Closed Loop Isoflurane Administration With Bispectral Index in Open Heart Surgery

Open Heart Surgery Clinical Trial

Official title:

Comparison of Isoflurane Anaesthesia by Closed Loop Controlled Administration Versus Manually Controlled Administration Using Bispectral Index in Open Heart Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01069562
• Other study ID #: closed loop isoflurane
• Status: Completed
• Phase: N/A
• First received: February 1, 2010
• Last updated: January 24, 2011
• Start date: January 2009
• Est. completion date: June 2010

Study information

• Verified date: July 2010
• Source: Postgraduate Institute of Medical Education and Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

With the advancement in microprocessor technology and better understanding of pharmacodynamics and pharmacokinetics of anaesthetic agents, computer facilitated closed loop control of anaesthesia using propofol has been shown to be accurate with better performance than manual control. Literature on computer controlled administration of inhalational anaesthetics is few, as it requires the computer to control the dial setting on the vapouriser. The investigators intend to compare the computer controlled closed loop administration of isoflurane by infusing it into the anaesthetic circuit with conventional vaporiser control in elective open heart surgery.

40 patients (ASA (American Society of Anesthesiology) class II-IV; 18- 65 years) undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB) will be randomly divided into manual or closed loop groups. Propofol will be used for induction of anaesthesia in both groups followed by isoflurane for maintenance. In the manual group, isoflurane will be administered through the Tech 7 vapouriser during pre and post CPB periods to target bispectral index (BIS) of 50. In closed loop group, isoflurane will be administered using infusion of liquid isoflurane into expiratory limb of the closed circuit. This rate of infusion though a conventional syringe pump will be controlled by algorithm termed 'Improvised Anaesthetic Agent Delivery System' (IAADS) to maintain BIS of 50. Patients in both groups will receive 500ml of 100 % oxygen as fresh gas flow. The % of time bispectral index (BIS) is within the 10 of set target BIS of 50 will be the primary outcome measure. The secondary outcome measures will be median performance error (MDPE)(2), median absolute performance error (MDAPE)(2), wobble(2), divergence(2), amount of isoflurane used and hemodynamic parameters will be secondary outcome measures.

Description:

The basic components in a closed loop anesthesia delivery system are: (1) a system under control- patient; (2) a controlled variable that measures depth of anesthesia, (3) a set point for this variable specified by the user, (4) an actuator which comprises an algorithm to translate a measured value of the controlled variable to a particular action or the actuator to steer the controlled variable closer to the target variable.

In the proposed study, the controlled variable will be BIS. The control actuator is a patented (2158/DEL/2007) pharmacodynamic- pharmacokinetic model based adaptive infusion system termed "Improved Anesthetic Agent Delivery System (IAADS"). An IBM compatible with PENTIUM 2 or higher processor personal computer (2 GHz) is used to implement the control algorithm, provide a user interface and control communication through serial ports (RS 232) with the infusion system (Pilot- C, Frasenius, France) and a Datex vital sign monitor. We will use Avance ventilator (Datex Ohmeda, software version 5.0) with carbon di oxide absorber and ascending bellows to provide constant volume ventilation. The amount of acceptable leak in the circuit will be reduced to ≤ 150 ml min-1 determined during ventilation of a test lung. Low fresh gas flows will be used during the study. Isoflurane will injected into the expiratory limb of circle system via 20 ml Plastipak (polyethylene BD) syringe with a 100 cm long polyethylene tubing (Vygon, India) using a Pilot C Infusion pump (Fresenius vial SA, France). The stated volumetric accuracy of the infusion pump is ±2 %.

After obtaining written informed consent, patients will be randomly allocated (by closed envelope technique using computer generated random numbers) to one of the two groups- manual and automatic. The investigator will be present during the procedure for data collection purpose only and will not be involved in the conduct of anaesthesia. All patients will receive 5- 10mg oral diazepam as per institutional protocol the night before and on the morning of surgery as pre-medication. After shifting the patient to the operation table, patients will be started on normal saline 100 ml/hr (1-2 ml/kg/hr). Routine physiological monitoring will be commenced (pulse oximetry, electrocardiography, non-invasive blood pressure monitoring). BIS (Bispectral index)will be obtained by disposable sensors (Aspect medical system Inc. MA USA) attached to the forehead of the patient. Patients will receive 0.15 mg/kg of morphine sulphate before induction in aliquots of 3-5mg, during which indwelling arterial cannula, central venous line and pulmonary artery catheters (if deemed to be necessary) will be inserted.

Before induction, patients shall receive fentanyl 3μg/kg over three minutes. In automatic mode, IAADS automatically will calculate and titrate the initial and subsequent propofol infusion rate according to the weight of the patient, risk status and target BIS value, which will be set at 50 for all cases with a range of 40-60. In manual group, the propofol infusion rate will be determined by the attending anaesthesiologist according to the weight of the patient, and the target BIS of 50, with the aim to maintain BIS within 40- 60. After loss of consciousness (LOC), patients will receive 0.1mg/kg vecuronium bromide and will be intubated after 4 minutes.

The circle system will be closed after ascertaining the correct position of the endotracheal tube. In the control group, isoflurane infusion will be started into the expiratory limb of the circle at predetermined rates. The isoflurane concentration in the circuit will be built gradually over a period of 10 minutes to attain a specified BIS value. During isoflurane anaesthesia, patients will be ventilated with 100% oxygen. Fresh gas flows will be started at 500ml/min, and the ventilation will be set so as to maintain an end tidal CO2 concentration of 30-35 mmHg. If the fresh gas flows are inadequate as determined by incomplete filling of bellows, the flows will be increased gradually by 100 ml/min till a maximum of 1000 ml/min. If still there is a leak, the study will be abandoned and patient ventilated with higher flows. Thus, patients will be maintained on isoflurane injected into the expiratory limb of the circuit. Analgesia will be maintained with fentanyl 1μg/kg/hr infusion with further boluses of 1μg/kg before skin incision, sternotomy and commencement of cardiopulmonary bypass (CPB). Muscular relaxation will be maintained with a continuous infusion of vecuronium bromide 50μg/kg/hr. After 30 minutes of induction, an arterial sample will be drawn to have baseline values for blood gases, activated clotting time (ACT), and blood glucose. Patients will receive a bolus of 3 mg/kg heparin to raise the ACT above 480s. In cases of lower values, further boluses of heparin will be infused as per bull and colleagues dose response curve for heparin.

In the manual group, after the confirmation of the placement of endotracheal tube, the circle system will be closed and fresh gas flows will be started at 1000ml/min. Inhalational anaesthetics will be delivered by Fluotech 7 vapouriser (Datex ohmeda) for isoflurane. The initial dial setting will be started at 3% and after 5 minutes, flows will be reduced to 500 ml/min and isoflurane concentration will be titrated by the anaesthesiologist to maintain BIS of 50. The dial setting will be increased or decreased to maintain BIS of 50 and the number of times the vapouriser dial setting is changed will be noted. Rest of the protocol will be similar to the computer control group described above.

After the initiation of CPB, arterial blood gases, ACT and blood glucose will be determined every half an hour. An arterial partial pressure of O2 of 300-400 mmHg, ACT >480s and blood glucose <180mg/dl will be maintained throughout the bypass period. After successful completion of cardiopulmonary bypass, heparin will be antagonised with protamine sulphate.

During episodes when the mean arterial pressure exceeds 25% of the baseline or heart rate exceeds 100 beats/ min or 25% of the baseline, analgesia will be supplemented with fentanyl 1μg/kg. In case of persistent hypertension or tachycardia with BIS < 50, nitroglycerine infusion will be started and titrated to control blood pressure; Esmolol (upto 0.5mg/kg IV) will be administered to control the heart rate (HR). Similarly, in case of fall in mean arterial pressure to less than 25% of the baseline in the presence of normovolemia, initially phenylephrine will be used in boluses of 0.5μg/kg. For persistent hypotension after a cumulative Phenylephrine dose of 2μg/kg, dopamine infusion will be started and titrated to maintain MAP within 25% of the baseline. Likewise, in case of decrease in HR to <45beats/min., atropine sulphate (10μg/kg IV boluses) will be administered after excluding other treatable causes.

During CPB, patients will be shifted to propofol infusion, as the equipment for delivering fresh gases during CPB requires large fresh gas flows and circle system is not possible presently. MAP will be maintained between 50- 80 mmHg and any deviation from theses limits shall be treated with Phenylephrine boluses or sodium nitroprusside infusion. Propofol will be administered as per IAADS in computer control group and manually in the manual group to maintain BIS of 50.

Five minutes after the end of CPB, patients will be shifted back to isoflurane. In the computer control group, the concentration in the circuit for the set BIS will be achieved over 10 minutes. In the manual control group, the dial setting will be started at 3% and titrated according to the BIS. Fresh gas flows will be maintained at the same rate before the initiation of CPB.

At the end of skin closure, isoflurane, fentanyl and vecuronium will be stopped and the study protocol terminated. Patient will be shifted to propofol infusion for post operative sedation and will be shifted to post anaesthesia care unit without antagonizing muscle relaxants for elective mechanical ventilation. Patients will be extubated on meeting standard criteria for extubation. All patients will be continuously monitored for hemodynamic stability and maintenance of blood gases upto 24 hrs postoperatively. Patients will be subjected to a structured interview as modified from Brice and colleagues and described by Nordstrom for conscious awareness; on discharge from post anesthesia care unit, the day after surgery and approximately a week later.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• American Society of Anesthesiology physical status 2- 4

• elective open heart surgery under general anaesthesia

• requiring Cardio Pulmonary Bypass (CPB)

Exclusion Criteria:

• body weight ±30% of the ideal body weight

• neurological disorder

• use of any psychoactive medication

• severe stenotic valve lesions

• severe pulmonary artery hypertension

• Tetrology of Fallot repair and other cyanotic heart diseases.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)

Related Conditions & MeSH terms

• Open Heart Surgery

Intervention

Other:
• Conventional control
The isoflurane administration to deliver anesthesia will be done conventionally through a Tec 7 vaporiser to maintain the bispectral index at 50.
• Closed loop control
The isoflurane administration to maintain anesthesia will be by infusion to the anesthesia circuit using syringe pump (injection technique). The rate of delivery of isoflurane will be regulated by computer that uses a control algorithm.

Locations

Country	Name	City	State
India	Post graduate institute of medical education and research	Chandigarh

Sponsors (1)

Lead Sponsor	Collaborator
Postgraduate Institute of Medical Education and Research

Country where clinical trial is conducted

India, 

References & Publications (4)

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. — View Citation

Locher S, Stadler KS, Boehlen T, Bouillon T, Leibundgut D, Schumacher PM, Wymann R, Zbinden AM. A new closed-loop control system for isoflurane using bispectral index outperforms manual control. Anesthesiology. 2004 Sep;101(3):591-602. — View Citation

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. — View Citation

Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992 Feb;20(1):63-94. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Time Bispectral Index Remains Within 10 of Target BIS of 50	The duration of time depth of anesthesia was maintained in the recommended range (as measured by BIS) during the period isoflurane (general anesthetic) was administered to the study population. This value expressed as percentage is the primary outcome. BIS is an objective measure of depth of anesthesia derived from statistical(bispectral) analysis of electroencephalographic waves. BIS ranges from 0 to 100. It decreases monotonically from 100 in the awake state to lower values with sedation and anesthesia.	8 hours (approximately)	No
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 isoflurane 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.	8 hours (approximately)	No
Secondary	Median Absolute Performance Error (MDAPE)	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.	8 hours (approximately)	No
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.	8 hours (approximately)	No
Secondary	Percentage of Time Heart Rate Remained Within 25% of Pre-op Baseline	The duration of time heart rate remained within 25% of the pre-operative baseline value during the period isoflurane (general anesthetic) was 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.	8 hours (approximately)	Yes
Secondary	Percentage of Time Mean Arterial Pressure Remained Within 25% of Pre-op Baseline	The duration of time mean arterial pressure remained within 25% of the pre-operative baseline value during the period isoflurane (general anesthetic) was administered to the study population. This value is expressed as percentage. This outcome is expressed as the mean of percentage of time per participant	8 hours (approximately)	Yes
Secondary	Intra-operative Awareness	The number of patients who were able to recall the intra-operative events when assessed postoperatively. This was assessed by a structured protocol	3 days (approximately)	Yes
Secondary	Fentanyl Used	The total amount of fentanyl that was used during the procedure.	8 hours (approximately)	No
Secondary	Intra Operative Adrenaline Used	The amount of adrenaline used during the procedure	8 hours (approximately)	No
Secondary	INTRA OPERATIVE PHENYLEPHRINE USED	The amount of phenylephrine used during the procedure.	8 hours (approximately)	No