title: Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study.
abstract: BACKGROUND
  Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful.
  
  
  OBJECTIVE
  Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam.
  
  
  METHODS
  Multicentre, double-blind, randomised equivalence trial.
  
  
  METHODS
  Ten UK PICUs.
  
  
  METHODS
  Children (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours.
  
  
  METHODS
  Clonidine (3 µg/kg loading then 0-3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0-200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine.
  
  
  METHODS
  Primary end point Adequate sedation defined by COMFORT score of 17-26 for ≥ 80% of the time with a ± 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data.
  
  
  RESULTS
  The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61).
  
  
  CONCLUSIONS
  Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN02639863.
  
  
  BACKGROUND
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information.
authors.affiliation: Bristol Royal Children's Hospital, Bristol, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Clinical Trials Research Centre, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McKay
authors.affiliation: Clinical Trials Research Centre, University of Liverpool, Liverpool, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Spowart
authors.affiliation: Clinical Trials Research Centre, University of Liverpool, Liverpool, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Granville
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Boland
authors.affiliation: Warwick Medical School, Warwick, UK.
authors.forename: Stavros
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Central Manchester University Hospitals NHS Trust, Manchester, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Sutherland
authors.affiliation: Clinical Trials Research Centre, University of Liverpool, Liverpool, UK.
authors.forename: Carrol
authors.initials: C
authors.lastname: Gamble
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016292:Procedural Sedation / Q000379:methods; D003362:Cost-Benefit Analysis; D016638:Critical Illness / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
chemical_list: D006993:Hypnotics and Sedatives; D003000:Clonidine; D008874:Midazolam