Development of PK/PD Model for Individualized Propofol Dosing
Condition: Obesity; Elective Surgery
Study type: Observational

Summary: 
      The U.S. National Health and Nutrition Examination Survey of 1994 indicated that 59% of
      American men and 49% of women have body mass indexes (BMIs) over 25. Extreme obesity, defined
      as a BMI of 40 or more, was found in 2% of the men and 4% of the women
      [http://www.cdc.gov/nchs/nhanes.htm]. The newest survey in 2007 indicates an alarming
      increase in BMI; 63% of Americans are overweight, with 26% now in the obese category. With
      extreme obesity as high as 26-30% in adults, obesity percentages in children are also sharply
      on the rise. These alarming numbers pose a major clinical problem in terms of the safe and
      effective use of drugs in children.

      Obesity may alter the disposition and/or clearance of drugs in the body as well as the
      response, which should be considered when using anesthetics in these patients. Total
      intravenous anesthesia (TIVA) with propofol is widely used in children, adolescents and
      adults undergoing surgery, because of rapid onset of action, ease of titration and rapid
      offset of action. While extensive research on optimal propofol dosing has been performed in
      non-obese adults, including in critically ill mechanically ventilated adult patients by the
      investigators' collaborators, there is no evidence on required dosages in morbidly obese
      adult or pediatric patients of this highly lipophilic agent. As a consequence, serious
      problems do arise due to under- and overdosing, increasing the risk of inadequate effects and
      adverse events, respectively. Crucial additional information is needed on the
      pharmacokinetics of drugs used in morbidly obese children to improve safety and efficacy.

      This proposal will test a novel approach by identifying pharmacokinetic/pharmacodynamic
      (PK/PD) factors that are associated with response to therapy and adverse events. If
      successful, this study will provide proof of concept data for PK/PD model-based dosing
      strategy that can be implemented into daily clinical care to allow tailoring of dose to
      individual needs. Propofol is a versatile anesthetic agent which if dosed to individual needs
      based on a patient's characteristics and specific PK/PD parameters, will allow individualized
      dosing, thereby greatly reducing related toxicities. The prospective identification of
      predictive factors in these morbidly obese high-risk patients represents a new approach to an
      increasingly common clinical problem. The investigators expect that this study will generate
      the PK/PD data necessary to continue with a well powered prospective clinical trial.
    

Detailed description: 
      STUDY OBJECTIVES Hypothesis: The inter-patient variability in propofol effects in relation to
      clinical response and adverse events in morbidly obese adolescents is associated with
      identifiable pharmacokinetic factors.

      Specific Aim 1: Determine to what extent body weight affects propofol pharmacokinetics (PK)
      and pharmacodynamics (PD) in morbidly obese adolescents.

      Specific Aim 2: Develop a PK/PD model-based dosing algorithm for individualized propofol
      dosing in morbidly obese adolescents.

      To address this hypothesis, we will conduct a clinical study evaluating the pharmacokinetics
      and pharmacodynamics of propofol in 20 morbidly obese subjects scheduled to undergo
      laparoscopic gastric banding or another elective procedure. Full PK/PD profiles will be
      obtained during surgery and the Bispectral index monitor will be used as a validated approach
      for PD monitoring, a measure of depth of anesthesia (5). The population nonlinear mixed
      effect modeling (NONMEM) approach will be used with extensive covariate analysis to account
      for observed inter- and intraindividual variability (6, 7). The potential covariates
      affecting propofol PK (and PD) we will explore include total body weight, lean body mass,
      Body Mass Index (BMI), Body Surface Area (BSA), height, age, gender, type of procedure, and
      duration of procedure.

      In addition, in an exploratory fashion, we will evaluate propofol pharmacogenetics. CYP2B6
      and UGT1A9 are highly polymorphic enzyme responsible for the metabolism of propofol (20, 21).
      Novel allelic forms of CYP2B6 (22) and UGT1A9 (23) were identified recently that potentially
      could explain some of the large between patient variability in clearance resulting in large
      differences in propofol blood concentrations and responses to standard doses.

      STUDY DESIGN Description of Study Design The study will be a clinical non-intervention study
      and will not interfere with the standard anesthetic and perioperative care except for BIS
      monitoring and additional blood sampling from an indwelling line during and following
      anesthesia. One blood sample for genetic testing (3 ml) and 1.0 ml for baseline PK/PD
      modeling will be drawn from a venous line placed for clinical standard of care. The remaining
      1.0 ml serial blood samples for pharmacokinetic modeling will be drawn from an indwelling
      venous line placed under anesthesia.

      The rate that propofol will be given will be standardized to minimize variability between
      anesthesiologists. Induction of anesthesia will be done with an infusion of 1000mcg/kg/min of
      propofol. This bolus will be followed by propofol infusion at a rate of 250-350 mcg/kg/min
      for 10 min, and then titrated to clinical needs by the anesthesia team.

      Propofol Concentration Measurements: Blood samples (1.0 ml) will be collected from an
      indwelling line in oxalate tubes. Samples will be collected at scheduled time points. The
      number of samples for subjects may vary depending on the amount of time subjects are in
      surgery. Samples may also be drawn at unscheduled time points if propofol dose adjustments
      are made during the surgical procedure. The total sample volume for propofol concentration
      measurements will not exceed 22ml.

      Samples will be collected at the following scheduled and unscheduled time-points. Times for
      sample collection are approximations. Ideally, samples beginning with the 15 minute
      collection should be obtained within +/- 5 minutes of the times listed, when possible:

      Scheduled time points:

      Baseline:

      • within 15 minutes prior to induction of propofol

      After induction of propofol:

        -  1-3 min

        -  5 min

        -  10 min

             -  15 min

             -  30 min

             -  45 min

             -  60 min

             -  120 min

             -  180 min

             -  240 min

             -  Within 5 min prior to stopping propofol infusion

      After the end of propofol infusion

        -  5 min

        -  10 min

        -  15 min

        -  30 min

        -  45 min

        -  120 min

      Unscheduled time points:

        -  Within 5 min prior to each dose adjustment

        -  60 min after each dose adjustment

      NOTE: If a scheduled sample collection falls within 10 minutes of an unscheduled sample
      collection, only the unscheduled sample will be collected.

      Whole blood samples will be stored at 4°C until analysis (within 1 month).

      BIS Monitoring: An age and head size-appropriate disposable BIS sensor (standard pediatric or
      XP sensor, Aspect Medical Systems, Norwood, MA) will be placed on each child's forehead and
      will be connected to a BIS monitor as directed by the manufacturer and described recently by
      us (5). The sensors are single-use and are latex/PVC free.

      Each sensor contains a strip of electrodes. This one-piece unit is coated with a medical
      grade adhesive to establish electrical contact when placed on the forehead, and is designed
      for symmetrical placement to capture bi-hemispheric data. The sensor is attached via a cable
      to a VISTA stand alone unit module that serves as an interface between the sensor and the BIS
      monitor. This module is a signal converter, which acquires the electroencephalogram (EEG)
      signal from the sensors and converts the EEG signal to digital format. The EEG signal is then
      processed and the BIS index is played on the monitor. Data output (processed and raw EEG)
      will be downloaded.

      The BIS monitor screen will be covered during the procedure to ensure that anesthesia
      personnel involved in the care will be blinded to the BIS score and trend screen to avoid BIS
      score influenced changes in propofol doses. At the end of the procedure, the BIS data will be
      electronically transferred to a computer along with time points and other study parameters
      (18). Data that will be collected on case report forms include the following: date and time
      of BIS data collection, including start and end times; minimum, average and maximum BIS
      values at various time points including during propofol bolus doses, rate changes and
      discontinuation; average Signal Quality Index (SQI);and average electromyography (EMG).

      Demographic and Clinical Data: We will use and analyze patient demographic and clinical data
      in combination with the PK/PD data (10, 11) for Pharmacokinetic /Pharmacodynamic modeling
      purposes. Patient data to be collected include: age, gender, ethnicity, weight, height and
      body mass index. Clinical data to be collected and recorded on case report forms include:
      blood pressure, heart rate, temperature and end tidal carbon dioxide level (ETCO2). Other
      clinical data that will be recorded on case report forms include: time needed to lose
      consciousness (loss of verbal contact), start/stop time of propofol dosing, propofol infusion
      rates, propofol dose adjustments, time to eye opening on verbal command post infusion, and
      sedation scores (Ramsey sedation scale) post-operatively every 10 minutes (+/- 2 minutes) for
      the first 30 minutes and thereafter every 30 minutes (+/- 5 minutes) while in the Post
      Anesthesia Care Unit (PACU).

      Pharmacogenetics: Participation involves the collection of one blood sample (3.0 ml) in an
      EDTA (lavender top) tube for pharmacogenetic testing. Genomic DNA will be extracted using
      standard procedures.

      Questionnaire(s): The Structured Awareness Screening Interview shall be used to detect
      awareness during the anesthetic period which can be an adverse event related to
      underdosing/reduced sensitivity to propofol effects (24). This questionnaire has been used to
      detect awareness and perioperative behavioral studies for children age 5 and older (25). The
      same questions will be used for all children. No incentives will be given for the children to
      answer, and no leading questions will be asked during the screening interview.

      For this study, the questionnaire will be administered two times, on post-operative day (POD)
      1 and 3. The POD1 questionnaire will be administered by a study anesthesiologist. If the
      subject answers "no" on question six, the anesthesiologist may decide to not continue the
      interview. For subjects discharged prior to POD 3, parents or a legal representative will be
      given a written set of questions before leaving the hospital and will be requested to ask
      their child the questions on POD 3, write down the child's responses, and mail the questions
      back. To justify repeated questioning, the parents will be told that a child's memories of
      their anesthetic might change with time. They shall be instructed to ask the questions
      exactly as they are written and to write down their child's reply verbatim. If a child
      answers the POD3 questions directly instead of being asked the questions by a parent, their
      responses will be evaluated for inclusion by the Principal Investigator. Subjects consented
      as adults may answer the questions directly.

      If a subject is still in the hospital on POD 3, a study anesthesiologist will administer the
      questionnaire.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients will be recruited from the Cincinnati Children's Hospital Medical Center Surgical
        Weight Loss Program for Teens (Thomas Inge, Director), supplemented with general surgery
        patients who are overweight and have a Body Mass Index (BMI) of more than 30.
      
Biospecimen description: 
      Participation involves the collection of one blood sample (3.0 ml) in an EDTA (lavender top)
      tube for pharmacogenetic testing. Genomic DNA will be extracted using standard procedures.
      Participation in pharmacogenetic testing is optional and requires additional consent;
      subjects who refuse pharmacogenetifc testing may still be enrolled in this study.
    
Keywords: propofol; elective surgical procedure; Obese subjects