The Bolus Dose of Dexmedetomidine (ED50) That Avoids Hemodynamic Compromise in Children
Condition: Hemodynamic Instability
Study type: Interventional

Summary: 
      Dexmedetomidine is a sedative drug that has many benefits when given to children under
      anesthesia, such as improved pain relief and reduced agitation following their surgery. It is
      usually given as an intravenous infusion over 10 minutes, to avoid the changes in heart rate
      and blood pressure that are occasionally seen when it is administered more quickly. However,
      this is often infeasible and usually inconvenient. The investigators aim to determine the
      dose of dexmedetomidine that can be given rapidly (over 5 seconds) without causing
      significant changes in heart rate and blood pressure. This will be the only study specific
      intervention.
    

Detailed description: 
      Purpose This study is being conducted to determine the dose of dexmedetomidine that can be
      given as a rapid bolus (over 5 seconds) following induction of anesthesia and insertion of a
      laryngeal mask airway (LMA) without causing significant hemodynamic compromise in healthy
      children.

      Hypothesis We hypothesize that a rapid bolus of dexmedetomidine does not cause significant
      hemodynamic effects in healthy children.

      Justification Dexmedetomidine given in a single peri-operative bolus without subsequent
      infusion has been shown to be beneficial. It would be arguably more practical to administer
      the dose as a rapid bolus. The hemodynamic effects of this have not been previously studied
      in healthy ASA I-II children (aged 5-10 years).

      Objectives The objective of this study is to determine the dose of dexmedetomidine that can
      be given as a rapid bolus in healthy children following induction of total intravenous
      anesthesia (TIVA) without causing significant hemodynamic compromise.

      Research Method This is a prospective, sequential design study using the up-and-down method
      (UDM) to determine the dose of dexmedetomidine that will prevent hemodynamic compromise
      following a rapid bolus in healthy children. The only study specific intervention will be a
      bolus of dexmedetomidine following induction of TIVA and insertion of an LMA.

      Pre-operatively Heart rate (HR), non-invasive blood pressure (NIBP), respiratory rate (RR)
      and oxygen saturation (SpO2) will be obtained in the SDCU. Topical local anesthesia will be
      applied to potential cannulation sites.

      Intra-operatively Following establishment of intravenous access, induction of anesthesia will
      proceed with lidocaine 1 mg/kg, propofol 4 mg/kg and remifentanil 2 mcg/kg, administered as a
      bolus over 5 seconds. Bag mask ventilation with 100% oxygen will then be administered whilst
      SpO2, electrocardiogram (ECG), NIBP and Bispectral Index (BIS) monitoring is attached.
      Maintenance of anesthesia will be commenced after 30 seconds, with total intravenous
      anesthesia (TIVA) prepared as a combined infusion of a fixed concentration of propofol 10
      mg/ml and remifentanil 5 mcg/ml (PR5) at a dose of propofol 200 mcg/kg/min and remifentanil
      0.1 mcg/kg/min, as is the routine practice at BCCH. If further anesthesia is required, rescue
      doses of PR5 will be administered as propofol 0.5 mg/kg combined with remifentanil 0.25
      mcg/kg until a satisfactory level of anesthesia is reached. Any rescue doses given will be
      documented. After the maintenance infusion is commenced, a NIBP will be recorded. A
      pre-programmed bolus dose of 10 ml/kg 0.9% saline will simultaneously be delivered (over 10
      minutes) when the maintenance TIVA infusion is commenced. Following this, the intravenous
      fluid infusion will be programmed to run at maintenance rates according to the weight of the
      child.

      One minute after induction, an LMA will be inserted and secured in place (T0). Positive
      pressure ventilation will be commenced, or the patient allowed to breathe spontaneously, as
      appropriate. Supplemental oxygen will be administered as needed to maintain SpO2 ≥ 96%. If
      further anesthesia is required, rescue doses of PR5 will be administered and documented, as
      above.

      One minute after successful LMA insertion (T1), a NIBP recording will be taken, along with a
      baseline HR that will be being monitored continuously. This will constitute the baseline NIBP
      and HR (pre-study drug intervention) and will be used to define changes in hemodynamics of
      systolic, mean, diastolic blood pressure (SBP, MAP and DBP, respectively) and HR following
      the study drug intervention.

      One minute after the baseline NIBP is recorded, a bolus dose of dexmedetomidine will be
      administered over 5 seconds (T2). The dose will be dictated by the UDM study design, with a
      starting dose of 0.5 mcg/kg. The dexmedetomidine will be diluted in 0.9% saline to achieve
      the required concentration of 4 mcg/ml prior to administration. NIBP readings will be
      recorded every minute following the bolus, for a period of 10 minutes (T3-12). After this
      time period, the study will be complete. A BIS value will be recorded before and after the
      dexmedetomidine bolus. The maintenance rate of TIVA will then be adjusted and further opioid
      given as per the anesthesiologist's preference, prior to and during surgery. NIBP readings
      will be recorded every 5 minutes throughout surgery and every 15 minutes in Post Anesthetic
      Care Unit (PACU), in addition to continuous ECG, HR and SpO2 monitoring.

      Statistical Analysis The turning point estimator of Choi will be used to estimate the target
      dose. This describes how values of pairs at the crossover points are averaged. It is a form
      of target dose estimation that is frequently used in anesthesia UDM research.
    

Intervention name(s): Dexmedetomidine
Intervention type(s): Drug
Intervention description(s): The bolus dose of dexmedetomidine given will range from 0.25-2.0 mcg/kg and will be based on the up-and-down method, such that subject 1 will receive 0.5 mcg/kg and if no significant hemodynamic changes occur (heart rate decrease < 20% or blood pressure decrease/increase < 20%) the does will be increased by 0.25 mcg/kg for the subsequent subject. If significant hemodynamic changes occur (HR decrease >/= 20% or SBP/DBP/MAP decrease or increase >/= 20%) the dose will be decreased by 0.25 mcg/kg for the subsequent subject. Each subject will be observed for 10 minutes following the dexmedetomidine bolus.
Other intervention name(s): Precedex
Intervention MeSH terms: Dexmedetomidine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dexmedetomidine; Precedex; TIVA; Rapid bolus