Safe Administration of Propofol for Sedation in Children
Condition: Sedation
Study type: Interventional

Summary: 
      Advances in health care require that more children are given sedation to allow doctors to
      perform investigations or minor procedures. Sedation drugs have traditionally been given
      orally (swallowed) by children. However, oral sedation drugs have unpredictable
      characteristics, such as duration of sedation, which may result in difficulties performing
      the planned procedure.

      Anesthetic drugs are now invariably used for sedation in children. These are given through an
      IV (skinny plastic tube inserted in to a vein). Propofol (white liquid) is the anesthetic
      drug most commonly used for sedation at BC Children's Hospital for sedation. Propofol has
      several advantages, including an accurately controllable depth of sedation (how deeply
      asleep), minimal effect on the heart and circulation and control of reflexes (e,g coughing)
      during the procedure. Propofol also promotes rapid recovery with less sickness and an earlier
      return to normal functioning following the procedure.

      While propofol has many advantages it can cause respiratory depression (reduced breathing
      rate). This reduction in breathing is more common if propofol is given quickly. When your
      child is given propofol for their proposed procedure this is performed by a pediatric
      anesthesiologist who is skilled in supporting breathing should this be required. If your
      child does not participate in this study they will still receive propofol administered by the
      anesthesiologist as this is our usual practice. It would be routine to administer the
      propofol rapidly and then support breathing for a few minutes. This is very safe in the hands
      of an expert anesthesiologist but can be sometimes more risky in other settings where
      extensive monitoring and anesthesiologists are not available. This is the setting that
      propofol is used in many institutions.

      Our goal is to determine how quickly propofol can be given without reducing breathing to the
      point that help with breathing is required.
    

Detailed description: 
      Purpose Advances in minimally invasive radiological and surgical techniques demand that
      increasing numbers of children are given sedation or anesthesia to facilitate these
      procedures, frequently performed on an out-patient or day-care basis. Most are performed
      outside the operating room environment, with intensivists and emergency physicians
      administering over 55 % of sedation episodes, and only 19% being performed by
      anesthesiologists in North America. It is well documented that risks of complications during
      sedation exceed those experienced during the much more controlled environment of general
      anesthesia, with a twelve-fold increased risk of mortality when sedation is administered
      outside the operating room.

      Sedative agents have traditionally been administered orally to children. However,
      characteristics of oral sedation drugs, such as unpredictable depth and duration of sedation
      resulting from variable drug absorption and prolonged duration of drug effect, have resulted
      in both high failure and complication rates. Recently, intravenous (IV) anesthetic drugs with
      more accurately titratable and predictable characteristics have gained popularity for a
      variety of sedation procedures. Propofol is the most commonly used intravenous agent for
      these procedures in North America.

      Hypothesis The maximum safe infusion rate for an induction dose of propofol administered to
      children for sedation can be reliably predicted. Safety will be optimized by preventing
      apnoea whilst minimizing the time for induction of sedation and ensuring an adequate depth of
      sedation is achieved.

      Justification Propofol is an intravenous (IV) anesthetic agent used for induction and
      maintenance of anesthesia in both adults and children. Propofol has several characteristics
      favouring its use, including an accurately titratable depth of anesthesia, cardiovascular
      stability, suppression of upper airway reflexes, rapid recovery with reduced post-operative
      nausea and vomiting and overall earlier return to pre-anesthetic functional state. At lower
      doses, propofol may also be used to maintain a level of sedation for radiological imaging or
      endoscopic investigations.

      While propofol provides many advantages it does cause significant respiratory depression.
      Adverse respiratory events have been reported to be similar in both adults and children.
      Propofol induced respiratory depression may lead to hypoxemia requiring the provision of
      supplemental oxygen by mask and/or manual positive pressure ventilation.8 Artificial
      ventilation requires significant expertise and if poorly managed may result in gastric
      insufflation, pulmonary aspiration or hypoxia, all of which can lead to devastating
      complications such as permanent brain injury or death. The maximum dose or rate of
      administration of propofol that causes respiratory depression in children has yet to be
      accurately defined. Age specific effects have also not been reported.

      Objectives

      Primary aim:

      •Develop a safe dosing schedule for propofol administration in children that will ensure
      spontaneous ventilation is maintained in at least 95% of subjects.

      Secondary aim:

      •Model the effects of propofol induction administered by intravenous infusion to facilitate
      the prediction of dosing schedules for different doses, different end-points in different
      clinical scenarios.

      Research Method Prospective randomized study. Subjects will be randomly assigned to receive a
      predetermined infusion rate for propofol during induction of sedation.

      Statistical Analysis A graphical representation of each data point with crossovers will be
      produced. Data will be analysed on a per protocol basis using the pooled-adjacent-violators
      algorithm to estimate the maximal infusion rate whilst preserving spontaneous ventilation. We
      will apply the boot-strap methods implemented by Pace to compute 95 % confidence limits. The
      effect of age, will be assessed by performing separate analyses in the age-strata.

      To model the ventilatory effects of propofol, we will develop a mathematical model of human
      respiratory control. We will base this on the respiratory model proposed by Ursino (Ursino
      Model)19-21 which is a three compartment model comprising the lung, brain and tissues for gas
      exchange. We will enhance the model to include ventilatory regulation, along with
      pharmacokinetic and pharmacodynamic models of propofol including a respiratory effect site.
      The identification of suitable parameters for the model will include non-linear fitting of
      the clinical data (age, weight, BSA, ventilatory volumes, CO2 excretion, respiratory rate,
      and entropy).
    

Intervention name(s): Propofol; Propofol
Intervention type(s): Drug; Drug
Intervention description(s): See detailed description; See detailed description
Intervention MeSH terms: Propofol
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Propofol; sedation; pediatric; Induction of sedation