An observational study in Pediatric Critical Illness, Brain Injuries, Traumatic and Brain Neoplasms, sponsored by University Hospital, Ghent. Completed at 1 site in Belgium. Open to participants aged 1 Month to 15 Years. Per ClinicalTrials.gov, last updated 2026-11-04.
Sponsored by University Hospital, Ghent · Observational
TIPPIC was a single-centre, prospective, observational pharmacokinetic study in critically ill children aged 1 month to 15 years who were admitted to the paediatric intensive care unit (PICU) of Ghent University Hospital with an external ventricular drain (EVD) in place and who received intravenous (IV) paracetamol as part of routine care.
Paracetamol is thought to act in the central nervous system and must cross the blood-brain barrier to reach its target. Severe intracranial pathology (for example traumatic brain injury or brain tumours) can disrupt this barrier, and critical illness and growth alter drug disposition. Cerebrospinal fluid (CSF) concentrations after IV paracetamol had not been described in this population. The EVD, in place for clinical reasons, allows repeated CSF sampling.
The study aimed to:
Blood and CSF were collected by volumetric absorptive microsampling (10 microliters per sample).
Design: single-centre, prospective, observational study in the paediatric intensive care unit (PICU) of Ghent University Hospital, Ghent, Belgium. Intravenous paracetamol was prescribed by the treating intensivist as part of routine clinical care (standard regimen 15 mg/kg every 6 hours); the study did not assign or change the treatment.
Blood sampling: through an arterial (preferred) or venous catheter already in place and different from the paracetamol infusion line, following an individualised sampling scheme: at most 5 samples at variable time points in the 0-6 h interval after the first IV paracetamol dose (first-dose conditions) and at most 5 samples in the 0-6 h interval after a dose at steady state (steady-state conditions).
CSF sampling: in a strictly aseptic way through the proximal three-way valve of the external ventricular drain system, less frequently than blood sampling: at most 5 samples at variable time points in the 0-24 h interval after the first paracetamol infusion (first-dose and steady-state conditions).
Each blood and CSF sample consisted of 10 microliters absorbed by a volumetric absorptive microsampling (VAMS) device. Per protocol, an additional 0.3 mL EDTA blood sample could be collected at each blood sampling moment to validate the VAMS technique. The total blood volume taken for study purposes was at most 4 mL per patient, below 2.4 mL/kg in line with EMA guidance for paediatric trials. Samples were stored at -80 degrees C in the biobank of the Heymans Institute of Pharmacology, Ghent University, and analysed with validated liquid chromatography methods at the Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Ghent University.
Clinical data: age, weight, length, primary reason for admission, pre-existing chronic disease (especially liver and kidney disease), PRISM II score at admission and, on sampling days, PELOD score, mechanical ventilation, vasopressors, intracranial pressure, serum creatinine and Schwartz creatinine clearance, serum albumin and serum cystatin C; dosing regimen (start and stop times of infusions), duration of treatment, co-medication and the catheter used for sampling.
Consent: written informed consent from the parents or legal representatives, and from the patient if older than 12 years (intubated patients older than 12 years were informed after extubation). When there was no time to obtain written consent before the first samples, oral consent was obtained by telephone from a legal representative in the presence of an independent member of the intensive care team, followed by written consent the same day. Samples were destroyed if consent was refused.
Sample size: 50 patients were planned (based on similar studies). Patients were enrolled between January 2017 and December 2018.
This study was registered retrospectively, after completion of enrolment.
1,824 studies on the registry are indexed under Brain Injuries, Traumatic; 462 are open to participants now.
This study's enrollment of 31 is below the median of 119 across 584 observational studies indexed under Brain Injuries, Traumatic.
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Critically ill children aged 1 month to 15 years admitted to the paediatric intensive care unit (PICU) of Ghent University Hospital with an external ventricular drain in place (e.g., for a brain tumour, intracranial infection, hydrocephalus or traumatic brain injury) who received intravenous paracetamol as part of routine clinical care.
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Exclusion Criteria:
Critically ill children aged 1 month to 15 years admitted to the paediatric intensive care unit (PICU) of Ghent University Hospital with an external ventricular drain in place and receiving intravenous paracetamol as part of routine clinical care. Study procedures: blood and cerebrospinal fluid microsampling.
Drug: Paracetamol · Other: Pharmacokinetic sampling (blood and CSF microsampling)
Intravenous paracetamol prescribed by the treating intensivist as part of routine clinical care (standard regimen 15 mg/kg every 6 hours). Dose and schedule were not assigned or changed by the study.
Also known as: Acetaminophen
Volumetric absorptive microsampling (10 microliters per sample) of blood through an existing arterial (preferred) or venous catheter other than the infusion line (at most 5 samples 0-6 h after the first dose and at most 5 samples 0-6 h after a steady-state dose) and of cerebrospinal fluid through the proximal three-way valve of the external ventricular drain (at most 5 samples 0-24 h after the first infusion).
Plasma pharmacokinetics of paracetamol after the first intravenous dose
Paracetamol concentrations (mg/L) measured in blood volumetric absorptive microsamples and converted to plasma concentrations, used to describe plasma pharmacokinetics (e.g., clearance and volume of distribution) in first-dose conditions.
Time frame: Up to 5 samples at variable time points 0-6 hours after the first intravenous paracetamol dose
Plasma pharmacokinetics of paracetamol at steady state
Paracetamol concentrations (mg/L) measured in blood volumetric absorptive microsamples and converted to plasma concentrations, used to describe plasma pharmacokinetics (e.g., clearance and volume of distribution) in steady-state conditions.
Time frame: Up to 5 samples at variable time points 0-6 hours after a steady-state intravenous paracetamol dose
Cerebrospinal fluid pharmacokinetics of paracetamol
Paracetamol concentrations (mg/L) in cerebrospinal fluid (CSF) sampled from the external ventricular drain, used to describe CSF pharmacokinetics and the penetration of paracetamol into CSF relative to plasma in first-dose and steady-state conditions.
Time frame: Up to 5 samples at variable time points 0-24 hours after the first intravenous paracetamol infusion
Plasma concentrations of toxic paracetamol metabolites (paracetamol-protein adducts)
Concentrations of paracetamol-protein adducts (measured as paracetamol-cysteine after proteolytic digestion), a biomarker of exposure to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), used to identify the risk of latent hepatotoxicity of paracetamol in children with severe intracranial pathology.
Time frame: At the blood pharmacokinetic sampling times (0-6 hours after the first dose and 0-6 hours after a steady-state dose)
Covariates of paracetamol pharmacokinetics
Patient characteristics (e.g., body weight, age, organ function and severity of illness) that explain between-patient variability in paracetamol pharmacokinetics, identified with a population pharmacokinetic model that is used to predict optimal dosing regimens in individual paediatric patients.
Time frame: All pharmacokinetic samples: 0-6 hours after the first dose and after a steady-state dose (blood), 0-24 hours after the first infusion (CSF)
Influence of blood-brain barrier disruption on paracetamol pharmacokinetics
Comparison of paracetamol plasma and CSF pharmacokinetics between subpopulations with different intracranial pathology (e.g., neurotrauma versus brain tumour) as an indicator of the influence of blood-brain barrier disruption on the pharmacokinetics of a centrally acting drug.
Time frame: Up to 5 CSF samples 0-24 hours after the first intravenous paracetamol infusion, with paired blood samples
Plan to share: No — Individual participant data will not be shared publicly because of the small paediatric cohort and the associated re-identification risk under the EU General Data Protection Regulation. De-identified data supporting published results may be made available on reasonable request to the principal investigator, subject to approval by the Ethics Committee of Ghent University Hospital and a data-transfer agreement.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
This study is completed, as verified in Oct 2026. You cannot join it, but the record below documents what was studied.
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