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The purpose of the study is to evaluate and compare the feasibility, efficacy and safety of IAADS (Improved Anaesthetic Agent Delivery System) for propofol anaesthesia against manual control using bispectral index in paediatric patients undergoing open heart surgery under cardio-pulmonary bypass.
Automated drug delivery has gained considerable interest in recent times. It is carried out by specially programmed electro-mechanical devices where dose rate adjustment is made independent of human intervention. The desired target is chosen by the clinician. The closed loop system depends upon a feedback signal to modify the rate of drug delivery. These have an advantage that they are able to overcome the individual pharmacokinetic and pharmacodynamic differences as well as the differing levels of surgical stimulation. Majority of studies on closed loop delivery of hypnotics has been done using propofol. CLADS(Closed loop anesthesia delivery system) is a BIS guided closed loop anaesthesia delivery system developed at PGIMER (Post graduate institute of medical education and research), Chandigarh and has been used successfully for administration of propofol in various situations, eg, non-cardiac surgery, cardiac surgery, post-operative sedation and high altitude. The system used will be IAADS, Improved anesthetic agent delivery system - the present and updated version of CLADS), a pharmacokinetic-pharmacodynamic model based adaptive system . There are only a few studies/reports regarding closed loop delivery of muscle relaxants in children. In this study, the efficacy of IAADS will be compared with manual control for administration of propofol using BIS as a control variable during induction and maintenance of anaesthesia in children undergoing elective open heart surgery.
After approval from the Institutional ethics committee and written informed parental consent, 40 children, aged 5-18 years and ASA physical status II-III, planned for elective open heart surgery under general anaesthesia will be studied. Patients will be randomly allocated to one of two groups - the manual group and the IAADS group using computer-generated random numbers in sealed opaque envelopes. Exclusion criteria will be: patients weighing more than ±30% of ideal body weight, those with neurological/psychological disorders, on psychoactive medications, belonging to NYHA class IV, those with severe stenotic valvular lesions, with known allergy to propofol or any of its constituents, having severe pulmonary arterial hypertension, with cyanotic congenital heart disease and those who may require deep hypothermic circulatory arrest for repair. The investigator will be present during the procedure for data collection purpose only and was not involved in the conduct of anaesthesia. Patients will be premedicated with oral midazolam syrup 0.25mg/kg 30 minutes before shifting to operating room. EMLA cream will be applied to the site of venipuncture for at least one hour. Intravenous access will be obtained in the operating room. Routine physiological monitoring will be commenced (pulse oximetry, electrocardiography, non-invasive blood pressure). BIS will be obtained by disposable sensors (Aspect Medical System Inc. MA USA) attached to the forehead of the patients. The children resisting venous cannula placement will be excluded from the study and subjected to inhalational induction.
Before induction, patients will receive fentanyl 3µg/kg over three minutes. In automatic mode, IAADS will calculate and titrate the initial and subsequent propofol infusion rate according to the weight of the patient, the risk status, the target BIS value which will be set at 50 for all cases. In manual mode, infusion rate will be determined by the attending anaesthesiologist according to the weight of the patient and target BIS of 50, with the aim to maintain BIS within 40-60. After loss of consciousness, patients will receive 0.1mg/kg of vecuronium bromide and trachea will be intubated after 4 minutes. The lungs will be ventilated with 100% O2; tidal volume and respiratory rate will be adjusted to maintain an EtCO2 of 30-35 mm Hg. Central venous catheter and arterial cannula will be inserted subsequently.
Analgesia will be maintained with infusion of fentanyl at 1µg/kg/hr and additional boluses of 1µg/kg will be administered before skin incision, sternotomy and commencement of cardio-pulmonary bypass. Muscle relaxation will be maintained with vecuronium bromide. Tachycardia and hypertension will be treated with fentanyl bolus, esmolol, nitroglycerine as appropriate. Hypotension will be treated with fluid bolus, phenylephrine, inotropes as appropriate. Significant bradycardia will be treated with atropine sulphate. During CPB, infusion of fentanyl and propofol will be continued. MAP will be maintained between 30-50 mm Hg and any deviation from these limits will be treated with phenylephrine boluses or nitroglycerine infusion. Propofol will be administered as per IAADS protocol in automatic group and manually in control group. The number of times propofol infusion rate that will needed to be changed in the manual group will be noted.
After skin closure, fentanyl and propofol infusion will be stopped, study protocol will be terminated and the patients will be shifted to ICU without antagonizing the muscle relaxant for elective mechanical ventilation. Patients will be given propofol infusion for postoperative sedation and will be extubated when standard criteria for weaning and extubation will be met. The children will be subjected to a structured interview as described by Lopez et a for conscious awareness; on second day after surgery and approximately one month later.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IAADS group | Experimental | dosage of propofol adjusted automatically by IAADS |
|
| Manual group | Active Comparator | dosage of propofol adjusted manually |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IAADS | Other | In automatic mode, the system requests an update of the BIS data every 5 seconds and calculates the BIS "error" (difference between the target and actual BIS value). This value along with the trends of BIS in the epoch of the last 30 seconds as well as in the last 5 minutes is passed on to a patient individualized, model based adaptive control algorithm. The algorithm uses the error to calculate an adjustment to the propofol delivery rate, but does not apply it immediately. Adjustments to the propofol delivery rate are only made every 30 seconds, taking into account the sum of previous six BIS "error" values, the trends of BIS in the epoch of last 30 seconds as well as in the last 5 minutes, time elapsed since the initiation of infusion, pharmacokinetics, the time delay factor between sensing and averaging of BIS data, the time delay factor between the change in infusion rate and the actual change in the plasma concentration of propofol as well as the peak effect of propofol. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Time Bispectral Index(BIS) Remains+/-10 of Target | The primary outcome to be measured is the ability of the system to keep the depth of anesthesia in the target range, i.e, Bispectral Index(BIS) value of 50+/- 10. This will assess the ability of the system to prevent intra-operative awareness of the patients and at the same time avoid excessive depth of anesthesia with its accompanying adverse effects. | Approximately 8 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Median Performance Error(MDPE) | The difference between the observed and target of measure of depth of anesthesia (BIS) expressed as percentage of target BIS is calculated as performance error every 30 seconds. This value may be either '+' or '_' indicating whether the observed measure is above the target (overshoot-+) or below the target (undershoot-_). The median value of all performance errors during propofol anesthesia is median performance error and is a measure of bias of the system. This outcome is expressed as the mean of Median Performance Errors per participant. |
| Measure | Description | Time Frame |
|---|---|---|
| Induction Dose of Propofol | Dose of propofol needed for induction | 10 minutes |
| Induction Time | Time required for the first time achievement of two subsequent BIS values below or equal to 55 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Indranil Biswas, MBBS | Post Graduate Institute of Medical Education and Research, Chandigarh | Principal Investigator |
| Goverdhan D Puri, MBBS,MD,PhD | Post Graduate Institute of Medical Education and Research, Chandigarh | Principal Investigator |
| Preethy J Mathew, MBBS,MD | Post Graduate Institute of Medical Education and Research, Chandigarh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Advanced Cardiac Centre.Postgraduate Institute of Medical Education and Research. | Chandigarh | Chandigarh | 160012 | India |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19243324 | Background | Agarwal J, Puri GD, Mathew PJ. Comparison of closed loop vs. manual administration of propofol using the Bispectral index in cardiac surgery. Acta Anaesthesiol Scand. 2009 Mar;53(3):390-7. doi: 10.1111/j.1399-6576.2008.01884.x. | |
| 20299990 | Background | Solanki A, Puri GD, Mathew PJ. Bispectral index-controlled postoperative sedation in cardiac surgery patients: a comparative trial between closed loop and manual administration of propofol. Eur J Anaesthesiol. 2010 Aug;27(8):708-13. doi: 10.1097/EJA.0b013e328335b2d4. |
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5 patients were initially excluded because of having cyanotic heart disease, 6 patients excluded subsequently as they resisted pre-induction venous cannula placement.
51 patients assessed in surgical ward between january 2012 to september 2012, after excluding 11 patients, 40 remaining patients were randomised into two groups(IAADS & Manual) of 20 each- all patients in each group received allocated interventions- no patients needed to be excluded from final analysis.
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| ID | Title | Description |
|---|---|---|
| FG000 | IAADS Group | Both induction and maintenance of anesthesia was done automatically by IAADS according to age, sex, height of the patient, target BIS(50) entered, risk status and maximum allowable rate entered. |
| FG001 | Manual Group | dosage of propofol was adjusted manually by the attending anesthesiologist through the keyboard of the PC attached to the syringe pump for both induction and maintenance. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | IAADS Group | Both induction and maintenance of anesthesia was done automatically by IAADS according to age, sex, height of the patient, target BIS(50) entered, risk status and maximum allowable rate entered. |
| BG001 | Manual Group |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Time Bispectral Index(BIS) Remains+/-10 of Target | The primary outcome to be measured is the ability of the system to keep the depth of anesthesia in the target range, i.e, Bispectral Index(BIS) value of 50+/- 10. This will assess the ability of the system to prevent intra-operative awareness of the patients and at the same time avoid excessive depth of anesthesia with its accompanying adverse effects. | Posted | Mean | Standard Deviation | percentage of time | Approximately 8 hours |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | IAADS Group | Both induction and maintenance of anesthesia was done automatically by IAADS according to age, sex, height of the patient, target BIS(50) entered, risk status and maximum allowable rate entered. |
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anesthesiologist could get visual impression of his performance.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr G D Puri | Postgraduate Institute of Medical Education and Research | 00919914209509 | gdpuri007@hotmail.com |
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| ID | Term |
|---|---|
| D058926 | Intraoperative Awareness |
| ID | Term |
|---|---|
| D007431 | Intraoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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|
| Manual propofol administration | Other | In "manual" mode, the user can also control the propofol infusion rate manually, using the keyboard or the mouse of the PC. The PC displays a graph of the propofol delivery rate and trend of BIS value. |
|
| Approximately 8 hours |
| Median Absolute Performance Error(MDAPE) | The difference between the observed and target of measure of depth of anesthesia (BIS) expressed as percentage of target BIS is calculated as performance error every 30 seconds. This value may be either '+' or '_' indicating whether the observed measure is above the target (overshoot-+) or below the target (undershoot-_).The median of the absolute values of performance errors (without considering the direction of error) is median absolute performance error. This outcome measures the magnitude of error or inaccuracy of the system studied. A lower value indicates a more precise system.This outcome is expressed as the mean of Median Absolute Performance Errors per participant. | Approximately 8 hours |
| Wobble | Wobble measures the intra-individual variability in performance error.The median of the difference between individual performance errors throughout anesthesia and the median performance error for each participant is the wobble of that participant. The mean value per participant is indicated in the outcome measure. | Approximately 8 hours |
| Percentage of Time Heart Rate Remains Within 25% of Pre-op Baseline | The duration of time heart rate remains within 25% of the pre-operative baseline value during the period propofol (general anesthetic) is administered to the study population. This value is expressed as a percentage. This outcome is expressed as the mean of percentage of time per participant. | Approximately 8 hours |
| Percentage of Time Mean Arterial Pressure Remains Within 25% of Pre-op Baseline | The duration of time mean arterial pressure remains within 25% of the pre-operative baseline value during the period propofol (general anesthetic) is administered to the study population. This value is expressed as percentage. This outcome is expressed as the mean of percentage of time per participant | Approximately 8 hours |
| Intra-operative Awareness | The number of patients who will be able to recall the intra-operative events when assessed postoperatively. This will be assessed by a structured protocol | Approximately 3 days and then 1 month later |
| Divergence | slope of the linear regression curve of performance error against time. | 8 hours (approx) |
| Global Score | overall performance assessment of the system calculated as= [(MDAPE+Wobble)/percentage of time BIS remains within target]x100 Lower score indicates better overall performance | 8 hours (approx) |
| Intraoperative Phenylephrine Used (Pre CPB) | total phenylephrine dose needed to be used in the pre CPB period to maintain hemodynamic stability | 2 hours(approx) |
| 10 minutes |
| Minimum BIS During Induction | Bispectral Index(BIS) is an EEG-based objective measure of anesthetic depth with values ranging from 100 to 0, lower number indicating greater depth of anesthesia. Values between 40 to 60 indicate adequate depth required for surgery. During induction of anesthesia, there is a tendency of overshooting the adequate depth of anesthesia, due to use of higher dose and rate of administration required for induction. The minimum BIS achieved during induction is a measure of this overshoot. The less the minimum value, the more is the overshoot, worse the outcome is. The minimum BIS during induction is automatically stored in the PC used for the study. | 15 minutes |
| Percentage Fall in MAP During Induction | percentage fall in mean arterial pressure from baseline during induction | 15 minutes |
| Total Propofol Used (mg/kg/hr) | total propofol used based on per kg body weight per hour for the whole duration of surgery | 8 hours (approx) |
| Total Fentanyl Used (µg/kg) | total fentanyl used in the whole duration of surgery on per kg body weight basis | 8 hours(approx) |
| Total Off CPB Propofol Used (mg/kg/hr | total dosage of propofol used on per kg body weight per hour basis in the period before and after cardiopulmonary bypass period. | 6 hours(approx) |
| Number of Times Rate of Propofol Changed Manually | Number of times rate of propofol needed to be changed manually | 8 hours(aprrox) |
| 17591128 | Background | Puri GD, Kumar B, Aveek J. Closed-loop anaesthesia delivery system (CLADS) using bispectral index: a performance assessment study. Anaesth Intensive Care. 2007 Jun;35(3):357-62. doi: 10.1177/0310057X0703500306. |
dosage of propofol was adjusted manually by the attending anesthesiologist through the keyboard of the PC attached to the syringe pump for both induction and maintenance.
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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dosage of propofol was adjusted manually by the attending anesthesiologist through the keyboard of the PC attached to the syringe pump for both induction and maintenance.
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| Secondary | Median Performance Error(MDPE) | The difference between the observed and target of measure of depth of anesthesia (BIS) expressed as percentage of target BIS is calculated as performance error every 30 seconds. This value may be either '+' or '_' indicating whether the observed measure is above the target (overshoot-+) or below the target (undershoot-_). The median value of all performance errors during propofol anesthesia is median performance error and is a measure of bias of the system. This outcome is expressed as the mean of Median Performance Errors per participant. | Posted | Mean | Standard Deviation | errors per participant | Approximately 8 hours |
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| Secondary | Median Absolute Performance Error(MDAPE) | The difference between the observed and target of measure of depth of anesthesia (BIS) expressed as percentage of target BIS is calculated as performance error every 30 seconds. This value may be either '+' or '_' indicating whether the observed measure is above the target (overshoot-+) or below the target (undershoot-_).The median of the absolute values of performance errors (without considering the direction of error) is median absolute performance error. This outcome measures the magnitude of error or inaccuracy of the system studied. A lower value indicates a more precise system.This outcome is expressed as the mean of Median Absolute Performance Errors per participant. | Posted | Mean | Standard Deviation | errors per participant | Approximately 8 hours |
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| Secondary | Wobble | Wobble measures the intra-individual variability in performance error.The median of the difference between individual performance errors throughout anesthesia and the median performance error for each participant is the wobble of that participant. The mean value per participant is indicated in the outcome measure. | Posted | Mean | Standard Deviation | errors per participant | Approximately 8 hours |
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| Secondary | Percentage of Time Heart Rate Remains Within 25% of Pre-op Baseline | The duration of time heart rate remains within 25% of the pre-operative baseline value during the period propofol (general anesthetic) is administered to the study population. This value is expressed as a percentage. This outcome is expressed as the mean of percentage of time per participant. | Posted | Mean | Standard Deviation | percentage of time | Approximately 8 hours |
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| Secondary | Percentage of Time Mean Arterial Pressure Remains Within 25% of Pre-op Baseline | The duration of time mean arterial pressure remains within 25% of the pre-operative baseline value during the period propofol (general anesthetic) is administered to the study population. This value is expressed as percentage. This outcome is expressed as the mean of percentage of time per participant | Posted | Mean | Standard Deviation | percentage of time | Approximately 8 hours |
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| Secondary | Intra-operative Awareness | The number of patients who will be able to recall the intra-operative events when assessed postoperatively. This will be assessed by a structured protocol | Posted | Number | participants | Approximately 3 days and then 1 month later |
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| Secondary | Divergence | slope of the linear regression curve of performance error against time. | Posted | Mean | Standard Deviation | errors per second | 8 hours (approx) |
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| Secondary | Global Score | overall performance assessment of the system calculated as= [(MDAPE+Wobble)/percentage of time BIS remains within target]x100 Lower score indicates better overall performance | Posted | Mean | Standard Deviation | percentage of time | 8 hours (approx) |
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| Secondary | Intraoperative Phenylephrine Used (Pre CPB) | total phenylephrine dose needed to be used in the pre CPB period to maintain hemodynamic stability | Posted | Mean | Standard Deviation | microgram per Kg body weight | 2 hours(approx) |
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| Other Pre-specified | Induction Dose of Propofol | Dose of propofol needed for induction | Posted | Mean | Standard Deviation | mg per kg body weight | 10 minutes |
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| Other Pre-specified | Induction Time | Time required for the first time achievement of two subsequent BIS values below or equal to 55 | Posted | Mean | Standard Deviation | seconds | 10 minutes |
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| Other Pre-specified | Minimum BIS During Induction | Bispectral Index(BIS) is an EEG-based objective measure of anesthetic depth with values ranging from 100 to 0, lower number indicating greater depth of anesthesia. Values between 40 to 60 indicate adequate depth required for surgery. During induction of anesthesia, there is a tendency of overshooting the adequate depth of anesthesia, due to use of higher dose and rate of administration required for induction. The minimum BIS achieved during induction is a measure of this overshoot. The less the minimum value, the more is the overshoot, worse the outcome is. The minimum BIS during induction is automatically stored in the PC used for the study. | Posted | Mean | Standard Deviation | Bispectral Index | 15 minutes |
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| Other Pre-specified | Percentage Fall in MAP During Induction | percentage fall in mean arterial pressure from baseline during induction | Posted | Mean | Standard Deviation | percentage of fall from baseline | 15 minutes |
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| Other Pre-specified | Total Propofol Used (mg/kg/hr) | total propofol used based on per kg body weight per hour for the whole duration of surgery | Posted | Mean | Standard Deviation | mg per kg body weight per hour | 8 hours (approx) |
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| Other Pre-specified | Total Fentanyl Used (µg/kg) | total fentanyl used in the whole duration of surgery on per kg body weight basis | Posted | Mean | Standard Deviation | microgram per kg body weight | 8 hours(approx) |
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| Other Pre-specified | Total Off CPB Propofol Used (mg/kg/hr | total dosage of propofol used on per kg body weight per hour basis in the period before and after cardiopulmonary bypass period. | Posted | Mean | Standard Deviation | mg per kg body weight per hour | 6 hours(approx) |
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| Other Pre-specified | Number of Times Rate of Propofol Changed Manually | Number of times rate of propofol needed to be changed manually | Posted | Median | Full Range | times per hour | 8 hours(aprrox) |
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| 0 |
| 20 |
| 0 |
| 20 |
| EG001 | Manual Group | dosage of propofol was adjusted manually by the attending anesthesiologist through the keyboard of the PC attached to the syringe pump for both induction and maintenance. | 0 | 20 | 0 | 20 |
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