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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: [email protected] Topics covered • Some news about old drugs • Something about a new drug • Focus: neonates and infants • Focus: outcome, safety and toxicity Propofol, neonates and haemodynamics Demographics Haemodynamics NIRS Authors’ conclusions 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 (BSIDII) 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 NSE and CRP Conclusions Dexmedetomidine (2 adrenergic agonist) 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? Dexmedetomidine attenuates isofluraneinduced neuroapoptosis Sanders et al. Acta Anaesthesiol Scand 2010 Sanders et al. Anesthesiology 2009 (Caspase 3-activation↓) Context sensitive half times of opioids Ideal opioid for neonates and infants? Tolerance and hyperalgesia? NICU/PICU? MAC↓ Neurotoxcicity? 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 Long term outcome 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 Conclusions • Carefull dosing of anaesthetics and analgesics in very premature infants • Impact of haemodynamics on anaesthesiainduced neurotoxicity? • Normal blood pressure? • How do we treat hypotension?