Critically-ill infants sometimes require extracorporeal membrane
oxygenation (ECMO) to provide adequate oxygenation and perfusion.
Pharmacokinetic data are often lacking for this particular population,
which leads to dose regimens that are based on personal experience or
extrapolation from studies in other patients. This thesis aims to add to
the understanding of determinants of drug behavior during ECMO, and to
provide dose recommendations for commonly used drugs.
Part I addresses practical problems that are encountered in pediatric
studies. We give an overview of sampling and assay methods.
Ultra-performance liquid chromatography with mass spectrometry (UPLC-MS)
drug assays using small volumes of plasma were developed for
beta-lactam antibiotics, sildenafil, midazolam, morphine and their main
metabolites.
In part II, drug adsorption was quantified in in vitro circuits.
Oxygenator size has little influence on drug loss, but losses are
correlated to the lipophilicity (log P value) of individual drugs. Drug
loss is smaller in circuits with a centrifugal pump.
Pharmacokinetic studies (part III) with cefotaxime, sildenafil and
midazolam show that, in general, ECMO patients have a slower metabolism
and excretion than non-ECMO patients, and a higher volume of
distribution. This combination would require doses to be increased, and
the dose interval lengthened. In contrast, within patients the period
between cannulation and decannulation shows an increased clearance
compared to pre- and post-ECMO, which suggests drug adsorption by the
circuit and membrane oxygenator, CVVH-clearance or improved hepatic and
renal perfusion. The poor predictability of these effects leads to the
conclusion that individual drugs should be studied in ECMO patients. The
methodology we present in this thesis can facilitate these studies.http://repub.eur.nl/res/pub/20771/100702_Ahsman%2C%20Maurice%20Ahsman%20-%20bewerktt.pdf
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