assess expressive language and verbal reasoning
  • Change in domain-specific function related to working memory
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Weschler Intelligence Scale for Children (WISC-IV) is used to assess working memory, attention and executive function.
  • Change in domain-specific function related to all executive function components
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Behavior Rating In Executive Function (BRIEF) is used to assess all components of executive function.
  • Change in domain-specific function related to selective attention and impulsivity
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Continuous Performance Test-II (CPT-II) is used to assess sustained and selective attention as well as impulsivity.
  • Change in domain-specific function related to cognitive flexibility aspects of executive function
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Delis-Kaplan Executive Function System (DKEFS) is used to assess cognitive flexibility.
  • Change in domain-specific function related to motor and processing speed
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Grooved pegboard and Weschler Intelligence Scale for Children (WISC-IV) are used to assess motor and processing speed
  • Changes in behavior
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Childhood Behavior Check List (CBCL) assesses emotionally reactive, anxious/depressed, somatic complaints, withdrawn, attention problems and aggressive behavior.
  • Changes in adaptive behavior
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Adaptive behavior is assessed using Adaptive Behavior Assessment Systems II (ABAS-II), which measures overall adaptive behavior and skills.
  • Changes in parental relationships
    • Time Frame: Varies; when the participant is 8-15 years of age
    • Parent Relationship Questionnaire (PRQ) is used to explore parents’ perspectives on parent-child relationship.

Participating in This Clinical Trial

Inclusion Criteria

Exposed cohort: 1. Subjects who had inguinal hernia surgery before 36 months of age 2. Ages 8 yr, 0 mo to 15 yr, 0 mo 3. Gestation age greater or equal to 36 weeks 4. Categorized as ASA I or ASA II 5. English speaking 6. Biologically related to the unexposed sibling Unexposed cohort: 1. Sibling within 36 months of age of the exposed cohort 2. Never had surgery or exposure to anesthesia prior to 36 months of age 3. Ages 8 yr, 0 mo to 15 yr, 0 mo 4. Gestation age greater or equal to 36 weeks 5. Categorized as ASA I or ASA II 5. English speaking 6. Biologically related to the exposed sibling Exclusion criteria:

Exposed cohort: 1. Gestational age less than 36 weeks at birth 2. No exposure to surgery or anesthesia prior to 36 months of age 3. Surgery/Anesthesia other than index hernia repair prior to 36 months of age 4. Not categorized as ASA I or ASA II 5. Not ages 8 yr, 0 mo to 15 yr, 0 mo 6. Not English speaking 7. Not biologically related to the unexposed sibling Unexposed cohort: 1. Gestational age under 36 weeks at birth 2. Any exposure to surgery or anesthesia prior to 36 months of age 3. Not categorized as ASA I or ASA II 4. Not ages 8 yr, 0 mo to 15 yr, 0 mo 5. Not English speaking 6. Not biologically related to the unexposed sibling

Gender Eligibility: All

Minimum Age: 8 Years

Maximum Age: 15 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Columbia University
  • Collaborator
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Lena S. Sun, Emanuel M. Papper Professor of Anesthesiology and Professor of Pediatrics – Columbia University
  • Overall Official(s)
    • Lena S Sun, MD, Principal Investigator, Columbia University

References

Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999 Jan 1;283(5398):70-4. doi: 10.1126/science.283.5398.70.

Anand KJ, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology. 2004 Aug;101(2):527-30. doi: 10.1097/00000542-200408000-00033. No abstract available.

Anand KJ. Anesthetic neurotoxicity in newborns: should we change clinical practice? Anesthesiology. 2007 Jul;107(1):2-4. doi: 10.1097/01.anes.0000268484.05444.35. No abstract available.

Olney JW, Young C, Wozniak DF, Jevtovic-Todorovic V, Ikonomidou C. Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol Sci. 2004 Mar;25(3):135-9. doi: 10.1016/j.tips.2004.01.002. No abstract available.

Walden M, Carrier CT. Sleeping beauties: the impact of sedation on neonatal development. J Obstet Gynecol Neonatal Nurs. 2003 May-Jun;32(3):393-401. doi: 10.1177/0884217503253454.

Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007 Mar;104(3):509-20. doi: 10.1213/01.ane.0000255729.96438.b0.

Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003 Feb 1;23(3):876-82. doi: 10.1523/JNEUROSCI.23-03-00876.2003.

Slikker et al. FDA science 2005 Forum

Slikker W Jr, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007 Jul;98(1):145-58. doi: 10.1093/toxsci/kfm084. Epub 2007 Apr 10.

Olney at al. FDA symposium. 2002:12:488-498

Jevtovic-Todorovic V. General anesthetics and the developing brain: friends or foes? J Neurosurg Anesthesiol. 2005 Oct;17(4):204-6. doi: 10.1097/01.ana.0000178111.26972.16. No abstract available.

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