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Daily interruption of sedation + protocolized sedation (DSI+PS) vs. protocolized sedation (PS) in critically ill children.

Projectomschrijving

Kinderen aan de beademing krijgen op dit moment continu sedatie (slaapmedicijnen). Het continue geven van sedatie heeft nadelen: er kan gewenning aan de medicijnen optreden, kinderen krijgen vaak ontwenningsverschijnselen bij het staken van de medicijnen en het kan leiden tot een vertraagd herstel. Bij volwassenen is bekend dat het dagelijks onderbreken van sedatie beter is. Ze hebben dan minder sedatie nodig, liggen minder lang aan de beademing- en op de intensive care. We onderzoeken of het bij kinderen aan de beademing ook beter en veilig is om de sedatie elke dag te onderbreken. Ook kijken we naar het effect van leeftijd, ziekte, ontsteking en genetische aanleg op de farmacokinetiek (medicijnspiegels in het bloed) en farmacodynamiek (het effect van het medicijn op het lichaam) van sedativa (midazolam en morfine).

Producten

Titel: A randomized controlled trial of daily sedation interruption in critically ill children
Auteur: Vet, Nienke J., de Wildt, Saskia N., Verlaat, Carin W. M., Knibbe, Catherijne A. J., Mooij, Miriam G., van Woensel, Job B. M., van Rosmalen, Joost, Tibboel, Dick, de Hoog, Matthijs
Magazine: Intensive Care Medicine
Titel: The effect of inflammation on drug metabolism: a focus on pediatrics.
Auteur: Vet NJ, de Hoog M, Tibboel D, de Wildt SN.
Magazine: Drug Discovery Today
Titel: Short-Term Health-Related Quality of Life of Critically Ill Children Following Daily Sedation Interruption.
Auteur: Vet NJ, de Wildt SN, Verlaat CW, Mooij MG, Tibboel D, de Hoog M, Buysse CM; Stichting Kinder Intensive Care (Dutch collaborative PICU research network).
Magazine: Pediatric Critical Care Medicine
Titel: Daily interruption of sedation in critically ill children.
Auteur: Vet NJ, Verlaat CW, de Wildt SN, Tibboel D, de Hoog M.
Magazine: Pediatric Critical Care Medicine
Titel: Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial.
Auteur: Vet NJ, de Wildt SN, Verlaat CW, Knibbe CA, Mooij MG, Hop WC, van Rosmalen J, Tibboel D, de Hoog M; SKIC (Dutch collaborative PICU research network).
Magazine: Trials
Titel: Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children
Auteur: Vet, Nienke J., Brussee, Janneke M., de Hoog, Matthijs, Mooij, Miriam G., Verlaat, Carin W. M., Jerchel, Isabel S., van Schaik, Ron H. N., Koch, Birgit C. P., Tibboel, Dick, Knibbe, Catherijne A. J., de Wildt, Saskia N.
Magazine: American Journal of Respiratory and Critical Care Medicine
Titel: Optimal sedation in pediatric intensive care patients: a systematic review.
Auteur: Vet NJ, Ista E, de Wildt SN, van Dijk M, Tibboel D, de Hoog M.
Magazine: Intensive Care Medicine

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Samenvatting van de aanvraag

Background: Pediatric intensive care (PICU) patients are frequently exposed to polypharmacy and more than 70% of drugs are prescribed either unlicensed or off-label. Both factors are associated with an increased risk of adverse drug reactions (ADR’s). Knowledge of factors influencing drug metabolism and effect are essential for striking a balance between efficacy and risks of ADR's in this population. Especially in critically ill children there is a significant lack of data both with regards to pharmacokinetics (PK) as to pharmacodynamics (PD). In addition to age and genetic variation, disease severity and inflammation status may influence PK as well as PD in children. Pediatric patients are therefore at risk for under- as well as overtreatment. In PICU patients, sedatives and analgesics are one of the most frequently used group of drugs. Most critically ill children receive these drugs continuously. It has been demonstrated that continuous sedation has deleterious effects such as tolerance and withdrawal. In children withdrawal effects occur in up to 57% of PICU patients. Daily interruption of sedation is an effective method of improving sedation management in adults. This method results in a decrease of the duration of mechanical ventilation, length of stay in the intensive care unit (ICU) and length of stay in the hospital. For critically ill children it is unknown if daily interruption of sedation is effective and feasible, as no adequately powered prospective randomised trials in critically ill children are available. Hypothesis: 1. Daily interruption of sedation combined with protocolized sedation in critically ill children receiving mechanical ventilation will result in more ventilator-free days than protocolized continuous sedation alone. 2. The pharmacokinetic-pharmacodynamic (PK-PD) relationship of sedative drugs in critically ill children is determined by the following co-variables: ontogeny, inflammation, disease state and pharmacogenetic profile. Objectives: 1. To determine the efficacy and feasibility of daily sedative interruption in critically ill children. 2. To determine the pharmacokinetic-pharmacodynamic (PK-PD) relationship of midazolam and morphine in critically ill children and the influence of co-factors (ontogeny, disease severity, inflammation and genetics) on variability in PK and PD. Study design: multicentre, randomized controlled trial. Study population: Infants between 0 and 17 years of age who require mechanical ventilation, with an expected duration of at least 48 hours, and need for sedative drugs. There will be a stratified randomization with regard to age in three groups, respectively 0-30 days, 30 days-2 year and 2-17 years. Intervention: Patients will be randomized to receive daily interruption of sedation combined with protocolized sedation or standard care (protocolized continuous sedation alone). In both groups blood samples will be taken for pharmacokinetic analysis of drugs, inflammatory markers and DNA (once). Disease severity will be determined using validated scores. Validated pain- and sedation scores will be used as pharmacodynamic endpoints. Relevance to clinical practice: This is the first large multicentre clinical trial to evaluate the effect and feasibility of daily sedative interruption in critically ill children. This study may result in a better treatment of critically ill children who need sedation by reducing the adverse effects of continuously sedation, increase the number of ventilator-free days and eventually length of stay. Moreover, this study will also generate unique data on the influence of age, disease state and genetic polymorphisms on drug metabolism and effect in critically ill children in relation to longitudinal PK data. Population PK-PD modeling of these factors will enable us to predict clinical effect in this vulnerable patient group and help to design new drug dosing regimen. Therefore, this study may lead to more evidence-based drug therapy in critically ill children.

Onderwerpen

Kenmerken

Projectnummer:
92003549
Looptijd: 100%
Looptijd: 100 %
2009
2015
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. M. de Hoog
Verantwoordelijke organisatie:
Erasmus MC