Closed Loop Isoflurane Administration With Bispectral Index in Open Heart Surgery
Condition: Open Heart Surgery
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Conventional control; Closed loop control
Intervention type(s): Other; Other
Intervention description(s): The isoflurane administration to deliver anesthesia will be done conventionally through a Tec 7 vaporiser to maintain the bispectral index at 50.; 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.
Other intervention name(s): MANUAL CONTROL; AUTOMATED CONTROL
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Keywords: closed loop control of anesthesia; isoflurane; open heart surgery