Ketamine/Propofol vs Ketamine Alone for Pediatric Fracture Reduction
Condition: Fractures
MeSH terms: Fractures, Bone
Study type: Interventional
Phase: Phase 4

Summary: 
      The objective of this study is to compare Ketamine-Propofol with Ketamine-only in a
      double-blind, randomised, controlled trial in a paediatric emergency department. We believe
      that the combination of these two agents will provide a new and more effective option for
      procedural sedation in paediatric emergency department patients. The hypothesis of the study
      is that paediatric emergency department patients requiring procedural sedation for an
      isolated orthopaedic injury with Ketamine-Propofol will have reduced total sedation time,
      time to recovery, complications and improved satisfaction scores compared to patients
      receiving Ketamine alone.
    

Detailed description: 
      Purpose: Procedural sedation has become an essential skill for emergency physicians, allowing
      for completion of painful procedures in a safe, comfortable and efficient manner. The ideal
      sedative agent would allow for an effective level of sedation, rapid onset and offset,
      absence of hemodynamic or respiratory compromise, and lack of post procedural side effects. A
      variety of agents have been studied for paediatric procedural sedation, however no currently
      used agent meets all of these criteria (1).

      Background: Ketamine and Propofol are two agents that have been well studied and are commonly
      utilized as single agents for sedation. Ketamine is a dissociative agent that has amnestic
      and analgesic qualities. It has the unique property of allowing for deep sedation with
      minimal effects on the patient's respiratory drive. Ketamine use does not cause hypotension
      and in fact can have a positive effect on blood pressure. Ketamine has been extensively
      studied in paediatric sedation and has been found to be a safe and effective (2,3,4). Side
      effects associated with Ketamine use include post procedural nausea and vomiting, and
      unpleasant emergence phenomena such as agitation or hallucinations. Ketamine sedation can
      result in prolonged recovery times compared to other sedative agents and has a low rate of
      respiratory depression, apnea and laryngospasm (1).

      Propofol is a sedative-hypnotic agent that has been popular for use in adult and paediatric
      procedural sedation for over a decade. The agent's rapid onset of effect and short duration
      of action allow for efficient sedation and recovery. Propofol has antiemetic properties and
      post-procedural side effects are rare. Caution must be used with Propofol, as it can be
      associated with significant respiratory depression and/or hypotension (1). The prolonged use
      of Propofol in children can produce acidosis, but this is not a problem for single use for an
      acute painful procedure.

      A number of studies have demonstrated that the combination of Ketamine and Propofol for
      sedation is safe and effective, with most of the data in adults or in adult-child studies
      with small number of children (5,6). The combination of the two agents appears to reduce side
      effects of each medication used alone, and allows for a rapid recovery time. A prospective
      case series of Canadian emergency department patients given Ketamine-Propofol for procedural
      sedation has recently been published (5). In this study, 22% of the patients were children.
      However, to date there has been no targeted research published comparing Ketamine-Propofol
      head to head with any other presently utilized sedation regimen in a paediatric emergency
      department setting.

      Objective & Hypothesis: The objective of this study is to compare Ketamine-Propofol with
      Ketamine-only in a double-blind, randomised, controlled trial in a paediatric emergency
      department. We believe that the combination of these two agents will provide a novel and more
      efficacious option for procedural sedation in paediatric emergency department patients. The
      hypothesis of the study is paediatric emergency department patients requiring procedural
      sedation for an isolated orthopaedic injury with Ketamine-Propofol will have reduced total
      sedation time, time to recovery, complications and improved satisfaction scores compared to
      patients receiving Ketamine alone.

      Experimental Design: This study will be a prospective, double-blind, randomised, controlled
      clinical trial with an expected enrolment of approximately 140 patients from June-October
      2007.

      n = 2 * (Z1-α/2 + Z1-β)2 * σ2 / ∆2

      n = 2 * (1.96 + 0.84)2 * 202 / 102

      n = 2 * 7.84 * 400 / 100

      n = 62.7 or 63 per group

      Based on the calculation above, 63 children are needed in each group to have an 80% chance of
      detecting a clinically meaningful difference in total sedation time of 10 minutes between the
      groups, assuming an alpha of 0.05, and a standard deviation of 20 minutes. We have added an
      additional 7 patients (10%) to each group to account for potential drop-outs. Written,
      informed consent will be obtained from a parent/guardian for all children that meet the study
      inclusion criteria. Additionally, all children over the age of eight will also be asked for
      their assent.

      Interventions: After giving informed consent, eligible patients will be assigned to either
      the Ketamine-Propofol group or Ketamine-placebo group through random allocation. Sealed
      envelopes containing a randomized assignment to either Ketamine-Propofol or Ketamine-only
      group will be prepared by an individual unconnected with the study using a web-based random
      number generator, balanced to ensure equal allocation to each group.

      Patients in the Ketamine-only group will receive an intravenous dose of 1.0 mg/kg Ketamine
      and patients in the Ketamine-Propofol group will receive an intravenous dose of 0.5 mg/kg
      Ketamine and 1.0 mg/kg Propofol at time zero. Two minutes after the initial dose of sedative
      agent, and every 2 minutes thereafter, the attending physician will assess the patient's
      level of sedation using the Children's Hospital of Wisconsin Sedation Scale (Appendix A). If
      the attending physician determines the level of sedation is not adequate (Sedation score ≥
      3), additional study drugs (Ketamine group: 0.25 mg/kg Ketamine; Ketamine-Propofol group: 0.5
      mg/kg Propofol) will be administered every 2 minutes until adequate sedation is achieved
      (deep conscious sedation = Children's Hospital of Wisconsin Sedation Scale Score < 3). Once a
      sedation score < 3 is achieved, the procedure will begin.

      All sedation will be performed under continuous cardiorespiratory monitoring based on current
      hospital guidelines under the care and surveillance of a pediatric emergency department
      registered nurse and physician. Vital signs including heart rate, blood pressure, respiratory
      rate and oxygen saturation will be monitored continuously and recorded every 2 minutes, with
      the exception of blood pressure, which will be recorded every 4 minutes. The assisting
      registered nurse will also record information regarding time of last liquid and solid intake
      and body weight on the hospital's standard procedural sedation and analgesia record form.

      A separate, standardized datasheet (Appendix B) will be used to collect the time when the
      study drug was first administered, the time when the procedure began, the time the procedure
      was completed and the time to recovery. Upon completion of the procedure, a recovery score
      based on a modified Aldrete Scale, will be recorded by a research associate blinded as to the
      intervention used every 2 minutes until full recovery, defined as a minimum cumulative score
      of 8. The attending physician will be asked to document any complications (including
      hypotension, apnea, hypoxia, laryngospasm and pain on injection) that occurred during the
      procedure and if any interventions were necessary. The nurse caring for the patient will also
      record any adverse events (nausea, vomiting, agitation) that occurred during recovery.

      Outcome Measures: The primary outcome will be total sedation time, defined as the time that
      the first study drug was injected until the patient is fully recovered with a minimum
      recovery score ≥ 8. Secondary outcomes will include time to recovery; patient, nurse, and
      physician satisfaction; complications and adverse events. The patient, nurse and physician
      will be asked to individually assess their level of satisfaction with the sedation procedure
      using a 7-point Likert scale (Appendices C-E).

      Analyses Strategy: The independent samples t-test will be used to compare differences in mean
      total sedation time and recovery time between the Ketamine and Ketamine-Propofol groups. The
      Mann-Whitney test will be used to compare differences in satisfaction levels (measured on an
      ordinal scale) between groups. Differences in proportions of complications during the
      procedure and adverse events during recovery will be assessed by the Chi-Square test between
      groups. A p value <0.05 will be considered statistically significant.

      Expectation: The expectation of the study is paediatric emergency department patients
      requiring procedural sedation for an isolated orthopaedic injury with Ketamine-Propofol will
      have reduced total sedation time, time to recovery, complications and improved satisfaction
      scores compared to patients receiving Ketamine alone.
    

Intervention name(s): Ketamine only; Ketamine - Propofol
Intervention type(s): Drug; Drug
Intervention description(s): Ketamine 1.0 mg/kg IV and placebo intralipid as initial sedation agents (double blinded).
Ketamine .25 mg/kg IV and placebo intralipid q2 minutes prn for additional sedation; Ketamine .5 mg/kg and Propofol 1 mg/kg as initial sedation agents (double-blinded).
Saline Placebo and Propofol .5 mg/kg q 2minutes for additional sedation
Intervention MeSH terms: Ketamine; Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ketamine; propofol; sedation; pediatric; emergency department; fracture