Clinical trial NCT03760978: Dexmedetomidine for Prolonged Sedation in PICUs
Official title: Efficacy and Safety of Dexmedetomidine for Prolonged Sedation in Pediatric Intensive Care Units
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Prolonged Sedation
Keywords: sedation
dexmedetomidine
Lead sponsor: Azienda Ospedaliera di Padova
Sponsor class: OTHER
Collaborators: name: IRCCS Azienda Ospedaliero-Universitaria di Bologna
First posted: 2018-12-03
Enrollment: 163
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Critically ill children admitted to PICU

Brief summary: Sedation management of the critically ill patients is still a challenge for the pediatric intensivists. Worldwide the most common sedation approach includes the concomitant use of opioids and benzodiazepines. The use of these drugs is associated with adverse events contributing with morbidity, such as decreased spontaneous ventilation, withdrawal syndrome and delirium onset. Moreover, benzodiazepine demonstrated a neurotoxic apoptotic effect that could potentially impact neurocognitive outcome.

Dexmedetomidine (DEX) is a selective alpha-2-adrenergic agonist with sedative, analgesic and anxiolytic effects. Its unique pharmacological profile allows reaching a conscious sedation state with minimal respiratory depression, promoting faster ventilation weaning and better collaboration with the medical staff. Moreover, DEX seems to present adjuvant properties towards withdrawal syndrome and delirium. Finally, some studies in animals suggested that Dexmedetomidine might have a role of neuro-protection, especially in a contest of cerebral ischemia.

Currently, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved DEX only for the adult population and for sedation lasting not more than 24 hours. The Italian Medicines Agency (AIFA), in January 2016, approve DEX in children for specific indications including difficult sedation in mechanically ventilated critically ill patients. Up to now, few data are still available regarding its efficacy and safety for prolonged sedation in Pediatric Intensive Care Units (PICUs) and no studies have reported the use of DEX after AIFA's approval so far.

Aims of the study are:

to evaluate the characteristics of DEX use for prolonged sedation ≥24 hours in critically ill children (indication, dosages, time of infusion, time of infusion weaning, association with other drugs); to evaluate its efficacy in terms of comfort and conventional drug sparing, using standardized and validate measures; further, to evaluate its efficacy in terms of reduction of incidence of withdrawal syndrome and delirium; to evaluate its safety profile collecting any adverse event potentially correlated with its administration; to define if efficacy and safety could differ among approved indications versus not-approved ones.

Design: Multicenter observational prospective study, involving tertiary-care PICUs.

Study period: From January 2016 up to reaching of the calculated sample size (N patients =163).

Population: All critically ill patients \<18 years who received prolonged sedation including DEX for ≥24 hours. In case of multiple infusions, only data regarding the first infusion will be included. Exclusion criteria: extreme prematurity (\<28 weeks of gestational age), hypersensitivity to the active substance, incomplete data form. .

Collecting data strategy: Data will be prospectively collected from each Institution by means of a anonymous standardized form completed by two different investigators per center. For each patient, the following variables will be collected:

demographics characteristics (age, gender, race, weight) and clinical features (main diagnosis, associated morbidities, PIM3 score ad admission, number of high intensity interventions during PICU-stay, mechanical ventilation features, inotropic drugs use, length of stay, survival at discharge); DEX administration characteristics (indication, loading dose, minimum and maximum dosages, duration of DEX infusion, duration of DEX infusion weaning) and information on concomitant use of analgesics or sedative drugs (name of drugs and respective dosages at DEX starting time and 24 hours later); clinical scores of analgesia and sedation (Comfort Behavior Scale, CBS), withdrawal syndrome (Withdrawal Assessment Toll-1, WAT-1) and delirium (Cornell Assessment of Pediatric Delirium, CAPD) depending on the respective indication, registered immediate pre-DEX and 24 hours later; any adverse event potentially related to DEX administration and any related intervention, if present. In particular, we the investigators evaluate if bradycardia, hypotension (with or without poor perfusion), hypertension, agitations or other events are registered during the infusion. Further, investigators will register if any sign of DEX withdrawal (tachycardia, hypertension, agitation, other) are present immediately after the infusion.

Statistical analysis: Descriptive and analytic statistics will be performed according with the variable characteristics. A causal multivariate model will be developed to identify any significant risk or protective factors towards adverse outcomes (ineffective sedation, onset of adverse events).


Eligibility criteria: Inclusion Criteria:

* age \<18 years
* admission to PICU
* sedation with dexmedetomidine lasted more than 24 hours
* written informed consent

Exclusion Criteria:

* extreme prematurity (\<28 weeks of gestational age)
* hypersensitivity to the active substance
* incomplete data regarding outcome measures

Primary outcomes:
measure: Comfort Behavior Scale (CBS)
timeFrame: Immediately before DEX start and 24 hours later
Secondary outcomes:
measure: Opioid and benzodiazepines dosage
timeFrame: Immediately before DEX start and 24 hours later.
Other outcomes:
measure: Withdrawal Assessment Tool-1
timeFrame: Immediately before DEX start and 24 hours later.
measure: Cornell Assessment of Pediatric Delirium, CAPD
timeFrame: Immediately before DEX start and 24 hours later
measure: Onset of adverse events
timeFrame: During and immediately after dexmedetomidine infusion.
Locations:
city: Alessandria
country: Italy
facility: Pediatric Intensive Care Unit, Children's Hospital C.Arrigo, Alessandria, Italy
city: Bergamo
country: Italy
facility: Pediatric Intensive Care Unit, ASST John XXIII Pope Hospital, Bergamo, Italy
city: Bologna
country: Italy
facility: Pediatric Intensive Care Unit, S.Orsola Malpighi Hospital, University of Bologna, Italy
city: Milano
country: Italy
facility: Pediatric Intensive Care Unit, Children's Hospital V.Buzzi, Milan, Italy
city: Novara
country: Italy
facility: Pediatric and Neonatal Intensive Care Unit, Maggiore della Carità Hospital, Novara, Italy
city: Padova
country: Italy
facility: Terapia Intensiva Pediatrica Azienda Ospedaliera di Padova
city: Roma
country: Italy
facility: Pediatric Intensive Care Unit, Bambino Gesù Children's Hospital, Rome, Italy
city: Rome
country: Italy
facility: Pediatric Intensive Care Unit, A.Gemelli Hospital, Sacro Cuore Catholic University, Rome Italy
city: Trieste
country: Italy
facility: Pediatric Intensive Care Unit, Burlo Garofalo Hospital, University of Trieste, Italy
Study officials:
affiliation: Azienda Ospedaliera di Padova
name: angela amigoni, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mondardini MC, Astuto M, Amigoni A. Inclusion of dexmedetomidine for pediatric indications in the list of medicinal products issued by the National Law 648/96. Minerva Anestesiol. 2017 Aug;83(8):891-892. doi: 10.23736/S0375-9393.17.11975-9. Epub 2017 Mar 3. No abstract available.
citation: Romagnoli S, Amigoni A, Blangetti I, Casella G, Chelazzi C, Forfori F, Garisto C, Mondardini MC, Moltrasio M, Pasero D, Principi T, Ricci Z, Tarantino F, Conti G. Light sedation with dexmedetomidine: a practical approach for the intensivist in different ICU patients. Minerva Anestesiol. 2018 Jun;84(6):731-746. doi: 10.23736/S0375-9393.18.12350-9. Epub 2018 Feb 5.
citation: Sperotto F, Mondardini MC, Vitale F, Daverio M, Campagnano E, Ferrero F, Rossetti E, Vasile B, Dusio MP, Ferrario S, Savron F, Brugnaro L, Amigoni A; Pediatric Neurological Protection and Drugs (PeNPAD) Study Group. Prolonged sedation in critically ill children: is dexmedetomidine a safe option for younger age? An off-label experience. Minerva Anestesiol. 2019 Feb;85(2):164-172. doi: 10.23736/S0375-9393.18.13062-8. Epub 2018 Oct 30.
citation: Grant MJ, Schneider JB, Asaro LA, Dodson BL, Hall BA, Simone SL, Cowl AS, Munkwitz MM, Wypij D, Curley MA; Randomized Evaluation of Sedation Titration for Respiratory Failure Study Investigators. Dexmedetomidine Use in Critically Ill Children With Acute Respiratory Failure. Pediatr Crit Care Med. 2016 Dec;17(12):1131-1141. doi: 10.1097/PCC.0000000000000941.
citation: Tabacco B, Tacconi C, Amigoni A. Survey on monitoring analgesia and sedation in the Italian Pediatric Intensive Care Units. Minerva Anestesiol. 2017 Oct;83(10):1010-1016. doi: 10.23736/S0375-9393.17.11707-4. Epub 2017 Mar 28.
citation: Mason KP, Lerman J. Review article: Dexmedetomidine in children: current knowledge and future applications. Anesth Analg. 2011 Nov;113(5):1129-42. doi: 10.1213/ANE.0b013e31822b8629. Epub 2011 Aug 4.