Background

Children are not small adults, hence outcomes to be used in clinical studies may also be different. Moreover, with the increased attention for long-term effects post PICU admission our recent focus on short-term outcomes may need to be revisited

Objectives

1. To present frequently used outcomes in PICU trials

2. To discuss the importance and strategy to choose relevant outcomes and how this may affect trial design

Methods

.Present examples of outcomes used in pediatric intensive care drug studies, including biomarkers, clinical outcomes, patient reported outcomes, pharmacokinetics

Results

Outcomes used in drug studies are for example: percentage of time sedated, ventilator free days, incidence of bacterial infections, quality of life

Conclusion

This presentation will not only focus on outcomes in prospective clinical trials, but will also provide guidance to study design of prospective cohort studies and retrospective studies and the strategy to choose the most optimal outcome

Ultimately, aclear understanding of the challenges and importance to choose the right outcome measure will improve the impact of your research!

Background

Human antithrombin (hAT) is commonly used to prevent artery thrombosis in early stage of liver transplantation (LT).

Objectives

We describe baseline AT activity level and pharmacokinetic (PK) profile of hAT in early stage of paediatric LT and then simulate appropriate dosing regimens.

Methods

We analyzed 22 children who received hAT with an empirical dosing of 50 U kg^-1. Measured AT activity levels were analyzed using a non-linear mixed effect modeling approach. Dosing regimens were simulated to obtain AT activity levels between 70 to 120 U dl^-1 throughout the dosing interval.

Results

Baseline AT activity level was 39 (19-68) U dl^-1. The relationships for endogenous production rate (q); constant of endogenous production recovery (Kq); clearance (CL) and volume of distribution (V) were:

q_i(t) = q0_pop x(1-fq0.e^-Kqi*t) x (BW_i/70)^0.75; Kq_i = Kq_pop x (LM_i/315)^1.47 where ; fq0, baseline fraction of endogenous production at recovery; BW, bodyweight; LM, liver mass

CL_i = CL_pop x (BW_i/70)^0.75 x (1+drain outflow_i/13)^0.04 , V_i = V_pop x (BW_i/70)¹

Figure: The solid and dashed lines depict the overall AT activity levels after hAT administration and the endogenous AT contribution. For a patient weighing 10 kg, the 3 {liver graft weight in g/drain outflow rate in ml.h^-1} scenarii are 150/100, 200/50 and 300/10 denoted by the green, blue and red curves

Conclusion

The best scheme to attain the target of 70 to 120 U dl^-1 required highest dosing regimens via an extended infusion of 3 hours for the youngest children with a low LM and high abdominal drain losses

Background

Propofol is used in neonatal intensive care for procedural sedation. Genetic factors affecting its pharmacokinetics haven’t been researched before, and current dosing is based on empirical experience.

Objectives

We investigated the association of propofol pharmacokinetic variables to genomic factors.

Methods

We recruited 40 neonates, who were treated with propofol. Median (range) postmenstrual age was 32,8 (22,9–42,5) weeks. Propofol dosing was based on clinical judgement (average 2,0 mg/kg). Blood samples were collected for 24 h after drug dosing for propofol concentration assays. Later during the treatment period, a single blood sample was drawn for exomic sequencing. Drug concentrations were used to create a pharmacometric population model using NONMEM software. The model was used to simulate non-compartmental pharmacokinetic variables C_max and AUC. Genetic variants were identified using GATK and VarScan. The genomic association analysis with simulated pharmacokinetic variables was performed with Plink software using linear regression. The false discovery rate was controlled by the Benjamini-Hochberg procedure.

Results

A single nucleotide polymorphism (c.372A>G, p.Arg124Arg, rs28365063) in UGT2B7, a phase II metabolism enzyme, was associated significantly with maximum concentration. C_max was 6-fold higher in genotype GG and 4-fold higher in genotype AG when compared to genotype AA.

Conclusion

UGT2B7 polymorphism seems to expose neonates to considerably high propofol maximum concentrations. The result needs to be prospectively validated before it can be used as a covariate in drug dosing.

Background

Electroencephalogram (EEG) is difficult to be performed in children with behavioural disorders without sedation. Dexmedetomidine, a safe highly selective α2-agonist sedative, does not affect EEG results.

Objectives

To evaluate the efficacy and safety of sedation with dexmedetomidine for EEG recordings in children with behavioural disorders.

Methods

Prospective observational study on children with behavioural disorders who had to undergo an EEG at the paediatric hospital in Padova, Italy. A bolus of dexmedetomidine (2 mcg/kg over 10 min) was administered, followed by an infusion (1-2 mcg/kg/h). The bolus could be repeated up 3 times to reach the target level of sedation assessed by the Pediatric Sedation State Scale. Vital signs (including EtCO2) were recorded before, during and after the procedure until complete recovery. EEG recording quality, and caregivers’ opinion on the quality of sedation and quality of sleep at home was assessed.

Results

For this preliminary study 13 patients were enrolled. Efficacy was 100%. Mean total dose of dexmedetomidine was 3,24±0,95 mcg/kg. Adequate sedation was achieved within 12±8,7 minutes. Time to first awakening was 24±25.5 minutes and to complete recovery 65±50 minutes. Adverse effects (hypotension, bradycardia) were reported in 6 patients and classified as “minor” requiring no intervention. EEG recording quality was good or excellent in 100% of patients. Parents referred an excellent quality of the procedure and a low incidence of sleep disorders.

Conclusion

Dexmedetomidine showed an excellent efficacy and good safety profile for EEG recording. More data are needed to confirm our preliminary findings.

Background

Studies in adults have reported high rates of hypotension following intravenous paracetamol administration.

Objectives

We aimed to investigate the hemodynamic effects of intravenous paracetamol in critically ill children.

Methods

One hundred pediatric intensive care patients who were treated with intravenous paracetamol (Perfalgan^TM) between March and September 2017 were included. A hemodynamic event was defined as a drop of more than 15% in systolic or mean arterial blood pressure within 120 minutes after drug administration. Hypotension was defined as either a drop in systolic blood pressure below the 5^th percentile for age or a hemodynamic event associated with tachycardia, increased lactate level, or treatment with a fluid bolus or vasopressors.

Conclusion

A hemodynamic event was observed in 39 patients (39%). In these patients, systolic blood pressure was in the pre-hypertension or hypertension values in 36/39 patients before paracetamol administration, median (IQR) systolic blood pressure decreased from the 99^th (95-99) percentile for age before to the 50^th (50-95) percentile after paracetamol (p <0.001) and mean heart rate was 137 bpm before treatment and 115 bpm after (p=0.002). In one patient the hemodynamic event was associated with tachycardia and defined as hypotension, but in no patient did the SBP values drop below the 5^th percentile. Shock, diagnosed on admission in 15 patients, was not associated with a change in the vasoactive-inotropic score after paracetamol administration.

In conclusion, intravenous paracetamol administration was found to be safe in critically ill pediatric patients. It is possible that the observed hemodynamic events were caused by pain relief induced by paracetamol.