Anesthetic Depth Control Using CLADS vs. TCI in Patients With LVSDF
Condition: Anesthesia
Study type: Interventional

Summary: 
      Advancement in techniques for anaesthetic drug delivery and real time monitoring has
      facilitated safe induction and maintenance of anaesthesia in severely compromised patients.
      Cardiac diseases are the commonest causes of morbidity and left ventricular failure is the
      commonest clinical presentation at the end stage. LV systolic dysfunction is defined as
      reduction in LVEF ≤55%. Patients with LVEF 55%-46% have mild, 45%-36% moderate and ≤35%
      severe LV systolic dysfunction. Patients with heart failure have a diminished cardiac reserve
      capacity that may be further compromised by anaesthesia. In addition to depression of
      sympathetic activity, most anaesthetics interfere with cardiovascular performance, either by
      a direct myocardial depression or by modifying cardiovascular control mechanisms. Propofol
      with fentanyl is advocated as the best anaesthetic combination for induction of anaesthesia
      in patients undergoing CABG. Propofol is a drug with narrow therapeutic index and may cause
      severe hypotension and hemodynamic instability during induction of anaesthesia, especially if
      it is given in too large doses.

      Automated drug delivery systems are popular for delivery of propofol. They can be of two
      types, depending on whether they are based on pharmacokinetic or pharmacodynamic principles.
      Closed Loop Anaesthesia Delivery system has been used world-wide and in our institute in
      patients of various age groups and in patients undergoing cardiac surgery. But still the
      studies are lacking in patients with moderate to severe left ventricular systolic
      dysfunction. Moreover none of the studies have compared the efficacy of anaesthetic drug
      delivery using these two devices in this group of patients.

      Thus there is paucity of literature regarding PK and PD of propofol in patients with cardiac
      failure. The investigators hypothesized that as the Closed Loop Anaesthesia Delivery System
      is based on pharmacodyanamic principles, it should perform better than the Target Control
      Infusion system, which works on pharmacokinetic principles. The investigators planned to
      conduct this study to determine the anaesthetic depth control using Closed Loop Anaesthesia
      Delivery system vs. manual control using Target Controlled Infusion in patients with moderate
      to severe left ventricular systolic dysfunction.
    

Detailed description: 
      MATERIALS AND METHODS:

      Patient will be pre-medicated with oral tablet alprazolam 0.25 mg the night before and on the
      morning of surgery. In the anesthetic room, 16 G i.v. cannula will be inserted and following
      monitors will be attached: continuous pulse-oximetry (SpO2), electrocardiogram (ECG),
      periodic non-invasive blood pressure (S/Anesthesia monitor, Datex Ohmeda Inc., Madison, WI) ,
      and continuous BIS (BIS XP, Aspect Medical Systems, Newton, MA in the S/5 Anesthesia
      monitor). Pre-induction arterial line and central line will be inserted in all patients and
      continuous arterial blood pressure and central venous pressure measurements will be recorded.
      Pulmonary artery catheter will also be inserted in all patients for monitoring of cardiac
      output. All invasive lines will be inserted under local anesthesia. NIBP measurements will be
      stopped after transducing arterial line, because it may interfere with the assessment of
      MOAA/S score.

      All the patients will receive i.v. fentanyl at a dose of 3µg.kg-1 over a period 3 minutes,
      followed by propofol administration either by CLADS or TCI.

      Group 1:

      Propofol will be administered with the Diprifusor (Marsh Pharmacokinetic model, Master TCI
      pump, Fresenius Kabi; Bad Homburg; Germany) starting at a predetermined target plasma
      propofol concentration (Cp) of 1.8µg.ml-1 based on a previous study. Further target
      concentrations were set according to the Dixon up and down method. A failure will be followed
      by an increase in the target plasma concentration in the next patient by 0.2µg.ml-1 and a
      success will be followed by a decrease in the target plasma concentration in the next patient
      by 0.2µg.ml-1. TCI pump will be controlled manually and all the data including BIS and vitals
      will be recorded through CLADS into a laptop. MOAA/S will be assessed every 15 second for
      assessing time to loss of consciousness; BIS and HR will be recorded every 5 seconds and MAP
      and PAP every 10 seconds. Thus, the anesthetic depth control will be assessed based on time
      to achieve loss of consciousness and by comparing the dose of propofol required for induction
      and maintenance. BIS overshoots and hemodynamic stability will be noted. In case the patient
      achieves loss of consciousness within 5 minutes, a 2 minutes observation period will be
      allowed for achieving target BIS. If the patient does not achieve target BIS after this
      period, the case will be considered a failure. On the other hand, if the patient achieves
      target BIS within this period it will be considered a success. In cases where neither LOC nor
      target BIS will be achieved within 5 minutes will also be considered a failure Vecuronium
      will be administered at a dose of 0.1 mg.kg-1 after the LOC and the patient will be intubated
      after 4 minutes. Patients will be ventilated through face mask to maintain normocapnia
      administering air-oxygen mixture with FiO2 of 0.6 during the period of induction till
      intubation. Fentanyl infusion 1µg.kg.h-1 will provide analgesia with additional boluses of
      1µg.kg-1 before skin incision, sternotomy and at the commencement of CPB. Additional bolus of
      analgesic supplements (fentanyl 1µg.kg-1) will be given when the mean arterial pressure (MAP)
      or heart rate exceeds 25% of the baseline <50. If hypertension or tachycardia persists with a
      BIS≤50, either nitroglycerine infusion or esmolol will be used. In conditions of hypotension,
      inotropic support and/or vasopressor will be initiated after ensuring normovolaemia. Atropine
      sulphate will be used to treat bradycardia (heart rate <45b.p.m.) after excluding other
      treatable causes. The MAP on CPB will be maintained between 50 and 80 mmHg using
      phenylephrine / nitroglycerine as required. Systemic hypothermia up to 28ºC will be practiced
      during CPB and patients will be actively re-warmed to 36ºC before separation from CPB.

      The number of patients exhibiting episodes of hypotension or hypertension and the number of
      episodes of hypotension or hypertension requiring a change in the propofol target
      concentration or the administration of any vasoactive drugs will be recorded.

      Based on response of the previous patient to propofol administration using Diprifusor at a
      predetermined target plasma propofol concentration (Cp), further increments or decrements of
      Cp in the subsequent patients will be based on Dixon's up and down method. The target Cp will
      be increased by 0.2 µg.ml-1 in patients who do not achieve BIS of 50 and Cp will be is
      decreased in subsequent cases by 0.2µg.ml-1 in patients who do. Thus, six to eight pairs of
      failure to success transition will be needed for calculation of the EC50 (i.e. the target
      concentration at which 50% of the patients achieve BIS of 50). The mean of the mid value of
      these transitions will be used to derive the EC50.

      At the end of the study the BIS data will be analyzed for offline determination of induction
      time. It is defined as the time at which the BIS reaches ≤50 for 2 consecutive readings from
      the start of propofol infusion.

      Group 2:

      In the CLADS group induction and maintenance will be carried out automatically according to
      the BIS. Hemodynamics will be controlled automatically through CLADS as well as through
      manual ionotropic support as described above.

      CLADS is a pharmacodynamic-pharmacokinetic model-based adaptive infusion system, which uses
      BIS as the controlled variable and standard infusion pump as the 'actuator'. The 'control
      algorithm' is based on the relation between various rates of propofol infusion (producing
      different plasma concentrations) and BIS, taking into consideration the pharmacokinetic
      variables (distribution, clearance). This was established in the developmental stage of
      CLADS. The algorithm alters the rate of propofol infusion to steer and maintain BIS to the
      set target taking into account existing BIS, time-elapsed since the initiation of infusion,
      pharmacokinetics, time-delay factor between sensing and averaging of BIS data, time-delay
      factor between change in infusion rate and actual change in the plasma concentration of
      propofol, as well as the peak effect of propofol.

      An IBM-compatible PC with PENTIUM 4 or higher processor is used to implement the control
      algorithm, provide a user interface, and control communication through serial ports (RS 232)
      with infusion system (Pilot-C; Fresenius, Paris, France) and vital sign monitor (AS5; Datex
      Ohmeda Division, GE Healthcare, Singapore). The drug delivery can operate in two modes
      -manual and automatic. In manual mode, rate of propofol infusion is controlled manually
      through the keyboard. In 'automatic' mode, the system automatically controls propofol /
      isoﬂurane administration as per the control algorithm. The automatic mode further has three
      options: (i) induction, (ii) maintenance, and (iii) induction combined with maintenance. The
      user must enter a target BIS value, age, weight, height along with the status of patient-low
      risk (ASA I-III), high risk (ASA III-IV, NYHA class III), very high risk (ASA IV-V, NYHA
      III-IV), or pediatric. The system can also function in 'monitor' mode, where it only updates
      BIS and other patient data and provides a graphic display of current and trend values.

      The system updates the electroencephalographic data every 5 s and calculates the BIS error
      (target BIS-actual BIS). It uses PID (proportional integral differential) algorithm based on
      this error to make the changes in propofol infusion rate to achieve target BIS. The algorithm
      ﬁne tunes the rate and duration of propofol delivery differently during induction and
      maintenance phases of anesthesia delivery. During induction, controller tries to achieve the
      target concentration in a stepwise fashion (while continuously receiving feedback of BIS
      every 5 s) on the basis of the relationship between plasma concentrations and BIS. During
      maintenance, 30 s is deemed as one epoch. The initial three as well as the last three BIS
      values of each epoch are averaged and compared to assess the trend. When the trends indicate
      an increasing BIS, higher target concentrations and so higher propofol rates are set and vice
      versa if the trends indicate a decreasing BIS. These trends are also cross-checked with
      larger epoch trends before making drug alterations.

      A safety feature has been added wherein propofol and other anesthetics are stopped
      automatically whenever hemodynamics drops below the safety limits set by the operator. This
      would restart automatically when hemodynamics improves to values above the predeﬁned lower
      limit. The time delay for this automatic cut-off is at the most 10 s, which is the interval
      at which the vitals are updated in the controller.

      Time to achieve loss of consciousness, dose of propofol required for induction and
      maintenance, BIS overshoots and hemodynamics will be recorded in patients administered
      propofol using CLADS.

      At the end of the surgery, CLADS/TCI will be discontinued and patient will be shifted to the
      post-surgical intensive care unit for elective mechanical ventilation.

      STATISTICAL ANALYSIS- Physiologic data are presented as mean (SD) and time intervals are
      presented as median (range). The performance of the system was assessed by calculating median
      performance error (MDPE), median absolute performance error (MDAPE), wobble and divergence
      (time related trends) using methods of Varvel et al.

      The performance error is given by the formula:

      PE = [(BISmeasured-BIStarget)÷BIStarget]×100 The median performance error (MDPE) which
      reflects the bias of CLADS in the ith subject is determined as MDPE=median {PEij
      j=1........Ni } where Ni is the number of (PE) values obtained in the ith sub Median
      Performance Error (MDPE) Median Absolute Performance Error (MDAPE)= median {I PEij
      j=1........Ni I} Wobble is determined from the equation Wobble=median {I PEij - MDPEiI ,
      j=1......Ni }

      Global Score (GS) - The Global Score is used to score EEG-guided depth of anesthesia control
      systems with one scalar:

      GS=(MDAPE+WOBBLE)÷fraction of time BIS∈(40,60) Divergence is the slope of the linear
      regression equation of absolute performance error against time and is expressed in units of
      percentage divergence per minute. A positive value indicates progressive widening of the gap
      between targeted and measured values, whereas a negative value indicates that the measured
      values are converging on target. MDPE and MDAPE are measures of bias and precision,
      respectively, wobble measures the intra- individual variability in the performance errors.
      The percent of time when BIS remains within ±10 of target BIS during closed-loop (CLADS
      group) or manual control (TCI group) will also be calculated. Adequacy of hemodynamic control
      will be adjudged by the percentage of anesthesia time the mean arterial blood pressure and
      heart rate (HR) are within ±25% of baseline.

      Differences between the groups will be analyzed using the unpaired t-test for parametric data
      and the Mann- Whitney U test for non-parametric data. Count data will be analysed using the
      chi-square test. All analyses will be performed using SPSS v21.0 for Windows (SPSS Inc.,
      Chicago IL, U.S.A.) and a P value <0.05 will be taken to be significant.

      For calculation of the EC50 (plasma concentration at which 50% patients achieve a BIS) of
      propofol required for induction will be calculated using Dixon and Massey method. Six to
      eight pairs are necessary to calculate EC50 from Dixon up and down method. Probit analysis of
      the data for TCI group will be then performed to determine EC50 and EC95.

      From a pilot study, the investigators estimated that manual control using TCI maintained BIS
      in the range of ±10 of the target 70% of the time. In order to assess the 20% improvement
      from this control, the investigators calculated that they would need to recruit 36 patients
      to achieve 80% power at 5% Type I error. A total of 40 patients were recruited, taking into
      account possible inadvertent patient attrition.
    

Intervention name(s): Target Controlled Infusion; Closed Loop Anesthesia Delivery System
Intervention type(s): Device; Device
Intervention description(s): Used to control intravenous propofol delivery with target plasma concentratioins changed manually; Used to deliver propofol automatically titrated to achieve a target BIS 50, and maintain it between 40 and 60.
Intervention MeSH terms: Anesthetics
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Health Services Research
Keywords: Closed Loop Anesthesia Delivery System; Target Controlled Infusion