Transcript Nashville, TN - 11/04/16 Stephen Robert Hays, MS, MD, FAAP

Anesthetic Strategies for Triple Endoscopy
4th Annual Contemporary Management of
Aerodigestive Disease in Children
Vanderbilt University Medical Center - Nashville, TN - 11/04/16
Stephen Robert Hays, MS, MD, FAAP
Associate Professor, Anesthesiology & Pediatrics
Vanderbilt University Medical Center
Pediatric Anesthesia/Pediatric Pain Service/Pediatric Pain Clinic
Monroe Carell Jr. Children’s Hospital at Vanderbilt
CME Requirements: Objectives
• Review recent animal data indicating significant adverse neuropathology
and behavioral abnormalities following anesthetic exposure in
developmentally vulnerable subjects.
• Discuss retrospective data in humans describing associations between
anesthetic exposure in infants and young children and subsequent
developmental disability, as well as prospective data suggesting otherwise.
• Consider relevance of available data to human anesthetic exposure, with
particular consideration of anesthetic strategies for triple endoscopy in
pediatric patients.
CME Requirements: Disclosures
I have no relevant financial relationships with
any commercial interests.
Vanderbilt is a site for GAS, PANDAS, HIP.
Site investigator for industry-sponsored
pediatric licensing studies including:
IR/ER oxymorphone - Opana®, ENDO
ER oxycodone - OxyContin®, Purdue Pharma
IV acetaminophen - Orfimev®, Mallinckrodt
ER hydromorphone - Exalgo®, Mallinckrodt
Tapentadol - Nucynta®, Janssen
(IV dexmedetomidine - Precedex®, Hospira)
CME Requirements: Off-Label
Many anesthetic agents and techniques are
widely used in children;
Many such agents and techniques are NOT
approved for such use.
Much of current pediatric anesthetic practice,
including strategies for triple endoscopy,
are still largely off-label/investigational.
Neonatal Pain & Adverse Outcomes
•Tobiansky R, et al. J Paediatr Child Health 1995(Jun);31(3):233-236.
•Chacko J, et al. Pediatr Surg Int 1999;15(7):496-499.
•American Academy of Pediatrics. Pediatrics 2000(Feb);105(2):454-461.
•Oberlander TF, et al. Pediatrics 2000(Jan);105(1):e6.
•Bhutta AT, Anand KJ. Clin Perinatol 2002(Sep);29(3):357-372.
•Grunau R. Clin Perinatol 2002(Sep);29(3):373-394,vii-viii.
•Fredriksson A, et al. Behav Brain Res 2004(Aug);153(2):367-376.
•Anand KJ, et al. Pediatrics 2006(Mar);117:S9-S22.
•Grunau RE, et al. Semin Fetal Neonatal Med 2006(Aug);11(4):268-275.
•Whitfield MF, Grunau RE. Clin Perinatol 2000(Jun);27(2):363-379.
Providing inadequate anesthesia is NOT appropriate.
Provocative Urologic Example
Taddio A, et al. Lancet 1995(Feb 4);345(8945):291-2.
Male infants circumcised as neonates exhibited exaggerated pain
behavior with subsequent immunization compared to uncircumcised
male infants.
Taddio A, et al. Lancet 1997(Mar 1);349(9052):599-603.
Confirmed the above; also demonstrated blunting of exaggerated
pain behavior with subsequent immunization if circumcision
performed under topical anesthesia.
Even seemingly minor procedures are of potential concern.
Ikonomidou C, et al. Science 1999(Jan 1);283(5398):70-74.
Developmental Neuroapoptosis
Developing neurons are programmed to commit suicide if they are
unsuccessful in meeting important developmental milestones:
• Such pruning is a normal part of development.
Many developing neurons successfully meet such milestones, so not all
are obliged to commit suicide:
• 1-2% of neurons at any given time are lost in this manner.
• Up to 50% of neurons in some loci may be eliminated.
Aberrant circumstances can interfere and cause:
• Failure of many neurons to meet important milestones;
• Death of many neurons that would have normally survived;
• Abnormal neurodevelopmental disturbances.
Saline Treatment
MK-801 Treatment
• Age dependent: greatest during brain growth spurt.
• Region dependent: cortex, hippocampus, thalamus.
• Significant apoptosis began by 4 hours after exposure.
• Initial investigations with MK-801 = dizocilpine.
• Ketamine: 7 injections of 20mg/kg over 9 hours.
Ikonomidou C, et al. Science 1999(Jan 1);283(5398):70-74.
Olney JW, et al. Anesthesiology 2004(Aug);101(2):273-275.
Mellon RD, et al. Anesth Analg 2007(Mar);104(3):509-520.
Human Relevance?
Animal study design issues:
• Dose differences: veterinary doses generally much higher.
• Durations of exposure: animal exposure generally much longer.
• Timing of exposure: animal development is not the same as human.
• No painful stimulus: animal exposure not for surgery.
• Inescapable uncertainty of inter-species comparisons.
Human Relevance: Dose
• Animal dose = 7 x 20 mg/kg = 140 mg/kg total.
• Human dose = 1-2 mg/kg total.
Ikonomidou C, et al. Science 1999(Jan 1);283(5398):70-74.
Human Relevance: Duration
Perinatal Development:
7 rat days  27 human months.
6 rat hours  1 human month.
Soriano S. Presentation to FDA Advisory Committee, Spring 2007.
Human Relevance: Timing
Correlation of developmental stages in animals in variable, non-linear, and
of obvious crucial importance:
Human Relevance: Surgery
Ketamine REDUCES neuronal cell
death induced by chronic pain in
a rat pup model using repetitive
formalin injection.
Anand KJ, et al. Pediatr Res 2007(Sep);62(3):283-290.
Human Relevance: Inter-Species
Human Infants  Rat Pups!
“Rodent data provide an imprecise basis at best, and an
irrelevant basis at worst, for evaluating human risk. An
important next step, therefore, would be to conduct well
designed nonhuman primate studies.”
Olney JW, et al. Anesthesiology 2004(Aug);101(2):273-275.
Primate Anesthetic Exposure
• Prolonged (24 h) ketamine exposure induces apoptotic
neuronal cell death in perinatal monkey brain.
• Shorter (3 h) ketamine exposure does NOT.
• Developmental immaturity (GD 122, PND 5; NOT PND 35)
represents a critical period of particular vulnerability.
• Up-regulation of NMDA receptor (NR-1 mRNA) correlates
with neuropathology.
Slikker W, et al. Toxicol Sci 2007(Jul);98(1):145-58.
Anesthetic and Life Support Drugs
Advisory Committee
March 2007
1. Please discuss whether there are sufficient data to determine the
applicability of the findings for anesthetics in non-clinical models to
humans? If not, what other data would be needed?
2. To what extent are the doses and durations of exposure to the
anesthetics used in non-clinical studies relevant to the clinical use of
these drugs?
3. Combinations of anesthetic drug products are frequently used in the
setting of pediatric anesthesia. Most of the preclinical data are
derived from studies of drugs examined in isolation. Does the
Committee have any advice on how FDA may best approach the issue
of neurologic toxicity of combination use?
Anesthetic and Life Support Drugs
Advisory Committee
March 2007
4. Are there feasible clinical or other study designs to assess the
potential neurological toxicities of exposing pediatric patients to
anesthetic agents? (Please discuss)
5. Given the risks associated with delay of surgical intervention or with
the use of sub-optimal anesthesia techniques, how does one
incorporate the current knowledge base into the practice of pediatric
anesthesia?
“there are many issues to be resolved before a definitive assessment of the risk
posed by anesthetics to the developing brain can be made.”
“there are no clinical data providing evidence suggesting the use of anesthetics
in the neonate or young child is associated with signs of developmental
neurotoxicity.”
Anesthetic and Life Support Drugs
Advisory Committee
March 2007
The committee unanimously voted no change in current practice is
indicated, including no change in current drug labeling.
The committee acknowledged relevance of animal data to anesthetic
exposure in human infants is unknown.
The committee agreed more specific patient research is indicated,
particularly regarding long term follow-up.
Anesthetic and Analgesic Drug Products
Advisory Committee
March 2011
The committee upheld previous recommendations:
“…progress has not been substantial and there is still too little
information to draw any firm conclusions.”
6-day old mice exposed to
3% sevoflurane for 6 h.
Satomoto M, et al. Anesthesiology 2009(Mar);110(3):628-37.
Satomoto M, et al. Anesthesiology 2009(Mar);110(3):628-37.
Forgetful Mice  Autistic Children
Animal Data: Summary
Parameter
Neurotoxicity
Comment
Human Correlate
Timing of exposure
Only following exposure during
Window varies by species
? 3rd trimester - ? age 3 y;
critical neurodev window
Anesthetic dose
Only following exposure above
Potentially much longer
Dose varies by agent, species Unknown
critical threshold dose
Anesthetic duration Only following exposure above
critical threshold duration
Concomitant pain
Duration varies by agent,
Unknown
species
Only following exposure without Untreated pain is neurotoxic; Untreated pain neurotoxic;
concomitant pain
Analgesia is neuroprotective
Analgesia neuroprotective
Retrospective analysis of healthy
children having urologic
procedures before age 6 y.
Kalkman CJ, et al. Anesthesiology 2009(Apr);110(4):805-12.
Retrospective analysis of all children born in
Olmsted County, MN between 1976 and 1982 who
received general anesthesia before age 4.
Wilder RT, et al. Anesthesiology 2009(Apr);110(4):796-804.
Conclusion: Exposure to anesthesia was a significant
risk factor for the later development of LD in children
receiving multiple, but not single anesthetics. These
data cannot reveal whether anesthesia itself may
contribute to LD or whether the need for anesthesia
is a marker for other unidentified factors that
contribute to LD.
Wilder RT, et al. Anesthesiology 2009(Apr);110(4):796-804.
Retrospective Human Data: Summary
Parameter
Neurotoxicity
Comment
Age at exposure
Birth through 10 years
Multiple cohorts studied
Single anesthetic exposure
No consistent association with ↑ risk of deficit
Multiple assessment parameters
Multiple anesthetic exposures Consistent association with ↑ risk of deficit
Multiple assessment parameters
Anesthetic type/dose
Causality unknown
Generally not specified/quantified
Prospective Human Studies
Study (Scope)
Design
Assessments
Comparison
Enrolment (Contact)
Human Subject Study
Retrospective cohort;
Hippocampal memory
Anesthesia <8y v.
Ongoing (goal 300 pts)
(single institution)
Prospective evaluation
No anesthesia
UCSF: Jeffrey Sall
MASK
Retrospective cohort;
Neurocognitive
Anesthesia <3y v.
Ongoing (goal 500 pts)
(single institution)
Prospective evaluation
battery
No anesthesia
Mayo Clinic: David Warner
PANDA
Retrospective cohort;
Neurocognitive
IHR <3y v.
Closed (105 sibling pairs)
(US: multi-site)
Prospective evaluation
battery
No surgery (sibs)
Columbia: Lena Sun
GAS
Prospective,
Periop outcomes;
General v.
Closed (722 subjects)
(international:
randomized
Neurocognitive
Awake regional
RCH: Andrew Davidson
multi-site)
(address causality)
battery
BCH: Mary Ellen McCann
PANDA Study
•
•
•
•
Pediatric Anesthesia and NeuroDevelopment Assessment Study
Multi-institutional collaborative effort.
Led by Columbia University.
Prospective observational trial:
– Inguinal hernia repair in infants.
– Sibling pairs requiring/not requiring repair as neonates.
– Neurodevelopmental assessments over time.
* Minimize environmental and genetic confounders.
* Cannot address causality.
PANDA Study
Association Between a Single General Anesthesia Exposure Before Age 36
Months and Neurocognitive Outcomes in Later Childhood
Lena S. Sun, MD; Guohua Li, MD, DrPH; Tonya L. K. Miller, MD;
Cynthia Salorio, PhD; MaryW. Byrne, PhD, MPH; David C. Bellinger, PhD,
MSc; Caleb Ing, MD, MS; Raymond Park, MD; Jerilynn Radcliffe, PhD;
Stephen R. Hays, MD, MS; Charles J. DiMaggio, PhD; Timothy J. Cooper,
PsyD; Virginia Rauh, ScD; Lynne G. Maxwell, MD; Ahrim Youn, PhD;
Francis X. McGowan, MD
JAMA. 2016;315(21):2312-2320. doi:10.1001/jama.2016.6967.
“Among healthy children with a single anesthesia exposure before age 36
months, compared with healthy siblings with no anesthesia exposure,
there were no statistically significant differences in IQ scores in later
childhood.”
GAS Study
•
•
•
•
General Anaesthesia compared to Spinal anaesthesia Study
Multi-national, multi-center collaborative effort.
US effort led by Children’s Hospital Boston.
Prospective randomized trial:
– Inguinal hernia in infants.
– Neuraxial (bupivacaine) versus general (sevoflurane) anesthesia.
– Neurodevelopmental assessments at 2 and 5 years.
Timeline
2007
2008
2009
Recruit
x
x
x
Yr 2 assessment
Yr 5 assessment
x
2010
2011
x
x
2012
2013
2014
x
x
x
GAS Study
“FINDINGS:
Outcome data were available for 238 children in the awake-regional
group and 294 in the general anaesthesia group. ... There was
equivalence in mean between groups (awake-regional minus general
anaesthesia 0.169, 95% CI -2.30 to 2.64).
INTERPRETATION:
… we found no evidence that just less than 1 h of sevoflurane
anaesthesia in infancy increases the risk of adverse neurodevelopmental
outcome at 2 years of age compared with awake-regional anaesthesia.”
Lancet. 2016 Jan 16;387(10015):239-50. doi: 10.1016/S01406736(15)00608-X. Epub 2015 Nov 4.
What We Know: Animal Data
• Failure to provide adequate anesthesia is causally
associated with adverse neurodevelopmental
outcomes in animal models and in humans.
• Long-term and/or high-dose exposure to anesthetic
agents induces threshold-sensitive dose-dependent
apoptotic neurodegeneration and adverse behavioral
sequelae in developmentally immature animals.
• Short-term and/or lower-dose exposure, or exposure
outside critical neurodevelopmental windows, or
exposure with concomitant pain, does not.
• Relevance of animal data to pediatric anesthetic
practice remains unknown.
What We Know: Human Data
• Multiple anesthetic exposure in
human infants and young children
exhibits a threshold-sensitive dosedependent association with learning
disability; causality is unknown.
• Single brief anesthetic exposure in
children is not associated with
increased risk of adverse
neurodevelopmental consequences,
independent of patient age, former
prematurity, or anesthetic technique.
PANDA Symposium 2016
• Risk of multiple and/or prolonged
anesthetic exposure remains
unknown.
What We Would Like to Do
• Provide appropriate anesthesia in all settings.
• Delay procedures in developmentally vulnerable
children if surgically reasonable.
• Consider alternatives to general anesthesia when
feasible.
•Minimize duration of exposure when general
anesthesia cannot be avoided.
• Encourage ongoing research efforts to provide
more definitive data on actual risk in humans.
Endoscopy3: What We Have to Do
• Allow spontaneous ventilation.
• Avoid airway support & instrumentation.
• Share airway access in confined space.
• Preserve stability despite physiologic fragility.
• Support multiple providers & procedures.
Anesthesia for Triple Endoscopy
• Stable adequate anesthesia is challenging.
• Procedural delay may not be reasonable.
• Alternatives to general anesthesia not feasible.
• Duration of exposure potentially prolonged.
• Definitive data generally lacking: Agent? How?
Challenge of Steady-State
Apnea
Movement
Disadvantage of Bolus Dosing
FINDINGS:
Under inhalational anesthesia with halothane, fentanyl 0.5 mcg/kg:
Apnea in 5% of patients without obstructive sleep apnea;
Apnea in 50% of patient with obstructive sleep apnea (mean AHI 29.4).
INTERPRETATION:
“The addition of an opioid analgesic … led to central apnea in
approximately half of the OSA group.”
Waters KA, et al.: Effects of OSA, inhalational anesthesia, and fentanyl on
the airway and ventilation of children. J Appl Physiol (1985) 2002
May;92(5):1987-94.
Advantage of Continuous Infusion
De Vito A, et al.: Drug-induced sleep endoscopy: conventional versus
target controlled infusion techniques--a randomized controlled study. Eur
Arch Otorhinolaryngol 2011 Mar;268(3):457-62.
Anesthesia for Endoscopy3: VCH
Mask inhalational induction (sevoflurane) v. IV induction (propofol)
Propofol IV infusion for maintenance (minimize bolus dosing): takes time!
Titrated supplemental agents as needed (ketamine > opioid): takes time!
Topical local anesthetic (lidocaine) for airway instrumentation: takes time!
Natural airway with minimal intervention for ENT (DISE, rigid)
Mask > LMA > ETT for pulmonology (flexible)
Airway of choice for GI (endoscopy)
PATIENCE & OPEN COMMUNICATION CRITICAL!
Special Thanks
Dr. Thanh T. Nguyen
Assistant Professor of Clinical Anesthesiology
Anesthesiology - Pediatric Division
Vanderbilt University Medical Center
Pediatric Anesthesiologist
Monroe Carell Jr. Children’s Hospital at Vanderbilt