Safe Administration of Propofol for Sedation in Children

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).