PANDA (Pediatric Anesthesia & NeuroDevelopment Assessment) Study

Anesthesia Exposure and Neurodevelopment in Infants and Children: Pediatric Anesthesia & NeuroDevelopment (PANDA) Study

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.

Study Overview

• Status: Completed
• Conditions: Cognition - Other
• Intervention / Treatment: Procedure: Inguinal hernia surgery; Procedure: General anesthesia

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.

• Study Type: Observational
• Enrollment (Actual): 369

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • New York
    • New York, New York, United States, 10032
      • Columbia University, 622 W. 168th St.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 15 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study will be a multi-center study based at Columbia University with the following participating centers: Boston Children's (Harvard University), Children's Hospital of Philadelphia (University of Pennsylvania), Monroe Carell Children's Hospital (Vanderbilt University), and Morgan Stanley Children's Hospital of New York (Columbia University). Children exposed to anesthesia prior to 36 months must be ages 8 yr, 0 mo to 15 yr, 0 mo and have a sibling with no history of surgery or anesthesia prior to 36 months of age.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.	Procedure: Inguinal hernia surgery; Non-experimental procedure; Procedure: General anesthesia; Non-experimental procedure/treatment
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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Office of Acquisitions and Grants Services (OAGS)
• Investigators: Principal Investigator: Lena S Sun, MD, Columbia University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: April 14, 2009
• First Submitted That Met QC Criteria: April 14, 2009
• First Posted (Estimate): April 15, 2009

Study Record Updates

• Last Update Posted (Actual): February 17, 2023
• Last Update Submitted That Met QC Criteria: February 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Children; Pediatric; Anesthesia; Neurodevelopment; Child development; Columbia; New York
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics
• Other Study ID Numbers: AAAC8756; R34HD060741 (U.S. NIH Grant/Contract); HHSF223200810036C (Other Grant/Funding Number: DHHS/FDA/OAGS/DCGM); SmartTots (Other Identifier: SmartTots)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED