safe and effective use of sedatives and analgesics in neonates Erasmus MC Rotterdam, the Netherlands KU Leuven, Belgium karel allegaert

SUGGESTION 1

Anand et al. New Engl J Med 1987 Taddio et al. JAMA 2002 Taddio et al. Lancet 1995 and 1997

SUGGESTION 2

Pacifici, Curr Ther Research 2015

Biodisponibility 0.54 rectal route oral route rectaal of oraal, 20 mg/kg single dose na NKO heelkunde rectal route Biodisponibility 0.54 oral route Anderson et al. Anesthesiology 1999

opioid sparing effect in non-cardiac surgery, newborns Ceelie et al. JAMA 2013

‘minor’ pain syndromes Pediatr Anesth, 2014

after procedural pain (heel prick), uniform negative Reference Study design and pain model Paracetamol dosing Results   Shah et al. Arch Dis Child Fetal Neonatal Ed 1998 Double blind placebo controlled trial 75 term neonates, heel prick. Facial action pain scores and cry score. Single oral paracetamol 20 mg/kg or placebo, 60 to 90 min before prick. No differences in facial action pain scores, nor in cry score. Bonetto et al. Arch Argent Pediatr 2008 Prospective randomized trial 76 term neonates, heel prick pain scores (NIPS, neonatal infant pain score>4) Placebo, dextrose (25%) EMLA or oral paracetamol (20 mg/kg, 60 min) NIPS<4 similar between placebo, paracetamol or ELMA (47, 42 and 63 %). Oral dextrose most effective (84% NIPS<4, NNT 2.7) Badiee et al. Saudi Med J 2009 Randomized placebo controlled trial in 72 preterm (mean 32 weeks) neonates, heel prick PIPP (premature infant pain profile) score Single (high dose) oral paracetamol (40 mg/kg) 90 minutes before prick. PIPP scores placebo (9,7, SD 4.2) were similar to paracetamol (11.1, SD 3.8)

SUGGESTION 3 the route of administration matters opioid sparing minor pain syndromes procedural pain

SUGGESTION 4 please consider a loading dose when you anticipate continuous or repeated administration

SUGGESTION 5 extensive variability in practices between units (when, how, what) please consider a loading dose when you anticipate continuous or repeated administration

pediatrix datasets (US) (Clark et al, 2006; Hsieh et al 2014, Zimmerman et al, 2017) 1997-2004 2005-2010 all cases morphine 5.6 (19th) 7 (7th) % fentanyl 3.5 (25th) 5.1 (14th) % VLBW, ventilated 1997 until 2012 Opioids cont 5 % 32 % ventilation days

extensive variability between units Canada and Europe (Borenstein-Levin et al, 2017; Carbajal et al, Lancet Resp Med 2015 ; Flint et al, 2018) extensive variability between units 23 % of ELBW cases exposed to opioids, but 3 to 41 % 2.5 fold (range 919 to 2278/1000 neonates) Europain: extensive variability associated with prolonged ventilation in part explained by the respiratory support prof B van Overmeire, La ventilation nécessite-t-elle une sédation systématique ?

less is more…?

individualized approach treatment maturational aspects unexplained variability assessment pain scales intersubjectivity prevention relevant limited individualized approach

Paper in press, to be added (Pain)

individualized approach treatment maturational aspects unexplained variability assessment pain scales intersubjectivity prevention relevant limited individualized approach

PHARMACOKINETICS PHARMACODYNAMICS DOSE FINDING Propofol blood (µV) 50 25 10 5 Propofol blood concentration Electrical brain activity on aEEG Propofol (ng/mL) 0 60 120 min % 90 60 30 Cerebral oxygenation: NIRS determined rScO2 0 60 120 min min Heart rate Peripheral oxygen saturation Respiration rate Blood pressure Vital signs DOSE FINDING 2 1.5 1 0.5 Propofol dose (mg/kg) Clinical scores: Relaxation, sedation ED50 euroanaesthesia london 28052016 Nr of patients

pain/exitocytosis exposure to analgesics apoptosis-synaptogenesis

SUGGESTION 5

Mind numbing: Anesthesia in baby rats stunts brain development. Common general anesthetics given at an early age may cause brain damage and other neurologic problems

Wilder et al. Anesthesiology 2009

de Graaf et al. Pain 2013 (8-9 year follow up after neonatal morphine)

Wait and accept is not acceptable Mieux vaut prévenir que guérir Paracetamol: opioid sparing and minor, YES How to give: loading dose When to give: extensive variability What to give: needs further study (dose seeking) Safety/toxicity remains a relevant issue