Paracetamol intravenously in neonates with a gestational age of less than 32 weeks

In neonatology therapeutic options to treat pain are sparse. Opiates are known
to have side effects like hypotension, decrease of intestinal function,
respiratory depression, habituation and withdrawal symptoms. For systemic
treatment of neonatal pain the only non-opioid alternative is paracetamol.
Pharmacokinetic data shows that absorption of this drug when administered
rectally is highly unpredictable. The source of neonatal pain frequently is
manipulation, and one has to manipulate the neonate when a drug is administered
rectally.
There is no evidence for the minimum amount of oral feeding a neonate has to
receive to safely administer drugs orally. In every day practice the neonate
receives medication orally only if feeding by mouth has reached 60 ml/kg/day.
In a preterm infant of less than 32 weeks that amount will be reached on the
4th day of life (day of birth being day 0). In a preterm of less than 28 days
60 ml/kg/day oral feeding will be reached no earlier than on the 7th day of
life. This means that currently the only therapeutic option to treat neonatal
pain in preterm infants of less than 32 weeks in the first 5 days of life are
opioids or paracetamol rectally.

The intravenous (i.v.) form of paracetamol (Perfalgan®) has recently become
available in the Netherlands. Until now, studies on i.v. paracetamol in
neonatology have mainly been performed with the pro-drug propacetamol or with
paracetamol in preterm infants > 32 weeks of gestation. Propacetamol is a
pro-drug of paracetamol and is hydrolyzed by plasma esterases after i.v.
administration such that 1 g of propacetamol is hydrolyzed to 0.5 g of
paracetamol. Limited data is available concerning the pharmacokinetics of
propacetamol and paracetamol. There is no data on the efficacy of parecetamol
intravenously.

Primary objective: to study the pharmacokinetics and pharmacodynamics of
paracetamol intravenously in preterm infants with a gestational age of less
than 32 weeks:

Secondary objective(s): to study the safety and dose-effect relationship of
paracetamol intravenously.

The study is a prospective, observational, longitudinal study.

As the cohort is, due to the gestational age, subject to frequent blood
sampling through an arterial indwelling catheter, the only burden consists of
little amounts of extra blood being sampled (5 times 0,25ml) for measurement of
paracetamol serum levels. Levels of unconjugated bilirubin, AST,ALT and
glutathion require a total of 2 x0,15 ml of blood. The risk of liver failure
due to high paracetamol serum levels is expected to be low.