Optimizing propofol dosing for (preterm) newborn infants that need endotracheal intubation

Propofol, a rapidly acting anaesthetic agent, is currently used unlicensed in
the clinical care of (preterm) neonates as sedative for endotracheal
intubation. Neonates receive the same propofol doses per kg bodyweight,
independent of their developmental stage (gestational age, postnatal age),
morbidity, co-medication, etc. This is related to a high failure rate of
intubation attempts and leads to hypotension in around 40 percent of patients.
Propofol research in newborn infants is on the recently published priority drug
research list of the European Medicines Agency (EMA). Propofol metabolism and
elimination (pharmacokinetics) as well as propofol effects (pharmacodynamics)
highly depend on the stage of development and on the genetic make-up of a
patient. This study is based on the hypotheses that currently used single doses
of propofol for newborn infants can be optimized and that this will improve the
quality of sedation and increase the safety of the patients.

To determine effective and safe age specific propofol dosing guidelines for
neonates of different age groups (both gestational age and postnatal age).
Secondary objective is to determine a new age specific PK/PD
(pharmacokinetic/pharmacodynamic), including a specific propofol genotype
(pharmacogenetic analyses) that enables much better prediction of the effects
and side-effects of propofol.

Prospective single dose optimizing and dose validation study

Adapted propofol dose. Starting dose is dependent on effects of previously
included patients. Dose is increased in case of insufficient sedation.
Intubation is started only after sedation level is adequate (titration with
additional propofol is possible because propofol is very fast acting)

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:
Propofol is used as a standard of care for sedation before intubation in
newborn infants. Drug metabolism, drug transporters and drug receptors are not
yet well developed in (preterm) newborn infants. Therefore PK/PD is very much
dependent on the developmental stage of the newborn infant and though changes
with age. This study can therefore not be done in another patient group (for
instance older patients or healthy volunteers).
Internationally used propofol starting doses in newborns vary between 1.0 to
2.5 mg/kg and are repeated if necessary. The current study will start with
propofol doses of 1.0 mg/kg in every age group. If the study starting dose is
insufficient, the patient will receive additional propofol doses (1.0 mg/kg)
until adequate sedation is acquired. No patient will be intubated before
adequate sedation is reached. This is possible because propofol is very fast
acting (1-2 minutes).
If the starting dose turns out to be insufficient in 5 patients per group it
will be increased in the following patients of that group. The effect of an
initial propofol dose is tested to find the optimal propofol doses for neonates
in different developmental stages. The study will be continued until the
appropriate dose for each age group is determined. The appropriate doses are
re-used in another 5 patients per age group to validate the predetermined
doses. Safety is monitored very intensively and if hypotension occurs this is
immediately treated. The patient will benefit from this intensive safety
monitoring, because side-effects will be detected earlier and can be more
effectively treated.
Included patients will be monitored with non-invasive techniques (videotaping,
cranial ultrasound, aEEG, NIRS) next to the standard intensive care monitoring
of physiological parameters.
Blood samples will only be collected from indwelling arterial lines or during
routine blood sampling because of normal patients care. An amount of 1.7 ml
blood (0.5 ml for DNA analyses, 2 times 0.6 ml for propofol PK analyses) is
taken if possible. Two saliva samples for cortisol analyses will be collected.