Anaesthetic pharmacology for children. Noel Roberts Monash Children s Hospital

Transcription

1 Anaesthetic pharmacology for children Noel Roberts Monash Children s Hospital

2 Aims To briefly summarize the evidence concerning neurotoxicity and its implications for pediatric anaesthetic practice To outline the advantages and potential problems of using remifentanil in children To assess the potential complications of post operative analgesia and strategies for reducing harm

3 GABA agonists, NMDA anatagonists Brain derived neurotrophic factor, instrinsic/extrinsic apoptosis Neuronal Apoptosis, Glial cells, Dendrites, Synapses, Window vulnerability 2 weeks post natal Parieto-temp Language 9/12 Frontal, Executive 2 yrs Histopathology Electrophysiology Behaviour, Learning Retrospective data Group/Individual testing Language, cognition, behaviour

4 9 human studies Robust methodology 6/9 -ve cognitive, academic or behavioral changes 3/9 no Δ academic/educational achievement 55 rodent studies 70% neuroapoptosis 10% learning and/or behavioural abnormalities 7 primate studies 4 ketamine apoptosis 2 isoflurane/n20 apoptosis 1 ketamine learning Ketamine 3 hrs, N2O or isoflurane alone, no Δ

5 We have administered to 7 day rats a combination of drugs commonly used in paediatric anaesthesia, midazolam, isoflurane and nitrous oxide. This caused widespread apoptosis, deficits in hippocampal function and persistent memory/learning impairments

6 Typical paediatric anaesthesia N2O 75%, Isoflurane 0.75%, Midazolam 9 mg/kg IP! 6 hrs Chamber, no monitoring No surgery ABG ventricle at 6 hrs 80% mortality, repeat study!

7 Animal studies, minimizing damage Dose eg 0.5 MAC, duration <4 hrs, agent Environmental enrichment Shih J, May LDV, Gonzalez HE, Lee EW, Alvi RS, Sall JW, et al. Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology Mar;116(3): Alpha 2 agonists? Xenon? B Estradiol, Melatonin? Hypothermia (30 deg!)

8 Raine study, effects of prenatal ultrasound, W.A 321 children surgery <3, 2287 controls, born Neuropsychological testing at age 10 Procedures included; myringotomy 25%, hernia 10%, circumcision 9%, tonsillectomy 7%, dental 6% Only 40 had multiple surgery No details on co-morbidity, anaesthesia

9 Ing C et al. Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. PEDIATRICS Sep;130(3):e

10 Disability assessed as -1.5 SD below mean= Disabled Unexposed 6-7% Disability, GA/Surgery 13-14% Disability CONCLUSIONS In this birth cohort, children exposed to anesthesia before age 3 had an increased long-term risk of clinical deficit in receptive and expressive language, as well as abstract reasoning Ing C et al. Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. PEDIATRICS Sep;130(3):e

11 Anaesthesia, neurocognitive and behavioural outcomes in children. Impaired.

12 Anaesthesia, neurocognitive and behavioural outcomes in children. No effect.

13 How does this affect my practice? Avoid halothane, N2O! Use oximetry, ET CO2! Delay all non essential surgery Surgical, anaesthesia, paediatric discussion re delay and risks Opioids and local anaesthetics seem safe GA Minimize dose GABA agonists Regional, Remifentanil Informed consent but can reassure you may have read about learning problems after GA. With appropriate precautions and a single episode of anaesthesia this is very unlikely SmartTots consensus statement, Dec 2012 Discuss with parents and other caretakers the risks and benefits of procedures requiring anesthetics or sedatives, as well as the known health risks of not treating certain conditions Stay informed of new developments in this area Recognize that current anesthetics are necessary for infants and children who require surgery SmartTots.org

14 Remifentanil- Well I love it! Switch on, switch off 50-80% MAC sparing Relative hemodynamic stability No post op resp depression Neurotoxicity very unlikely Suppression of airway reflexes

15 Remi 0.8 mcg/kg/min!, PPF 7 mg/kg/hr, Fent 4 mcg/kg Sevoflurane, Fentanyl 5 mcg/kg Remi, lower HR (111 vs 128) Remi, higher MAP (58 vs 51) No evidence of hyperalgesia, tolerance (24 hr morphine dose)

16 Maximum remifentanil rate 0.14 μg/kg/min, propofol 200 mcg/kg/min. No severe breath holding or body movements were observed. SpO2 below 90% occurred in 10 (16.7%) cases. No progressive desaturation. PACU, no hypoxemia, mean recovery time 23 min. No laryngospasm, pneumothorax or arrhythmias Conclusion: Propofol remifentanil TIVA and spontaneous ventilation are an effective and safe techniques to manage anesthesia during airway FB removal in children with preoperative respiratory impairment.

17 Problems with ventilation in 9/12 9/12, PHx Bronchiolitis, hypospadias repair ETT, IPPV, Sevo, Remifentanil 0.1 mcg/kg/min, caudal ropivacaine/clonidine Difficult ventilation, Low Vt, chest clear? patient, ETT, circuit Remifentanil 20 mcg/ml instead of 3 mcg/ml! =0.7 mcg/kg/min! Atracurium Problem solved! Standardized dilutions, check, 4 mcg/ml

18 Remifentanil in neonates/infants; Practical considerations Remifentanil 4 mcg/ml (2 mg/500 mls) 1.5 ml/kg/hr=6 mcg/kg/hr=0.1 mcg/kg/min Minimize dead space If bolus <0.5 mcg/kg Start at 0.2 mcg/kg/min and titrate to RR Maintenance mcg/kg/min Alternative analgesia eg LA, opioids, adjuncts

19 Risk factors for OIRD in a case report literature review Drug administration error Calculation, dilution, substitution Codeine and CYP2D6 ultra metabolism Adenotonsillectomy and OSA Renal failure

20 CYP2D6 A review of cases reported to the FDA s Adverse Event Reporting System between 1969 and May 2012 identified 10 deaths and 3 overdoses in children who had been treated with codeine. 8 occurred in children after tonsillectomy Physicians should not use Codeine to treat pain in children after tonsillectomy warns the US Food and Drug Administration CYP2D6 Ultra Metabolizers 30% Nth African 10% Middle East 2% Caucasian PainStop 0.5 mg/kg codeine, 12 mg/kg paracetamol

21 Adjunct non opioids reduce the risk of adverse events and rescue Opioid resp adverse events 0.16 ( C.I) Rescue 0.14 ( C.I) Conclusions: Findings from this study suggest that strategies such as early use of adjuvant non opioids may reduce risk of opioid-ades postoperatively

22 NSAIDS Opioid sparing, improved analgesia, decreased PONV Concerns regarding bleeding (particularly surgical concerns) COX 2 inhibitors fewer complications but concerns regarding few pediatric studies, approval, efficacy and potential renal complications

23 Anesthesia and Analgesia 2012; 114, Meta-analysis, 27 studies, NSAID use on analgesia, opioid consumption and PONV Decreased opioid use 24 hrs SMD=-0.83 (-1, -0.55) Improved analgesia PACU SMD=-0.85 (-1.2,-0.47) Decreased PONV 24 hrs OR=0.75 ( ) Paracetamol improved analgesia 24 hrs 2 rofecoxib trials, no significant diff c/w paracetamol

24 Clinical practice guidelines, paed tonsillectomy Strong recommendations; single dose of dexamethasone, decreased PONV, pain and improved oral intake Recommendations; advocate for adequate pain management, NSAIDS can be used safely except for ketorolac

25 36 studies, 1747 children, 1446 adults No bleeding children OR 1.06 ( ) No bleeding adults OR 1.3 ( ) No bleeding with multiple doses (eg pre/post op) Cardwell.M et al. Nonsteroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy (Review). Cochrane Review. 10/2010 (2005 Update) 15 trials, 1046 children NSAIDs did not significantly alter the number of perioperative bleeding events requiring surgical/non surgical intervention: (OR) 1.32 (95% (CI) 0.47 to 3.70). OR 1.00 (CI 0.39 to 2.53)

26 38 children, 1 mg/kg, 1-13 yrs Parecoxib Carboxylester ases Valdecoxib 1 mg/kg maintains valdecoxib therapeutic levels >12 hrs MMC guidelines Panadol, ibuprofen, tramadol 24 hrs Parecoxib alternative Panadol, ibuprofen home Oxycodone if inadequate

27 Plante J, et al. Effect of systemic steroids on post-tonsillectomy bleeding and re-interventions: systematic review and meta-analysis. BMJ: British Medical Journal. BMJ Group; 2012;345. e5389. Systemic steroid use is associated with a raised incidence of operative re-interventions

28 314 children, Dex 0.5 mg/kg, 14 day follow up In conclusion, perioperative dexamethasone administration was not associated with more level II or III bleeding events than placebo

29 I don t have trouble with the police, I just have trouble with drugs! Neurotoxicity, association or causation? Definitely in rats, concerns in children, <2-3 essential surgery Codeine, going, going, gone! NSAIDS underutilized because of unjustified bleeding concerns Dexamethasone, effective and generally safe