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

4. SUGGESTION 1

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

7. SUGGESTION 2

11. Pacifici, Curr Ther Research 2015

12. 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

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

14. ‘minor’ pain syndromes
Pediatr Anesth, 2014

15. 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)

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

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

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

22. pediatrix datasets (US) (Clark et al, 2006; Hsieh et al 2014, Zimmerman et al, 2017)
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

23. 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 ?

24. less is more…?

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

28. Paper in press, to be added (Pain)

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

30. PHARMACOKINETICS PHARMACODYNAMICS DOSE FINDING Propofol blood
(µV) 50 25 10 5
Propofol blood
concentration
Electrical brain activity on aEEG
Propofol (ng/mL)
min % 90 60 30
Cerebral oxygenation:
NIRS determined rScO2
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
Nr of patients

33. pain/exitocytosis
exposure to analgesics
apoptosis-synaptogenesis

34. SUGGESTION 5

35. 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

36. Wilder et al. Anesthesiology 2009

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

41. 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