Heather J. Rankin, DNP, CRNA Children s of Alabama Birmingham, AL AANA Treasurer.

Transcription

1 Heather J. Rankin, DNP, CRNA Children s of Alabama Birmingham, AL AANA Treasurer hrankin@aanabod.com

2 Define neuroapoptosis Identify medications that have been shown to induce neuroapoptosis in animals Review medications Identify potential complications to humans when exposed to these medications

3

4 Apoptosis simply defined is programmed cell death Neuroapoptosis is cell death in the brain Majority of neurons which are differentiated become integrated during synaptogenosis, with only a small amount undergoing non programmed apoptosis under normal circumstances

5 Injury happens to a cell causing the Bax protein to move the surface of the mitochondrion Cytochrome c leaks from the mitochondrion Caspase 3 is activated and the cell is now committed to cell death Cells with caspase 3 activated are easily detected with staining

6 Bax Cytochrome c Caspase 3 Activation Cell Death

7

8 N-methyl-D-aspartate (NMDA) receptors Gamma-aminobutyric acid (GABA) receptors

9 Glutamate receptor family Excitatory Binding site for ketamine and phencyclidine

10 Principal inhibitory neurotransmitter Binding sites for benzodiazepines, alcohol, and barbiturates Mainly found in the central nervous system Synergist effects

11 Neocortex glutamate and GABA Hippocampus spatial learning and memory Hypothalamus - behavior Amygdala memory, emotions, fear

12 that affect these receptors

13 Both NMDA and GABA Fetal Alcohol Spectrum Disorder Studies Klintsova et al. (2007) - hippocampus Wozniak et al. (2004) profound However can recover

14

15 Mechanism of Action Effect Na+ and Ca++ ion transport Most GABA agonists, some NMDA antagonists Studies Bittigau et al. (2003) widespread & dose dependent (rats) Sterfovska et al. (2009) no apoptosis, but impaired neurogenesis Bromley et al. (2007) 7 fold higher autism Meador et al. (2014) no difference in IQ age 6

16

17 NMDA Antagonist Pharmacokinetics Metabolism CYP450 Dosage 1-2 mg/kg IV 3-6 mg/kg IM 30 mcg/kg/min 75 mcg/kg/min 2-5 mg/kg PO Side Effects CV Pulmonary Neuro

18 Why do we like it? Amnesia Analgesia Cardiac profile!!! What pediatric populations would get this? Cardiac patients, especially unrepaired ER Uncooperative Neonates Burn patients Mitochondrial disorders

19 Studies Slikker et al. (2007) Significant apoptosis after 24 hours Age/dose dependent On monkeys Zou et al. (2009) PND 7 rats 5, 10, and 20 mg/kg subcutaneous Showed dose dependent Huang et al. (2015) inhibit proliferation of neural stem cells - alter neurogenesis

20 GABA agonist Pharmacokinetics Crosses BBB, absorbed in GI Metabolism CYP450 Dosage mg/kg IV mg/kg PO or IN Side Effects CV Pulmonary Neuro

21 Why do we like it? Anxiolysis Amnesia Can be administered PO What pediatric population would get it? Preop to decrease separation anxiety Rare to give to neonates Studies Young et al. (2005) infant mouse Jevtovic-Todorovic et al. (2003) infant rats Dose dependent effects

22 Both NMDA and GABA Pharmacokinetics Metabolism Dosage Side Effects Neuro CV Pulmonary

23 Why do we like it? Quick on and quick off Easily accessible Low side effect profile Antiemetic and anticonvulsants effects What pediatric population would get it? Who wouldn t get it? Studies Cattano et al linear relationship

24 MOA Pharmacokinetics Metabolism Dosage Side Effects Neuro dec O2, inc CBF & ICP CV BP and HR Pulmonary dec resistance

25 Studies Stratmann et al. (2009) neurogenesis and neurocognitive effects (iso) Satomoto et al. (2009) learning and social impairments similar to autism (sevo) Liang et al (2010) iso > sevo Rhesus macaques Brambrink et al. (2012) widespread, gray and white matter

26 First and most research with isoflurane Recent studies comparing isoflurane, desflurane, and sevoflurane No real advantage shown with any agent No evidence to show the mechanism with respect to the selectivity with volatile agents N20 alone does not show apoptosis, but does in conjunction with others

27 Studies found the highest degree of damage when combinations of inhaled anesthetics were used with ketamine, midazolam, or N 2 O Lunardi et al. (2010) Jevtovic-Todorovic et al. (2003)

28 Lithium Hypothermia Methazolamide and Melatonin Xenon Dexmedetomidine Much more research needs to be done in this area

29 Works at the site of extracellular signal regulated kinase (ERK) sites Lithium stimulates ERK phosphorylation Studies have shown neuro-protective effects with ethanol, ketamine, propofol, and isoflurane Young et al. Future use?

30 Yon et al (2006) 17 day old rats 1, 5, 10, 20 mg/kg sc 15 minutes prior and midway through Damage was reduced in a dose dependent fashion Cerebral cortex and anterior thalamus

31 Dose dependent attenuation of isoflurane induced neuroapoptosis Protected long term memory Α 2 receptor sites Doses? Sanders et al. Timing?

32 How cold do you go? 30 C? Optimal time frame? Complications that can arise Slower drug metabolism Impaired coagulation Shivering postop Surgical wound healing

33 Animals have problems with spatial learning and memory Decreased social interactions Increased contextual fear conditioning Some recovery by adulthood

34 Many of them kill the animals right after exposure to examine brain and apoptotic sites Some studies show interactions and stimulation decrease developmental deficiencies Many studies looked at clinically irrelevant doses of anesthetics Although there have been studies with animals to show adult behavioral and cognitive dysfunctions, there has not been that with humans Majority of studies are in non-primates

35

36 Mostly restrospective Kalkman et al. (2009) Divided into <2 and >2 years of age Child Behavior Check List Urologic procedures < 6 years Trend towards increased risk, but not significant Adjusted OR 1.38, 1.19, 1.2

37 Wilder et al. (2009) Children under the age of 4 who received multiple anesthetics had a significantly higher incidence of learning disabilities Ratio with 1 anesthetic = 1.0 Ratio with 2 anesthetics = 1.6 Ratio with 3 or more = 2.6 Higher physical status classification was not a risk factor

38 Flick et al. (2011) Matched cohort study Looked at children under age 2 (n=350) with 700 nonexposed Complete access to school records Matched to unexposed controls eval age 19 Nonexposed to anesthetic LD= 21.3% Exposed one controls LD = 23.6% Exposed to multiple anesthetics LD = 36.6% (HR 2.16) Repeated anesthetics independent risk factor for LD with HR 2.16

39 DiMaggio et al. (2009) hernia repair HR 2.3 behavioral issues Bartels et al. (2009) Twin study finding no differences, though pairs with anesthesia scored lower Guerra et al. (2011) neonates and cardiac surgery Prospective follow up study months Bayley scale of infant or toddler development Multiple regression analysis found no association between exposure and significant mental, motor, or vocabulary delay

40 Neurodevelopment = language, cognition, learning disabilities, behavior, academics children < 4 years (mean 3y) Development evaluated between 1 and 16 yo Overall HR 1.23 Multiple exposure HR 1.75 Time exposure 1.08

41 Hansen et al, 2013 Cohort of pylorics <3 months 9 th grade test scores adjusted Test scores were higher in nonexposed Unadjusted risk for nonattainment was higher in exposed group (OR 1.37) BUT when adjusted for weight, other congenital problems no difference Strength of this study

42 Infants requiring cardiac surgery within first month of life CPB for >60 min, 35 week, 2 kg (single ventricle, TOF) Preop and postop MRI Totaled for LOS with first surgery and any subsequent admission/surgery/procedure Bayley III: cognitive, motor, and language at 12 months

43 N = 39 Preoperative injury Postop injury Total with WMI, infarction, hemorrhage, N (%) 18 (46%) 28 (71%) WMI, N (%) 12 (31%) 14 (36%) WMI severity: mild/moderate/severe (N) 8/3/1 10/4/0 Infarction, N (%) 9 (23%) 10 (26%) Infarction severity: mild/moderate/severe (N) 5/3/1 10/0/0 Hemorrhage, N (%) 4 (10%) 10 (26%) Hemorrhage severity: mild/moderate/severe (N) 4/0/0 9/0/1

44 Longer ICU stay, lower Bayley scores (all 3) More VA, lower cognitive scores (p=0.28) New postop injury, lower cognitive language (p = 0.039, 0.020) Higher opioid doses, higher cognitive and language (p = 0.025, 0.007) Higher benzo, higher cognitive (p = 0.48) Abnormal chormosomes (motor and language p = 0.031, 0.030)

45 Ko et al., August 2014, Eur J Anaesthesiology Matched cohort study from Taiwan 5,197 children with exposure <2 yo Matched 20,788 examining diagnosis of autism Exposed group: (0.96%) Nonexposed group (0.89%) P = 0.62 HR = 0.93

46 Morriss et al., June 2014, JAMA VLBW ( g) from Evaluated at months GA vs. non-ga vs. no surgery OR surgery OR major surgery 1.52

47 Yan et al., 2014 Ketamine for laser surgery treatment 1, 2, or 3 treatments Bayley II scale 3 or more exposures had significantly lower scores and can adversely affect development

48 Not enough human studies Cohort studies Data lacking when examining human studies Single seems safe Multiple???

49 53 exposed < 4 yoa compared to 53 nonexposed Test scores WNL for all BUT Significantly lower listening comprehension and performance IQ Lower gray matter

50 Mayo Anesthesia Safety in Kids Ongoing Cohort GA (single or multiple) <3 yoa vs. control testing hour neuropsychological testing National Center for Toxicological Research Operant Test Battery

51 Pediatric Anesthesia NeuroDevelopment Assessment 28 exposed/nonexposed sibling pairs Exposed IHR < 36 months of age Similar testing results Brief single exposure not a problem

52 Multicenter, randomized controlled trial, headed in Boston with 30 clinical sites Examining RA vs. GA/RA in infants with IHR Outcome measures WPPSI III scale at 5 yo Bayley scale at 2 yo Number of postop apneic events At 2 year evaluation - no changes Will also have a 5 year f/u

53 Ing, et. al (2017) Not global developmental delays More delays found in language and cognition Again looking at anesthesia less than age 3 years

54 International Anesthesia Research Society Strategies for mitigating anesthesia related neurotoxicty in tots launched 2010 Funding multiple research studies now Lots of articles to research FDA 2016 statement

55 The U.S. Food and Drug Administration (FDA) is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children s brains. Further research is needed discuss with healthcare provider Warning label to specific drugs

56 List of General Anesthetic and Sedation Drugs Affected by this Label Change* Generic Name /Brand Name desflurane Suprane etomidate Amidate halothane Only generic is available isoflurane Forane ketamine Ketalar lorazepam injection Ativan methohexital Brevital midazolam injection, syrup pentobarbital Nembutal propofol Diprivan sevoflurane Ultane, Sojourn

57 One brief anesthetic is fine Multiple we are not sure of based on the data out there now Caution against delaying a needed procedure Weigh it carefully

58 Andropolous and Greene, New England Journal of Medicine perspective Changing the way they discuss anesthesia with parents of children under 3 Including the FDA warning Materials for education will be available

59 So many questions Children with disabilities Adjustments for life changing events later in life (e.g. death of a parent) Some surveys filled out by parents, not professional Questionnaire focus

60 Children having multiple anesthetics may have an underlying condition which predisposes them to increased change of having a learning disability Stress response to surgery Many animal studies use nonclinical doses or time periods Human studies - halothane

61 No elective surgery is recommended in neonates and infants More follow up research is necessary, especially in primates Neonates having surgery No change to the way you practice, but there is suggestive evidence that multiple anesthetics = increased chance for LD

62 Watch for more retrospective and prospective studies and results Possible changes in practice??? Honestly answer parents concerns if asked

63

64 @alacrna