Efficacy and safety of dexmedetomidine for prevention of withdrawal syndrome in the pediatric intensive care unit: protocol for an adaptive, multicenter, randomized, double-blind, placebo-controlled, non-profit clinical trial

Abstract

Background: Prolonged treatment with analgesic and sedative drugs in the pediatric intensive care unit (PICU) may lead to undesirable effects such as dependence and tolerance. Moreover, during analgosedation weaning, patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicate that dexmedetomidine, a selective α2-adrenoceptor agonist, may be useful to prevent WS, but no clear evidence supports these data. The aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during analgosedation weaning, and to clearly assess its safety.

Methods: We will perform an adaptive, multicenter, randomized, double-blind, placebo-controlled trial. Patients aged < 18 years receiving continuous intravenous analgosedation treatment for at least 5 days and presenting with clinical conditions that allow analgosedation weaning will be randomly assigned to treatment A (dexmedetomidine) or treatment B (placebo). The treatment will be started 24 h before the analgosedation weaning at 0.4 μg/kg/h, increased by 0.2 μg/kg/h per hour up to 0.8 μg/kg/h (neonate: 0.2 μg/kg/h, increased by 0.1 μg/kg/h per hour up to 0.4 μg/kg/h) and continued throughout the whole weaning time. The primary endpoint is the efficacy of the treatment, defined by the reduction in the WS rate among patients treated with dexmedetomidine compared with patients treated with placebo. Safety will be assessed by collecting any potentially related adverse event. The sample size assuring a power of 90% is 77 patients for each group (total N = 154 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017.

Discussion: The present trial will allow us to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during weaning from analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine.

Trial registration: ClinicalTrials.gov, NCT03645603. Registered on 24 August 2018. EudraCT, 2015-002114-80. Retrospectively registered on 2 January 2019.

Keywords: Abstinence syndrome; Analgesia; Dexmedetomidine; Pediatric intensive care unit; Sedation; Withdrawal syndrome.

Conflict of interest statement

Orion Pharma assured the liability insurance of the study (total amount €10,758). The supporter had no role in the study design, decision to publish and preparation of the manuscript, and will have no access to or role in data collection and analysis. The authors have not received any personal funding or compensation for the research. Therefore, the authors did not have any personal interest to declare.

Figures

Fig. 1

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure: schedule of enrolment, interventions and assessments of the trial. AE adverse event, AR adverse reactions, AS analgosedation, PICU pediatric intensive care unit, SUSAR serious adverse events and suspected unexpected serious adverse reaction, treatment A receiving dexmedetomidine, treatment B receiving placebo, WAT-1 Withdrawal Assessment Tool version 1

Fig. 2

Study protocol flow chart. AV atrio-ventricular, iv intravenous, PICU pediatric intensive care unit, WAT-1 Withdrawal Assessment Tool version 1, WS withdrawal syndrome