Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

Background. Children with cancer and infection may develop glomerular hyperfiltration (GH). With the aim to determine the prevalence of GH in children and young adults with haemato-oncological disease and infection we developed population pharmacokinetic model of iohexol. We further aimed to assess the accuracy of estimated glomerular filtration rate (eGFR) equations and single- or two-point measured GFR (mGFR) formulas compared with GFR based on iohexol clearance from our population pharmacokinetic model (iGFR). Procedure. Hospitalized patients (0.5-25 years) with haemato-oncological disease and infection were included if their eGFR was ≥80 mL/min/1.73 m2 at the screening visit. Iohexol plasma concentrations were described by population pharmacokinetic model. Bias, precision and accuracy of 23 eGFR equations and 18 mGFR formulas were calculated. Results. Total of 32 iohexol administrations was performed in 28 patients. Median (range) eGFR was 136 (74-234) mL/min/1.73 m2 and age 15.1 (0.8-26.0) years. Three-compartment model with allometric scaling of central, one peripheral compartment and clearance (with power 0.75) to weight fitted the best. Median (range) iGFR was 103 (68-140) mL/min/1.73 m2. All except one eGFR equation overestimated GFR. Lund-Malmö revised eGFR equation performed the best, followed by Gao equation. Of single- or two-point mGFR formulas 15 overestimated iGFR. Modified Jacobsson formula at 5.5 h performed the best, followed by Fleming formula at 3 h. Conclusions. In children and young adults with haemato-oncological disease and infection renal function is best described by iohexol clearance from three-compartmental pharmacokinetic model, while eGFR equations and single- and two-point mGFR formulas overestimate iGFR.