Validation of the Bispectral Index Monitor During Living Donor Liver Transplantation
Condition: Liver Cirrhosis
MeSH terms: Liver Cirrhosis
Study type: Observational

Summary: 
      Bispectral index (BIS) monitoring during living donor liver transplantation (LDLT) may be
      influenced with several factors rather than the depth of anesthesia such as bradycardia,
      hypotension, hypothermia, and mixed venous oxygen saturation (SvO2). The investigators tested
      the validity and the independent factors which may alter of BIS readings during LDLT.

      Up to the investigators best knowledge, the independent predictors for BIS monitoring were
      not identified yet during the three phases of liver transplantation.
    

Detailed description: 
      Forty two American Society of Anesthesiologists physical class III-IV patients aged 20-50
      years with severe liver dysfunction (Child-Pugh Class C) due to liver cirrhosis undergoing
      living donor liver transplantation in the Mansoura University Liver Transplantation Program
      from 2007 to 2010 were included in this prospective, observational study after obtaining
      approval of the local ethical committee and an informed written consent from all
      participants. The etiology of liver cirrhosis was hepatitis C, Budd Chiari syndrome,
      hepatocellular carcinoma and autoimmune in all patients.

      Anesthetic technique was standardized for all patients. All patients received preoperative
      intravenous 40 mg of pantoprazole. Patients were monitored with three leads
      electrocardiography, pulse oximeter, and noninvasive blood pressure. BIS recording electrodes
      (Aspect Medical Systems. Inc., One Upland Road, Norwood, MA 02062 USA) were applied to the
      forehead of each patient according to the manufacturer recommendations. The BIS monitor was
      masked with opaque sheet and BIS data was recorded prior to induction of general anesthesia
      then continued throughout the procedure. All information obtained from the BIS monitor was
      continuously downloaded to a computer for offline analysis. The patient's management was not
      guided by the changes in BIS readings. Before induction of anesthesia, all patients were
      premedicated with 1-2 mg of intravenous midazolam.

      Independent anesthetists, who were not involved in the collection and analysis of the
      patient's data, provided the perioperative anesthetic management. After preoxygenation,
      anesthesia was induced with lidocaine 0.75 mg/kg, propofol 1.5-2.0 mg/kg and fentanyl 2µg/kg.
      Rocuronium 1-1.2 mg/kg was given to suppress the first response on the train-of-four (TOF)
      stimulations of the ulnar nerve. After tracheal intubation, the lungs were ventilated with an
      inspired fraction of oxygen (FiO2) of 0.4 to maintain an arterial carbon dioxide tension at
      35-45 mm Hg and monitoring of end-tidal carbon dioxide and sevoflurane concentration, direct
      arterial pressure monitoring through a radial artery catheter and a tympanic membrane
      temperature were implemented.

      A 7.5 Fr continuous thermodilution fiberoptic pulmonary artery catheter (CCO/SvO2) Edwards
      Life Science, Irvine, CA, USA) was floated through the right internal jugular vein to the
      right pulmonary artery using waveform and fluoroscopic guidance to measure cardiac output
      using Angstrom AS5 Monitor (Datex - Ohmeda AS5, Microvitec Display LTD, Bolling Road,
      Bradford, UK). The final position was confirmed by fluoroscopy and when PAOP less than
      pulmonary artery diastolic pressure (PADP).

      Anesthesia was maintained with 0.5-1.5 minimum alveolar concentration (MAC) of sevoflurane
      and continuous intravenous infusion of fentanyl (1-3 µg/kg/h) titrated to maintain the mean
      arterial blood pressure (MAP) and heart rate (HR) within 20% of their baseline values.
      Rocuronium 0.1-0.3 mg/kg/h was used to maintain suppression of the second twitch in the TOF.

      Normothermia was maintained using intravenous infusions of warm fluid and blood products and
      water-filled thermal mattress according to the authors' protocol. Fluid boluses were given in
      250 ml aliquots of either 5% hydroxyethyl Starch 130/0.4 (Voluven® 6%, Fresenius Kabi, Bad
      Hombourg, Germany) as needed to maintain the CVP and/or PAOP between 5 and 7 mm Hg and the
      stroke volume (SV) within 20% of its baseline value. Albumin 5% was given as needed to treat
      hypoalbuminemia. Transfusion of salvaged blood from the cell saver and packed red blood cells
      was administered as clinically indicated to maintain a hemoglobin level ≥7 g/dL.
      Intraoperative changes in electrolyte levels and acid-base balance were regularly monitored
      and treated as appropriate. Hemodynamic control was standardized according to the authors'
      center protocol. Hypotension (MAP decreased < 20% from the mean baseline and SVR < 600
      dyne.sec-1.cm-5) was treated with boluses of fluids, ephedrine 5 mg, or epinephrine 5 µg, as
      needed. Norepinephrine infusion was used for persistent hypotension with low SVR. Dobutamine
      or epinephrine infusion was administered if the MAP was ≥ 70 mm Hg, CVP and/or PAOP ≥ 7 mm Hg
      and the cardiac output was < 4.0 L. min-1. Hypertension (MAP increased > 20% from the mean
      baseline) was treated with deepening of anesthesia, bolus doses of nitroglycerin 0.05 mg or
      labetalol 20 mg. Tachycardia (HR > 20% from the baseline values) was treated with boluses of
      esmolol 20 mg.

      All operations were performed by the same surgeons using the piggyback technique. After
      portal vein clamping, infusion rates of fentanyl and rocuronium were reduced by approximately
      50%. Fentanyl and rocuronium infusions were discontinued after peritoneal closure. After
      completion of skin closure, sevoflurane was discontinued. The patients were transferred to
      the ICU immediately after surgery, while intubated and postoperative analgesia was achieved
      with rescue boluses of fentanyl 0.5 µg/kg when needed.

      Extubation criteria included cooperative, alertness, train-of-four ratio ≥ 0.9, spontaneous
      breathing with tidal volume > 5 mL/kg, respiratory rate > 10 and < 28 breaths/min, maximum
      inspiratory pressure ≤ -20 cm H2O, stable hemodynamics, minimal bleeding, core temperature >
      35.5°C, urine output > 0.5 mL/Kg/h, arterial carbon dioxide tension ≤ 45 mm Hg, arterial
      oxygen tension > 100 mm Hg and FiO2 < 50%.

      On the second postoperative day, the patients were asked about perioperative awareness and
      recall by asking three simple questions using standard interview "What was the last thing you
      remembered happening before you went to sleep? What is the first thing you remember happening
      on waking? Did you dream or have any other experiences whilst you were asleep?" Another
      investigator, who was not involved in the patient's management, collected the saved patients'
      data. Preoperative MELD score, durations of warm ischemia and anhepatic phase, intraoperative
      blood loss and fentanyl consumption were collected. Preoperatively (baseline) absolute values
      and intraoperative average values for BIS, Et-Sevo, heart rate (HR), MAP, CVP, MPAP, CO,
      PAOP, SVR, PVR, core temperature, pH, PaCO2, PaO2, SaO2 SvO2, and PvO2 were recorded during
      hepatic dissection, anhepatic, and neohepatic phases and during surgical closure.
      Postoperative total bilirubin, albumin level, liver enzymes (AST, ALT, GGT, and alkaline
      phosphatase), PT, factors V and VII, time to extubation, ICU and hospital length of stays,
      neurological complication, encephalopathy and 3 months-mortality were recorded.

      Data were tested for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis
      of variance was used for analysis of serial changes in the patients' data at different times.
      Fisher exact test was used for categorical data. Postulated independent predictors of BIS
      readings included age, gender, MELD score, durations of surgical phases and warm ischemia,
      Et-Sevo, average of intraoperative hemodynamic, temperature, oxygenation and acid base
      variables, intraoperative blood loss and fentanyl consumption, were examined in a stepwise
      manner into a multiple regression model, with entry and retention set at a significance level
      of P < 0.05 and removal set at P ≥ 0.1. Moreover, multivariate logistic regression was done
      to identify the correlations between BIS values and blood loss, time to tracheal extubation,
      postoperative liver function and coagulation variables, ICU length of stay, and 3
      months-mortality.

      To evaluate the accuracy of BIS in predicting survival rate after liver transplantation,
      receiver operating characteristic (ROC) curves were generated to describe the performance
      characteristics of the BIS readings during different phases of surgery in predicting the
      survival outcome. An ROC area of 1.0 is characteristic of an ideal model, whereas an area of
      0.5 indicates a model of no diagnostic value. Cutoff values for mortality with the best
      diagnostic sensitivity and specificity were derived from the ROC curve analyses. Unweighted
      accuracy ((sensitivity + specificity) / 2) was also reported.

      The studied patients were further divided according to their outcome variables into survivors
      (n = 32) and non-survivors (n = 10) subgroups. Independent Student-t- and Mann Whitney tests
      were used as appropriate. Data were expressed as mean (standard deviation), number (%), or
      median [range]. A value of P < 0.05 was considered to represent statistical significance.
    

Intervention name(s): Bispectral index monitoring (BIS)
Intervention type(s): Device
Intervention description(s): BIS recording electrodes (Aspect Medical Systems. Inc., One Upland Road, Norwood, MA 02062 USA) were applied to the forehead of each patient according to the manufacturer recommendations. The BIS monitor was masked with opaque sheet and BIS data was recorded prior to induction of general anesthesia then continued throughout the procedure. All information obtained from the BIS monitor was continuously downloaded to a computer for offline analysis. The patient's management was not guided by the changes in BIS readings.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Mansoura University Liver Transplantation Program
      
Keywords: Bispectral index; anesthesia; liver transplantation; independent factors; outcome; Living donor liver transplantation