Search

Study Objective: Withdrawal syndrome (WS) may be a critical drawback of opioid/benzodiazepine weaning in children. The most effective intervention to reduce WS prevalence is yet to be determined. Dexmedetomidine (DEX) was estimated to be effective in reducing WS-related symptoms, but no randomized trial has been conducted to prove its efficacy so far. We aimed to evaluate the efficacy and safety of DEX in reducing the occurrence of WS., Design and Setting: This was an adaptive randomized double-blind placebo-controlled trial conducted at three Italian Pediatric Intensive Care Units (PICUs)., Patients: It included children admitted to PICU, undergoing at least five days of opioids/benzodiazepines continuous infusion, and ready to start the analgosedation weaning., Intervention: Twenty-four hours before the start of weaning, an infusion of DEX/placebo was started. WS symptoms were monitored using the Withdrawal-Assessment-Tool-version-1 (WAT-1). In case of WS symptoms (WAT-1 ≥ 3) an opioid/benzodiazepine bolus was given and the DEX/placebo infusion-rate was increased., Measurements: The primary outcome measure was the prevalence of WS. Secondary outcomes were the trend of WAT-1 over time, number of rescue doses, length of weaning and PICU-stay, and onset of adverse events (AEs)., Main Results: Forty-five patients were enrolled, of whom 5 dropped-out and 40 entered the interim analysis. There were no significant baseline differences between groups. WS prevalence did not significantly differ between groups (77.8% DEX vs 90.9% placebo, p = 0.381). By generalized linear mixed modeling, the WAT-1 trend showed a significant increase per unit of time in the DEX arm (estimate 0.27, CI 0.07-0.47, p = 0.009) compared to placebo. Most frequent AEs were hemodynamic, and all of them happened in the DEX arm., Conclusions: A continuous infusion of DEX, started 24 h before the analgosedation weaning and increased based on WS signs, was not able to significantly modify the prevalence of WS in children who received at least five days of opioids/benzodiazepines treatment compared to placebo., (© 2021 Pharmacotherapy Publications, Inc.)

Objectives: We aimed to systematically describe the use of dexmedetomidine as a treatment regimen for prolonged sedation in children and perform a meta-analysis of its safety profile., Data Sources: PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, ClinicalTrials.gov, and CINAHL were searched from inception to November 30, 2018., Study Selection: We included studies involving hospitalized critically ill patients less than or equal to 18 years old receiving dexmedetomidine for prolonged infusion (≥ 24 hr)., Data Extraction: Data extraction included study characteristics, patient demographics, modality of dexmedetomidine use, associated analgesia and sedation details, comfort and withdrawal evaluation scales, withdrawal symptoms, and side effects., Data Synthesis: Literature search identified 32 studies, including a total of 3,267 patients. Most of the studies were monocentric (91%) and retrospective (88%); one was a randomized trial. Minimum and maximum infusion dosages varied from 0.1-0.5 µg/kg/hr to 0.3-2.5 µg/kg/hr, respectively. The mean/median duration range was 25-540 hours. The use of a loading bolus was reported in eight studies (25%) (range, 0.5-1 µg/kg), the mode of weaning in 11 (34%), and the weaning time in six of 11 (55%; range, 9-96 hr). The pooled prevalence of bradycardia was 2.6% (n = 10 studies; 14/387 patients; 95% CI, 0.3-7.3; I = 75%), the pooled prevalence incidence of bradycardia was 2.6% (n = 10 studies; 14/387 patients; 95% CI, 0.3-7.3; I = 75%), the pooled incidence of hypotension was 6.1% (n = 8 studies; 19/304 patients; 95% CI, 0.8-15.9; I = 84%). Three studies (9%) reported side effects' onset time which in all cases was within 12 hours of the infusion starting., Conclusions: High-quality data on dexmedetomidine use for prolonged sedation and a consensus on correct dosing and weaning protocols in children are currently missing. Infusion of dexmedetomidine can be considered relatively safe in pediatrics even when longer than 24 hours.

Objectives: We sought to evaluate dexmedetomidine efficacy in assuring comfort and sparing conventional drugs when used for prolonged sedation (≥24 hr) in critically ill patients, by using validated clinical scores while systematically collecting drug dosages. We also evaluated the safety profile of dexmedetomidine and the risk factors associated with adverse events., Design: Observational prospective study., Setting: Nine tertiary-care PICUs., Patients: Patients less than 18 years who received dexmedetomidine for greater than or equal to 24 hours between January 2016 and December 2017., Interventions: None., Measurements and Main Results: One-hundred sixty-three patients (median age, 13 mo; interquartile range, 4-71 mo) were enrolled. The main indication for dexmedetomidine use was as an adjuvant for drug-sparing (42%). Twenty-three patients (14%) received dexmedetomidine as monotherapy. Seven percent of patients received a loading dose. The median infusion duration was 108 hours (interquartile range, 60-168 hr), with dosages between 0.4 (interquartile range, 0.3-0.5) and 0.8 µg/kg/hr (interquartile range, 0.6-1.2 µg/kg/hr). At 24 hours of dexmedetomidine infusion, values of COMFORT-B Scale (n = 114), Withdrawal Assessment Tool-1 (n = 43) and Cornell Assessment of Pediatric Delirum (n = 6) were significantly decreased compared with values registered immediately pre dexmedetomidine (p < 0.001, p < 0.001, p = 0.027). Dosages/kg/hr of benzodiazepines, opioids, propofol, and ketamine were also significantly decreased (p < 0.001, p < 0.001, p = 0.001, p = 0.027). The infusion was weaned off in 85% of patients, over a median time of 36 hours (interquartile range, 12-48 hr), and abruptly discontinued in 15% of them. Thirty-seven percent of patients showed hemodynamic changes, and 9% displayed hemodynamic adverse events that required intervention (dose reduction in 79% of cases). A multivariate logistic regression model showed that a loading dose (odds ratio, 4.8; CI, 1.2-18.7) and dosages greater than 1.2 µg/kg/hr (odds ratio, 5.4; CI, 1.9-15.2) increased the odds of hemodynamic changes., Conclusions: Dexmedetomidine used for prolonged sedation assures comfort, spares use of other sedation drugs, and helps to attenuate withdrawal syndrome and delirium symptoms. Adverse events are mainly hemodynamic and are reversible following dose reduction. A loading dose and higher infusion dosages are independent risk factors for hemodynamic adverse events.

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.

Background: Dexmedetomidine (DEX) is an alpha-2-adrenergic agonist, recently approved by Italian-Medicines-Agency for difficult sedation in pediatrics, but few data exist regarding prolonged infusions in critically-ill children, especially in younger ages. Aim of our study was to evaluate DEX use and safety for prolonged sedation in Pediatric Intensive Care Units (PICUs)., Methods: Patients receiving DEX for ≥24 hours were retrospectively evaluated to analyze DEX indications, dosages, use of analgesics or sedatives, adverse events (AEs), withdrawal syndrome or delirium., Results: Forty-seven patients (median 0.7years) from nine PICUs were enrolled. Main indications were adjuvant for drugs sparing (59.6%) and for analgosedation weaning (36.2%). Median infusion duration was 82.0 hours (IQR 62.2-126.0), with dosages between 0.4 (IQR 0.2-0.5) and 0.8 mcg/kg/h (IQR 0.6-1.2). Fifty-nine-percent of patients received other sedatives, 83% other analgesics. Twenty-one-percent presented withdrawal syndrome, 4.2% delirium, none of them DEX-related. Forty-six-percent experienced a potentially-DEX-related AE. AEs were all hemodynamic, 14.9% requiring intervention but none DEX interruption. The median minimum and maximum dosages were significantly higher in patients with AEs (0.5 vs. 0.3,P=0.001; 1.0 vs. 0.7,P<0.001), without correlations with the infusion duration. AEs rate was higher in patients receiving benzodiazepines (P=0.020) or more than one analgesic (P=0.003) and in those presenting withdrawal syndrome (P<0.001)., Conclusions: DEX was confirmed as useful and relatively safe drug for prolonged sedation in critically-ill children, particularly in younger ages. Main AEs were cardiovascular, reversible, related with higher doses, with the concomitant use of benzodiazepines or multiple sedation drugs and with the presence of withdrawal syndrome.