Anesthetic Neurotoxicity Will this anesthetic make my kid stupid:

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1 Vexing issues in pediatric anesthesia 1 -Will this anesthetic make my kid stupid: Anesthetic Neurotoxicity 2- Parental Presence, Premedication and Induction Techniques Peter J. Davis MD Professor of Anesthesia and Pediatrics University of Pittsburgh School of Medicine Anesthesiologist in Chief Childrens Hospital of Pittsburgh Anesthetic Neurotoxicity Will this anesthetic make my kid stupid: NMDA antagonists, GABA agonist neuronal injury Window vulnerability ~ synaptogenesis Synaptogenesis species-specific timing Dose and duration Gene-regulated Species differences Receptor Activity of Commonly Used Anesthetic Agents Anesthetic Agent NMDA antagonist GABA-mimetics Volatile Anesthetics Halothane Isoflurane Desflurane Enflurane Sevoflurane Injectable Anesthetics Propofol Barbiturates Etomidate Benzodiazepines Ketamine Medical Gases Nitrous Oxide Opioid Analgesics Morphine Methadone Meperidine Fentanyl Chloral Hydrate Pathways of Cellular Apoptosis )Hotchkiss: NEJM 2009;361:1570) Anesthetic Neurotoxicity Rat model conception to PND 28 50, 100, 200 ppm halothane Lower density cerebral synapses ppm linear effect 200 pm plateau Learning behavior impaired (Uemura et al. Exp Neurology 1985;89:520) (Uemura et al. Exp Neurology 1980;69:135) Anesthetic Neurotoxicity 1 P7 rats most vulnerable Cocktail: midazolam isoflurane N 2 O Histology AND behavior 6 HR exposure - control 10% DMSO (Jevtovic-Todorovic, J Neurosci 2003(23):876) 1

2 Anesthetic Neurotoxicity (2) Histology. Caspase-3 and silver staining N 2 O alone, no apoptosis Midazolam alone, no apoptosis Isoflurane, dose dependent apoptosis Midazolam + isoflurane apoptosis > isoflurane alone Midazolam + N 2 O + isoflurane, apoptosis greater (Jevtovic-Todorovic, J Neurosci 2003(23):876) Anesthetic Neurotoxicity (3) Behavior Morris Water Maze Radial Arm Maze Early and late learning deficits Mice model No hypoglycemia MAC hr effect variability of controls Johnson SA et al., J Neurosurg Anesthesiol, vol 20(1), 21-28, January, 2008 Neurotoxicity Anesthetic Neurotoxicity Monkeys: GD 122, PND 5, PND 35 Ketamine: 3 HR or 24 HR Exposure-related: related: 24 HR not 3 HR Age-related: PND 35 Unaffected Plasma concentration: 5-10 x human levels (Slikker et al. Toxicological Science 2007;98:145) Neurotoxicity and Protection Slikker W, et al., Toxicological Sciences, 98(1), , 2007 Rat pup model Single repetitive pain Pain causes cell death, age-related areas Ketamine decreases cell death Pain-associated learning impairments (Anand et al. Peds Res 2007;62: ) 2

3 Results What about me 4,933 enrolled 4,401 no NEC, 532 NEC 2,703 No NEC follow up 245 NEC follow up 124 surgical NEC 121 medical NEC (Hintz et al. Pediatrics 2005;115:696) (Hintz et al, Pediatrics 2005;115:700) (Kabra et al, J Pediatr 2007; 232) Behavior and Development in Children and Age at the Time of First Anesthetic Exposure (Kalkman et al: Anesthesiology 11:805, 2009) Behavior and Development Retrospective cohort study Children urological surgery 0-6 years 1987, 1991, 1993, 1995 Academic pediatric hospital-ultrecht Netherlands Predominant inhalational anesthesia Appropriate exclusion Parental survey (Kalkman et al: Anesthesiology 11:805, 2009) 3

4 Behavior and Development Age at first exposure before 24 mos, after 24 mos Dutch translation child behavior checklist CBCL / 448 Developed validated in USA Parental report child s competencies & behavior Behavior & Development CBCL reports only on behavior screening tool of problematic behavior needs confirmation of psychopathology (Kalkman et al, 2009) (Kalkman et al: Anesthesiology 11:805, 2009) Results 368 patients qualified 314 questionnaires sent 249 questionnaires returned 243 questionnaires analyzed 75% anesthesia before age 2 71% more than 1 operation before age 6 (Kalkman et al: Anesthesiology 11:805, 2009) (Kalkman et al: Anesthesiology 2009;110(4): 805) Results Trend not statistically significant Sample size analysis 6,020 to confirm/refute for less than 2 years Anesthesia & Learning Disabilities: Population Based Birth Cohort Mayo Clinic, Olmsted County Minnesota Birth 1976 to 1982 Remained in community 5 years School records private and public Reading Centers/ Dyslexia Institute of Minnesota (private tutoring agency) LD diagnosed by preset criteria formula: reading, written language and math (Wilder, Anesthesiology 2009;110:796) 4

5 Anesthesia and Cognitive Performance in Children: No evidence for a causal relationship Bartels et al: Twin Research and Human Genetics 12:246, 2009 (Wilder, Anesthesiology 2009;110:796 Twin Study Netherlands Twin Registry 1143 monozygotic twins Anesthesia before age 3 Anesthesia between ages 3-12 Educational achievement age 12 Cognitive problems age 12 Twin Study Educational achievement (EA) (CITO) Correlated IQ Cognitive problems (Bartels et al, 2009) (Bartels et al, 2009) Twin Study Exposed before age 3 EA lower scores than nonexposed Unexposed co-twin from discordant pairs not different from exposed (Bartels et al: Twin Res Hum Genet 2009;12 5

6 Summary FDA Panel Are there sufficient data to determine applicability of the findings of anesthetics in nonclinical models to humans No To what extent are dose and duration of anesthetic exposure relevant to clinical use Unclear No scientific basis to recommend changes in clinical practice Vexing issues in pediatric anesthesia Parental Presence, Premedication and Induction Techniques Anxiety Factoids 75% children psychological and/or physiological anxiety Postoperative behavioral changes Sleep disturbances Acting out Poor school performance Clinging behavior Enuresis Distress During Induction & Postoperative Behavior Unpremedicated children 1-7 years No parental presence Temperament, anxiety compliance Post hospitalization behavior questionnaire Correlation of induction anxiety with emergence agitation Correlation of induction anxiety with postoperative behavior (Kain et al., Anesth Analg ) Age-related Psychological Concerns Fear of separation Stranger anxiety Fear of the unknown put to sleep Loss of control Fear of mutilation Knowing boundaries and limits (Kain et al., Anesth Analg 1998;88:1042) 6

7 Anxiety Effects Recovery kain et.al. Anesth Analg 2004;99: patient database Anxiety (mypas) modified Yale Preoperative Anxiety Scale PHBQ, Post-hospital behavior questionnaire Level anxiety as postop behavior worsens (Kain et al., Anesth Analg 2004;99:1652) Childhood Risk Factors Age: 1-5 years, highest risk Temperament: Shy and inhibited, higher risk Socially adaptive, less risk Experience previous medical experiences Parental trait anxiety: Anxious parents create anxious kids Parental Risk Factors for Anxiety Divorce, lower educational levels Parents whose children NOT in day care Parents of children < 1 year of age Parents who were frequent patients It s all in the preparation Parental presence Programs Music therapy Acupuncture Hypnosis Premedication Parental Presence (A) Initial surgery assigned intervention 83 children subsequent surgery Oral midazolam PPI PPI and midazolam No intervention Kain et al., Anesth Analg 2003;96;970) 7

8 Parental Presence (B) 80% parents chose PPI ± midazolam 70% parents of PPI chose PPI subsequent 23% midazolam initial, requested midazolam 15% no intervention, requested no intervention (Kain et al., Anesth Analg 2003;96:970) (Kain et al., Anesthesiology 2000;92:939) Parental Presence Perceptions Parents prefer, regardless of child s age 68% parents believe anesthesiologist s job easier 90% parents believe parent helpful to child 98% parents would do it again (Kain et al., Anesthesiology 2007;106:70) (Kain et al., Anesthesiology 1996;84:1060) Parental Presence Perceptions Anesthesiologist 21% anesthesiologists believe more difficult 12% anesthesiologists believe helpful 38% anesthesiologists believe no effect (Kain et al., Anesthesiology 1996;84:1060-7) Children s State of Anxiety during Induction of Anesthesia by Cohort Group Children s state anxiety during induction of anesthesia Cohort group With PPIA Without PPIA P value Calm parent, calm child 39.9 ± 22 (63) 34.7 ± 20 (68) Calm parent, anxious child 51.9 ± 24 (47) ± 26 (28) Overly anxious parent, calm 52.4 ± 28 (55) 39.4 ± 21 (75) child Overly anxious parent, anxious child 71.0 ± 23 (35) 66.6 ± 27 (26) *As measured by the modified Yale Preoperative Anxiety Scale (mypas) Values are mean ± SD (n) PPIA = parental presence during induction of anesthesia Denotes statistically significant differences 8

9 Parental Acupuncture If calm parents create calm kids treat the parents? 67 mother-child pairs Ear acupuncture at relaxation, tranquilizer master cerebral points Ear show acupuncture hand point, wrist point, extraneous point Certified acupuncturist Maternal and child anxiety (MYPAS) (Wang et al., Anesthesiology 2004;100:1399) (Wang et al., Anesthesiology 2004;100:1399) (Wang et al., Anesthesiology 2004;100:1399) Premedication Techniques (every orifice has been used and reported) Rectal Oral Nasal Buccal Intravenous Transdermal Intramuscular (Wang et al., Anesthesiology 2004;100:1399) 9

10 Premedications (Modified from McCann and Kain, Anesth Analg 2001;93:98) Premedication Dose (mg/kg) Bioavailability Time of onset (min) Midazolam (oral) % 10 Clonidine (oral) >90% 45 Ketamine (oral) % 10 Midazolam % 10 (intranasal) Midazolam (rectal) % 10 Oral Transmucosal % 30 Citrate Ketamine (intranasal) <10 Ketamine (rectal) % Midazolam Factoids Bioavailability related to vehicle Antacids may speed onset sedation Grapefruit juice inhibit CYP 3A Commercial syrup, lowest dose 0.25 mg/kg effective 14% of patients still distressed on induction ( Midazolam Factoids Midazolam paradox Implicit memory still intact Explicit memory impaired α- 2 Adrenergic Agonists Factoids Clonidine Oral 2-4 mics/kg Effective plasma con 0.3 to 0.8 ng/ml Not psychotropic Not amnestic Sedating Dexmedetomidine Factoids α 2 adrenergic 82% bioavailability via buccal route Adult volunteers, 1.0 and 1.5 μg/kg IN Peak sedation min Significant sedation min Dexmedetomidine Oral 0.5 mg/kg midazolam v 0.5 or 1.0 μg/kg Dex (IN) 1 μg Dex more effective than 0.5 μg Dex Dex comparable to midazolam at parental separation and induction (Yuen, Anesth Analg 2007;105:374) (Yuen et al., Anesth Analg 2008;106:1715) 10

11 Induction Techniques Hypnosis Inhalational Intravenous Induction Techniques - Caveats Sevoflurane Single breath inductions 8% start Infants and children rapid rate rise (FE/FI) Spontaneous ventilation Parental Presence Children s behavior with medical evaluations Older children Calm parents Parental belief in preparation Parents with coping skills Summary Kids know who their friends are Some of us have it, some of you don t No universally correct method Institutions play a major role (Kain et al., Pediatr Anesth 2006;16:627) Thank you 11