Obesity, Pharmacodynamics
Conditions
Keywords
Propofol, Childhood obesity, Pharmacodynamics
Brief summary
Obesity in children,as in adults,has rapidly become a public health concern. Studies in adults have shown that obesity, now considered to be a disease state, is a modifier of the effect of drugs on the body as well as how the body handles the drug.The anesthetic management of obese children poses a variety of significant challenges which include determination of the appropriate dose of anesthetic intravenous agents. Dosing of most drugs is calculated based on the effective dose in 50% of patients but the more practical and required information is the effective dose in 95%(ED95%)of patients. The aim of this study is to determine the effective dose in 95% of patients(children). The hypothesis is the ED95 of propofol in obese children will be higher than that of non-obese children.
Detailed description
All subjects were fasted in keeping with our institutional NPO guidelines and had IV access established in the upper extremity in the pre-anesthesia area. No pre-induction sedative drugs were administered. Routine ASA monitors were applied and in cooperative children, a bispectral index (BIS) monitor pad (Aspect Medical Systems, Inc., Shattuck, MA) was applied over the forehead. Each child was given a water-filled syringe to hold tightly in the hand contralateral to the IV site. Lidocaine 1 mg/kg IV (maximum of 60 mg) was administered to decrease pain with propofol injection. A predetermined sequential dose of propofol (Diprivan, APP Pharmaceuticals, LLC, Schaumburg, IL) was administered IV rapidly over 10 seconds, followed by a normal saline flush. Biased Coin Design An independent observer blinded to the propofol dose tested for lash reflex at 20 seconds, and also recorded the vital signs; level of sedation, using the University of Michigan sedation scale (UMSS)10; and the BIS values at 20, 60, and 120 seconds after propofol administration, along with the time the patient dropped the handheld syringe. The study was terminated after 120 seconds and additional propofol administered if needed. Both nonobese and obese patients were studied in parallel using the biased coin design (BCD), in which a certain number of dose levels (k levels) are chosen with a fixed constant interval. In the absence of dose-ranging data in obese children, we chose a low starting dose of 1.0 mg/kg for the first patient in both groups to avoid missing a desired response in this patient population. If the desired effect (loss of lash reflex at 20 seconds) was not observed, the next patient in the assigned group received the next higher dose of propofol in predetermined increments (0.25 mg/kg) from the previous dose. If the desired effect was observed, the next patient in the same assigned group was randomized with a 0.95 probability to receive the same dose or a 0.05 probability to receive the next lower dose (also in 0.25 mg/kg decrements).
Interventions
DRUGPropofol
Each Obese child/subject in this group will receive a predetermined dose of propofol ranging from 1.0mg/kg to 4.25mg/kg to induce loss of consciousness depending on the response (presence or absence of lash reflex) of the preceding patient to his/her assigned dose (biased coin design)
Sponsors
Baylor College of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Children between the ages of 3 and 17 years who fall into the categories of non-obese(BMI percentile between 25-84th percentile) or obese(\>95th percentile) 2. American Society of Anesthesiology(ASA) classification 1 or 2-
Exclusion criteria
1. Patients classified as ASA (American Society of Anesthesiology) Class 3 or greater. 2. Patients with documented kidney or liver disease or those presenting for open surgery on the liver or kidney. 3. Patients who will NOT be receiving propofol for induction as part of their anesthetic regimen. 4. Patients who are currently on anti-convulsant medication or receiving drugs with sedative effects. 5. Patients currently being treated for attention deficit disorder. 6. Patients who are diagnosed with failure to thrive or those with a BMI less than 25th percentile. 7. Patients who are hemodynamically unstable. 8. Patients with egg allergy. 9. Patients with low levels of albumin -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose of Propofol That Caused Loss of Consciousness in 95% (ED95) of Obese and Non-obese Children | 20 seconds | Propofol is administered over 10 seconds. 20 seconds after adminstration, loss of consciousness is assessed by the presence or absence of a lash reflex. The dose responsible for loss of lash reflex/consciousness in 95% of patients was determined in mg/kg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depth of Sedation | 30 seconds, 1 minute, and 2 minutes | After propofol administration, the patient was assessed for depth of sedation at 30 seconds, 1 minute, and 2 minutes using the University of Michigan Sedation Scale (UMSS) and Ramsay Sedation Scale. UMSS assesses the level of alertness on a five-point scale ranging from 1 (wide awake) to 5 (unarousable with deep stimulation). Ramsay Sedation Scale assesses the level of sedation on a six-point scale ranging from 1 (Patient is anxious and agitated or restless, or both) to 6 (Patient exhibits no response). |
Countries
United States
Participant flow
Recruitment details
Patients were recruited in the operating room setting between the period of April 2008 to December 2011
Pre-assignment details
A total of 213 patients were screened for study eligibility. Eighty-two patients were excluded; 51 did not meet inclusion criteria either becasue they declined participation, did not have intravenous access, were re-scheduled due to inadequate preparation for surgery or patient illness. All patients enrolled completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Obese Children Obese children are categorized as those with a body mass index \>95th percentile
Propofol : Each Obese child/subject in this group received a predetermined dose of propofol ranging from 1.0mg/kg to 4.25mg/kg to induce loss of consciousness depending on the response (presence or absence of lash reflex) of the preceding patient to his/her assigned dose (biased coin design) | 40 |
| Non-obese Non-obese children categorized as those with a body mass index(BMI)between 25-84th percentile
Propofol : This arm of patients(non-obese)served as the control group for the obese children. Each non-obese child/subject received a predetermined dose of propofol from a range of 1.0mg/kg to 4.25mg/kg depending on the response of the previous patient to their assigned dose( biased coin design) | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | Obese Children | Non-obese | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 40 Participants | 40 Participants | 80 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.69 years STANDARD_DEVIATION 2.89 | 12.70 years STANDARD_DEVIATION 3.9 | 12.69 years STANDARD_DEVIATION 3.43 |
| Body Mass Index | 30.29 kg/m^2 STANDARD_DEVIATION 5.12 | 19.01 kg/m^2 STANDARD_DEVIATION 2.6 | 24.65 kg/m^2 STANDARD_DEVIATION 6.95 |
| Region of Enrollment United States | 40 participants | 40 participants | 80 participants |
| Sex: Female, Male Female | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 22 Participants | 24 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 0 / 40 | 0 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
Dose of Propofol That Caused Loss of Consciousness in 95% (ED95) of Obese and Non-obese Children
Propofol is administered over 10 seconds. 20 seconds after adminstration, loss of consciousness is assessed by the presence or absence of a lash reflex. The dose responsible for loss of lash reflex/consciousness in 95% of patients was determined in mg/kg.
Time frame: 20 seconds
Population: The sample size of 40 patients in each group was based on previous simulation studies which used the biased coin design in which a group size of 20-40 patients was shown to demonstrate stable estimates of the target dose for most scenarios.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Obese Children | Dose of Propofol That Caused Loss of Consciousness in 95% (ED95) of Obese and Non-obese Children | 2 mg/kg |
| Non-obese | Dose of Propofol That Caused Loss of Consciousness in 95% (ED95) of Obese and Non-obese Children | 2.125 mg/kg |
Secondary
Depth of Sedation
After propofol administration, the patient was assessed for depth of sedation at 30 seconds, 1 minute, and 2 minutes using the University of Michigan Sedation Scale (UMSS) and Ramsay Sedation Scale. UMSS assesses the level of alertness on a five-point scale ranging from 1 (wide awake) to 5 (unarousable with deep stimulation). Ramsay Sedation Scale assesses the level of sedation on a six-point scale ranging from 1 (Patient is anxious and agitated or restless, or both) to 6 (Patient exhibits no response).
Time frame: 30 seconds, 1 minute, and 2 minutes
Population: Due to unavoidable circumstances during a clinical surgery, depth of sedation was not able to be collected on every subject at every time point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Obese Children | Depth of Sedation | UMSS - 30 seconds | 3.65 units on a scale |
| Obese Children | Depth of Sedation | UMSS - 1 minute | 3.86 units on a scale |
| Obese Children | Depth of Sedation | UMSS - 2 minutes | 3.82 units on a scale |
| Obese Children | Depth of Sedation | Ramsay - 30 seconds | 5.74 units on a scale |
| Obese Children | Depth of Sedation | Ramsay - 1 minute | 5.92 units on a scale |
| Obese Children | Depth of Sedation | Ramsay - 2 minutes | 5.92 units on a scale |
| Non-obese | Depth of Sedation | Ramsay - 1 minute | 5.83 units on a scale |
| Non-obese | Depth of Sedation | UMSS - 30 seconds | 3.57 units on a scale |
| Non-obese | Depth of Sedation | Ramsay - 30 seconds | 5.71 units on a scale |
| Non-obese | Depth of Sedation | UMSS - 1 minute | 3.73 units on a scale |
| Non-obese | Depth of Sedation | Ramsay - 2 minutes | 5.86 units on a scale |
| Non-obese | Depth of Sedation | UMSS - 2 minutes | 3.67 units on a scale |