Analgesics and hypnotics (APA Cambridge 20. June 2013

Tom G. Hansen, MD, PhD, Department of Anaesthesia & Intensive Care Odense University Hospital & University of Southern DenmarkDENMARKEmail: tomghansen@dadlnet.dk

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 (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

NSE and CRP

Conclusions

Dexmedetomidine(2 adrenergic agonist)

Dexmedetomedine(Mason & Lerman Anesth Analg 2011)

Licenced for PICU OR+sedation (resp)

Problems: PK/PDInfants & neonates?slow onset/prolonged durationindication?haemodynamics (BP↓↑,HR↓)premedication?drug synergism?

Dexmedetomidine attenuates isoflurane-induced neuroapoptosis

Sanders et al. Acta Anaesthesiol Scand2010

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 groupsComposite primary outcome: Death, IVH and PVLResults: 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: 2419-27Simons et al. Arch Dis Child Fetal Neonatal Ed2005; 90: F36-40 Simons et al. Arch Dis Child Fetal Neonatal Ed2006; 91: F46-51Placebo-controlled RCT (n=150) in preterms onIPPV 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/hIVH in morphine group, but similar analgesia andneurological outcome

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?