1. Analgesics and hypnotics (APA Cambridge 20. June 2013 Tom G. Hansen, MD, PhD, Department of Anaesthesia & Intensive Care Odense University Hospital & University of Southern Denmark DENMARK Email: tomghansen@dadlnet.dktomghansen@dadlnet.dk

2. Topics covered Some news about old drugs Something about a new drug Focus: neonates and infants Focus: outcome, safety and toxicity

3. Propofol, neonates and haemodynamics

4. Demographics

5. Haemodynamics

6. NIRS

7. Authors’ conclusions

11. Endpoints? Biomarkers for CNS injury (Neuron-specific enolase (NSE) and s-100β protein (t=0 h, after CPB, 6 h, 24 h, 48 h) Inflammatory mediators Bayley Scales of Infant Development, 2nd Ed (BSID- II) before and 2-3 w after surgery MRI with spectroscopy (MRS) just before surgery and just before hospital discharge (n=5): N-acetyl aspartate (NAA), creatine (Cr) and glutamate/glutamine sum NIRS < 24 h

12. NSE and CRP

14. Conclusions

15. Dexmedetomidine (  2 adrenergic agonist)

16. Dexmedetomedine (Mason & Lerman Anesth Analg 2011) Licenced for PICU  OR+sedation (  resp) Problems: PK/PD  Infants & neonates? slow onset/prolonged duration indication? haemodynamics (BP↓↑,HR↓) premedication? drug synergism?

17. Dexmedetomidine attenuates isoflurane- induced neuroapoptosis Sanders et al. Acta Anaesthesiol Scand 2010 Sanders et al. Anesthesiology 2009 (Caspase 3-activation↓)

18. Context sensitive half times of opioids

19. Ideal opioid for neonates and infants? Tolerance and hyperalgesia? NICU/PICU? MAC↓  Neurotoxcicity?

22. NEOPAIN (Anand et al Lancet 2004; 363: 1673-82) RCT, 16 centers: IPPV treated preterm infants, Morphine group (MG; n=449) and placebo group (PG; n=449) Intervention: preemptive morphine in IPPV LD 0.1 mg/kg, followed by CI 10  g/kg/h (GA 23-26) 20  g/kg/h (GA 27-29) 30  g/kg/h (GA 30-32) + open label morphine (OLM) for both groups Composite primary outcome: Death, IVH and PVL Results: Analgesia  but similar rates of deaths, IVH and PVL - OLM  ↑ CO and ↑severe IVH in MG vs. PG + OLM  ↑CO in PG +OLM  IVH in MG

23. Long term outcome

24. Long term outcome The original Dutch studies (2000-2002) Simons et al. JAMA 2003; 290: 2419-27 Simons et al. Arch Dis Child Fetal Neonatal Ed 2005; 90: F36-40 Simons et al. Arch Dis Child Fetal Neonatal Ed 2006; 91: F46-51 Placebo-controlled RCT (n=150) in preterms on IPPV receiving morphine: LD 0.1 mg/kg CI 10  g/kg/h +open label morphine: LD 0.05 mg/kg, CI 5-10  g/kg/h IVH  in morphine group, but similar analgesia and neurological outcome

27. Conclusions Carefull dosing of anaesthetics and analgesics in very premature infants Impact of haemodynamics on anaesthesia- induced neurotoxicity? Normal blood pressure? How do we treat hypotension?