Propofol-based total intravenous anesthesia (TIVA) has been used successfully for liver transplantation (LT) in recent years. However, there are few discourses in the literature which focus on the merits and weakness in perioperative management, biochemical changes, and postoperative recovery between TIVA and desflurane anesthesia (DES).
We retrospectively compared the circumstances of liver transplantation recipients who had the surgery carried out under propofol-based TIVA or DES in the period from September 2007 to August 2010. Preoperative characteristics, date of intraoperative management, hemodynamic profiles, concentration of anesthetics, biochemical changes, and circumstances of postoperative recovery were retrieved from the hospital database for analysis.
We included 111 patients who received the surgery under either TIVA (n = 66) or DES (n = 45). Patient demographics, baseline laboratory data, operation time, and fluid management did not differ between the two groups. In comparison with the DES group, fewer patients had to be administered norepinephrine (21.2% vs. 42.2%; p = 0.020) in the TIVA group; moreover, the total dosage of norepinephrine was lower (0.003 ± 0.005 mg vs. 0.006 ± 0.008 mg; p = 0.012) in the TIVA group during liver reperfusion phase. Blood lactate level was higher in the DES group than in the TIVA group after the anhepatic phase. TIVA patients woke up faster than those in the DES group (54.0 ± 33.4 minutes vs. 95.0 ± 78.3 minutes; p = 0.034).
Our results suggest that propofol-based TIVA may provide better hemodynamics and microcirculation during the anhepatic phase in liver transplantation.
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Inhalation anesthesia is still the mainstream for liver transplantation (LT) because volatile anesthetics have little influence on liver function and their concentrations could be measured in real time. Previous studies have shown that propofol-based total intravenous anesthesia (TIVA) offers faster emergence and better quality of recovery, causes lower incidence of postoperative nausea and vomiting, and shortens the discharge time of patients in general surgeries.1, 2, 3, 4, 5 However, the benefit of propofol-based TIVA has not been tested in LT due to the unpredictable pharmacokinetic response of propofol. Recently, TIVA with continuous propofol infusion had been used successfully for LT.6, 7, 8 In studies of LT with propofol-based TIVA, a significant increase of plasma propofol was observed in the anhepatic phase; it might lead to overdose of propofol and compromise the intraoperative hemodynamics.
Target-controlled infusion (TCI) devices allow anesthesiologists to provide safe anesthesia by controlling the theoretical target concentration of the drug. Wu et al7 have demonstrated that the Marsh pharmacokinetic model of TCI is not suitable for LT patients and suggested that anesthesiologists should use an effective parameter, such as the bispectral index, spectral entropy, or auditory evoked potential (AEP), to monitor and control the propofol level during LT. Regarding the propofol pharmacokinetics during the anhepatic phase, a case series also advocated the use of bispectral index to monitor the titration of propofol during TCI.8 The composite arterial-line autoregressive index (AAI) of the AEP monitoring has been suggested as an adequate parameter for monitoring the anesthetic depth,9, 10, 11, 12, 13, 14, 15 which has been routinely used in our anesthesia for LT. We have had established protocols for LT in the past years and overcome the difficulty of using propofol-based TIVA by the aid of AEP and TCI, but we are eager to know its benefits. Therefore, the aim of this retrospective study was to compare the perioperative management, biochemical changes, and postoperative recovery between propofol-based TIVA and desflurane anesthesia (DES).
After the approval by the Institutional Review Board of Tri-Service General Hospital Taipei, Taiwan, medical records of all the LT recipients who received the organ from primary deceased donors (donation following brain death) or partial organ from living donors were collected and reviewed. Liver recipients who underwent LT under TIVA with propofol (TIVA group) or under DES (DES group) were enrolled during the 3-year study period (from September 2007 to August 2010). The exclusion criteria were as follows: the presence of encephalopathy, requirement for pretransplant endotracheal intubation with mechanical ventilation, or use of vasopressors prior to transplantation.
Anesthetic and surgical managements were pursuant to the institute's standard protocol of LT, and were entrusted to a special team of anesthesiologists and surgeons. The use of TIVA or volatile anesthesia was according to the choice of the anesthesiologist in charge.
Our routine practice in TIVA was as follows: induction of anesthesia was made possible with intravenous fentanyl (1–2 μg/kg) and lidocaine (2%, 1 mg/kg), followed by administration of propofol of an effective concentration (Ce) (3-5 μg/mL) via the TCI system (Fresenius Orchestra Primea, France). Rocuronium bromide (0.6 mg/kg) was administered after the loss of eyelash reflex and the endotracheal tube was placed 90 seconds later. Anesthesia was maintained with propofol administered via the TCI system and 100% oxygen at a flow rate of 0.3 L/minute was given; repetitive bolus of cisatracurium and fentanyl was prescribed as needed throughout the procedure.
Our routine practice for DES anesthesia was as follows: anesthesia was induced with intravenous fentanyl (1–2 μg/kg), lidocaine (2%, 1 mg/kg), and propofol (2 mg/kg). After loss of eyelash reflex, rocuronium bromide (0.6 mg/kg) was administered for endotracheal intubation. Anesthesia was maintained by desflurane in 100% oxygen with wash-in at 2 L/minute for 15 minutes, followed by a flow rate of 0.3 L/minute thereafter. The desflurane concentration or Ce of propofol was reduced or increased by 2% and 0.5 μg/mL, respectively, in order to keep the AAI within 15–25 throughout the operation, as suggested by the AEP Monitor/2 (Danmeter A/S, Odense, Denmark). The ventilation rate and maximum airway pressure were adjusted to maintain the end-tidal carbon dioxide at 35–45 mmHg. Attempts were made to maintain the core body temperature at > 36°C by warming all intravenous fluids and blood products, and using a conventional warming device.
Demographics and pretransplant characteristics were retrieved, including age; sex; height; weight; etiology of liver disease; history of chronic systemic hypertension, diabetes mellitus, ascites, and variceal bleeding; and requirements for pretransplant hemodialysis. Baseline laboratory data, including hematocrit, international normalized ratio (INR) of prothrombin time (PT), blood urea nitrogen, serum creatinine, serum potassium (K+), platelet count, albumin, total bilirubin, alanine aminotransferase (ALT), and base excess, were also recorded (Table 1).
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Our perioperative monitoring items, which included pulse oximetry, electrocardiography, invasive blood pressure, and central venous pressure, were surveyed pursuant to our institution standards. Three electrodes (A-Line AEP electrodes; Danmeter A/S) were positioned at the mid-forehead (+), left forehead (reference), and left mastoid (−). Continuous cardiac output (CO) monitored by the PiCCOplus system was essential in all recipients. A 4-French thermistor-tipped arterial catheter (Pulsiocath thermodilution catheter) was inserted into the right femoral artery, and its tip was advanced to the abdominal aorta and connected to a stand-alone PiCCOplus monitor (software version 6.0; Pulsion Medical Systems, Munich, Germany). Coagulation function is guided by the thromboelastogram. Record the effective concentration (Ce) of propofol and end-tidal concentration (FE%) of desflurane, calibration of the PiCCOplus system, measurement of cardiovascular parameters and coagulation function, and arterial blood gas analysis were performed and recorded at the following time points: 10 minutes postintubation (T0); 60 minutes (T1) and 120 minutes (T2) after the start of the dissection phase; 10 minutes after the start of the anhepatic phase (T3); 10 minutes prior to the end of the anhepatic phase (T4); 10 minutes (T5), 50 minutes (T6), and 90 minutes (T7) after the start of the neohepatic phase; and end of surgery (T8).
Fluids and blood products were administered if clinically indicated, and hemoglobin was maintained at 9–11 g/dL throughout the procedure. Management in the intraoperative course of LT was registered by collecting the following data: transfusion requirements for each blood component (packed red blood cells, fresh frozen plasma, cryoprecipitate, and platelets), intraoperative estimated blood loss, urine output, fluid infusion, administration of intravenous insulin (continuous infusion or bolus for hyperkalemia prophylaxis or treatment), duration of the anhepatic phase and operation, requirement for intraoperative vasopressors, and norepinephrine use during reperfusion. The use of intraoperative vasopressors was defined as administration of epinephrine, norepinephrine, vassopressin, or dopamine, or that of epinephrine or norepinephrine in boluses during LT to maintain the mean arterial blood pressure of >60 mmHg or cardiac index of at least 2.5 L/minute/m2 after adequate fluid resuscitation (stroke volume variation < 12%). After reperfusion, boluses of norepinephrine might be used to keep the mean arterial pressure >60 mmHg or within 30% of pre-reperfusion systolic arterial pressure. The antifibrinolytic agent tranexamic acid was used for coagulation rescue guided by the thromboelastogram. After the surgery, the patients were sent to the surgical intensive care unit (ICU) for further management. Time to opening eyes was recorded by the ICU staff. The criteria for extubation and weaning protocol at our ICU were as follows: the initial step was to identify patients who could be candidates. All candidates should have adequate arterial oxygenation at an FiO2 of ≤0.5, with an extrinsic positive end-expiratory pressure of ≤5 cmH2O, and their respiratory frequency was ≤35 breaths/minute, tidal volume ≥5 mL/kg of body weight, maximum inspiratory pressure lower than −20 cmH2O, and rate/tidal volume <105/minute/L. The patients were allowed to breathe humidified O2 spontaneously with a T-piece for 1 hour. If they could tolerate the trial well, extubation could be carried out without question.
Postoperative recovery outcomes, including awake time (the time elapsed between discontinuation of anesthetics and opening of eyes), extubation time, time to normal INR or PT time, ICU stay, vasopressor requirements during ICU stay, and days in hospital were reviewed and compared. ALT concentration at 24 hours after transplantation was also compared.
2.1. Statistical analysis
The primary endpoint was the norepinephrine use during reperfusion. Secondary outcome variables were the awake time, extubation time, normal INR or PT time, ALT concentration 24 hours after transplantation, ICU stay, and days in hospital.
All data are expressed as mean (standard deviation) or in percentages. Statistical analyses were performed using the SPSS 12.0 for Windows (SPSS Inc., Chicago, IL, USA). The means of two groups were compared by Student t test, following the conversion of raw data into a logarithmic scale when appropriate. Categorical variables were analyzed by the Chi-square test or Fisher's exact tests for proportions, and continuous variables by two-tailed unpaired t tests (Bonferroni t test). A p value of <0.05 was considered significant.
In order to enhance the comparability between TIVA or DES treatments, we performed a case matching analysis for the primary endpoint. We chose cadaveric donor LT/living donor LT, Child–Pugh’s classification, the model for end-stage liver disease score, and age (±10 years) as the matching variables (Table 2).
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We reviewed 111 patients who received either of the following anesthetic techniques: TIVA (n = 66) or DES (n = 45). There was no difference between the two groups of patients in terms of demographics, preoperative clinical characteristics, and baseline laboratory data (Table 1). The three main causes of LT were hepatitis B cirrhosis (54.1%), hepatitis C cirrhosis (21.6%), and alcoholic cirrhosis (16.2%). The mean pretransplant model for end-stage liver disease score was 10.4 ± 3.0 for the TIVA group and 10.0 ± 3.4 for the DES group (Table 1). There was no significant difference in patients receiving cadaveric donor LT (45.5% vs. 40.0%) or living donor LT (54.5% vs. 60.0%) between two groups (Table 1). No significant difference was observed between the two groups with respect to the intraoperative use of vasopressors (15.2% of TIVA vs. 20.0% of DES; p = 0.06; Table 3). Both patient percentages received norepinephrine (21.2% vs. 42.2%; p = 0.02), and the total dosage of norepinephrine (0.003 ± 0.005 mg of TIVA vs. 0.006 ± 0.008 mg of DES; p = 0.012) during reperfusion was significantly lower in the TIVA group than that in the DES group (Table 3). There was no significant difference in operation time (9.4 ± 2.1 hours vs. 9.0 ± 1.6 hours), fluid management, blood transfusion, and use of insulin (37.9% vs. 55.6%) between groups (Table 3). Moreover, no significant difference was observed in intraoperative hemodynamic parameters between groups (Fig. 1). Blood lactate concentration was significantly increased after the anhepatic phase in the DES group than in the TIVA group (Fig. 2).
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The Ce of propofol and FE% of desflurane are shown in Fig. 3. There were no significant differences in the FE% values of desflurane with time. In TIVA patients, the Ce of propofol at the anhepatic phase (T3, 1.2 ± 0.8 μg/mL; T4, 1.0 ± 0.6 μg/mL) were significantly lower than those in the baseline and paleohepatic phase (T0, 2.5 ± 0.7 μg/mL; T1, 2.2 ± 0.8 μg/mL; T2, 2.0 ± 0.9 μg/mL; p < 0.05). An increase in the Ce of propofol was observed after reperfusion and 10 minutes prior to the end of the anhepatic phase (T4, 1.0 ± 0.6 μg/mL); it was significantly lower than that at 90 minutes of the neohepatic phase (T7, 1.3 ± 0.7 μg/mL; p < 0.05) and at the end of surgery (T8, 1.4 ± 0.7 μg/mL; p < 0.05; Fig. 3).
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TIVA patients waked up faster (54.0 ± 33.4 minutes in TIVA vs. 95.0 ± 78.3 minutes in DES; p = 0.034), but the extubation time (12.5 ± 13.0 hours in TIVA vs. 20.5 ± 18.7 hours in DES; p = 0.126), ICU stay (84.2 ± 127.4 hours in TIVA vs. 103.6 ± 167.9 hours in DES; p = 0.504), and hospital days (24.8 ± 18.1 days in TIVA vs. 24.5 ± 25.5 days in DES; p = 0.960) were similar in both the groups (Table 4). No significant difference was observed in plasma ALT concentrations between the two groups 24 hours after transplantation as well as in the INR (Table 4). No patient reported awareness during the operation.
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The major finding of our study is that AAI-guided propofol-based TIVA via TCI appears to be a reasonable alternative of, if not a substitute for, DES for LT because it may provide better hemodynamic stability and microcirculation during the anhepatic phase and earlier recovery.
4.1. Pharmacological changes of propofol during LT
LT is a unique pharmacokinetic situation, and the anhepatic phase is associated with 42% decrease of the apparent systemic clearance of propofol in comparison with the dissection phase.6 Hemodynamic instability may be noted for magnitudinous changes of volume status, and it indicated that the hemodynamic change cannot serve as a reliable guide for the anesthetic depth. Moreover, hemorrhage and subsequent volume replacement can alter propofol kinetics and concentration.16 Researchers have investigated the influence of blood loss on the pharmacology of propofol: an equivalent dosing leads to a higher drug concentration in the setting of severe blood loss than in euvolemic/normotensive condition.17, 18, 19 In addition, a reduced CO will influence the pharmacokinetics of propofol by reducing the hepatic blood flow and possibly decelerating the distribution of blood to peripheral tissues; the venous return may be reduced by cross-clamping of the portal vein and inferior vena cava, and so CO significantly reduced to subsequently affect the clearance of propofol during the anhepatic phase. This may explain the reduction of target propofol concentration observed in this phase in all patients of the TIVA group. Therefore, TCI alone appears to be inadequate to adjust propofol concentration to achieve the desired target depth of anesthesia during LT, and AAI or bispectral index may be used to facilitate propofol adjustment.7 Because of the feasibility of the facility, we routinely used AEP monitoring in our LT patients.
4.2. Utilization of anesthetic depth monitoring for propofol adjustment in LT patients
Our data support that AEP monitoring is a useful tool to guide TCI propofol adjustment in LT patients. A good compromise was found between the anesthetic depth and hemodynamic stability under an AAI value between 15 and 25. Moreover, a significant reduction of target propofol concentration was observed in all patients during the anhepatic phase compared with the dissection phase. It has been reported that propofol pharmacokinetic is influenced by CO.20, 21 In our observation, no significant difference in cardiac index was observed during the two phases; therefore, the reduction of propofol target concentration, according to the AAI, to maintain adequate anesthetic depth might be due to the decrease of the systemic clearance of propofol during the anhepatic phase secondary to liver exclusion rather than CO change. Therefore, using AAI to adjust target propofol concentration, instead of guidance by the hemodynamic changes, could be safe in LT patients, because plasma concentration might be variable in each patient in different phases of LT.
4.3. With AAI and TCI, TIVA leads to an even earlier recovery despite unpredictable pharmacokinetic response in LT patients
TIVA of propofol incorporating the use of remifentanil has been shown to provide more rapid emergence from anesthesia than other anesthetic techniques.22, 23 In a randomized controlled study, an earlier discharge was reported when propofol was used compared with desflurane for laparoscopic cholecystectomy.1 In our previous studies, we found that propofol-based TIVA with TCI provided faster emergence and better quality of recovery than desflurane and sevoflurane in laparoscopic gynecologic and prolonged lumbar spine surgery.2, 3, 4 In the present study, propofol-based TIVA provided faster emergence compared with DES. This may be explained by the fact that a prolonged anesthesia procedure increases the emergence time because the inhaled desflurane is redistributed in the fatty tissue and muscle, and the optimal effective site concentration of propofol can be maintained and there is less accumulation in the TIVA with TCI during AEP monitoring.
4.4. Does TIVA provide better cardioprotection and microcirculation than DES during ischemia–reperfusion in LT patients?
Many studies had reported that propofol could provide protection against ischemia–reperfusion injury, namely, cardioprotection,24, 25, 26, 27, 28, 29 neuroprotection,30 renoprotection,31 and hepatoprotection,32, 33 via many pathways. The antioxidant properties of propofol on ischemic reperfusion-induced formation of lipid peroxides in liver transplant recipients,32 which significantly decreased the leakage of liver enzymes and markedly reduced lesions in histologic examination of the liver in ischemia–reperfusion injury in rabbit model,33 were demonstrated.
Propofol was also reported to have free radical scavenging property, providing both vascular and cardiac protection against ischemic–reperfusion injury.24, 25, 26, 27, 28 In addition, Li et al29 reported that propofol provided a postconditioning protection effect through prosurvival signal transduction pathways. Recently, Liang et al30 showed that propofol could exert its postconditioning neuroprotective effects, in an animal model, on brain ischemia–reperfusion injury partially through the induction of the heme oxygenase-1 expression. Propofol also conveyed renoprotection against ischemia–reperfusion injury by preservation of antioxidation ability and attenuation of inflammatory response in hyperglycemic rats.31 In the present study, we first found that propofol-based TIVA required a lower norepinephrine dose to maintain stable hemodynamics than DES during the reperfusion phase of LT. Lactate has been shown to monitor the microcirculation conditions during anesthesia. In our study, we found that blood lactate concentration was higher in the DES group than in the propofol-based TIVA group during the anhepatic phase; it is likely that TIVA provided a better microcirculation than DES during the ischemia–reperfusion phase in LT patients. However, due to the limitations of a retrospective study, it is impossible to conclude that propofol-based TIVA is better than DES. Further prospective studies are absolutely necessary to explore the effect of propofol on cardiac protection against ischemia–reperfusion injury in LT patients.
4.5. Postreperfusion injury, graft function, and recovery outcome
Ischemia–reperfusion injury in LT can result in significant graft dysfunction in the postoperative period. ALT is commonly used to assess graft injury after LT, and factors such as ischemic time and vascular anastomosis steatosis may influence the level of ALT.34 Moreover, normal INR or PT is also used to assess the graft function after LT. In our study, no significant difference was observed between groups in ALT 24 hours after surgery. Normal INR and ALT were suggestive of a similar effect on the postreperfusion injury and graft function by two anesthetic techniques; this also suggested that no patient suffered from postreperfusion syndrome. Extubation time was similar in the two groups, which might be due to the fact that we sedated patients overnight after surgery and we tested their weaning profiles in the morning.
There are several limitations in this study. First, the reliability of a parameter derived from AEP for setting an anesthetic dose has not yet gained widespread acceptance. In addition, the AEP system is not used anymore. Our data appear to show greater hemodynamic stability and better anesthetic maintenance with propofol-based TIVA than with desflurane, although AAI may be affected differently by different anesthetic agents in the same depth of anesthesia produced. Second, plasma propofol concentrations were not measured. Propofol Ce is just a predicted concentration of propofol from TCI and the predicted amount and rate of drug administration. Therefore, a lack of parallelism in the time course of propofol Ce and arterial blood concentrations cannot be ruled out. Third, a retrospective medical data review in a single center has great limitations. The results of this study may not apply to other centers, because the patient populations and disease severity index vary from center to center. Fourth, although the management of intraoperative variables was standardized, individual practitioner preferences during patient allocation and intraoperative hemodynamic management may influence the results of the study. Fifth, the donor characteristics and quality of the graft might also influence the postoperative recovery, which was not addressed in the study. Lastly, in the present study, we found that propofol-based TIVA required fewer norepinephrine doses during the reperfusion phase and lower blood lactate concentration during the anhepatic phase than DES. However, it is impossible to conclude whether propofol-based TIVA is better than DES clinically.
AAI is a good parameter to guide propofol-based TIVA in LT. Regarding the alteration of propofol pharmacokinetics during LT, this study advocates the usefulness of AEP monitor to titrate propofol infusion using TCI, which can result in an earlier recovery, better hemodynamic stability, and microcirculation possible. A further prospective study should be performed in order to determine whether propofol-based TIVA given by TCI would result in an improvement in the perioperative anesthetic management and postoperative recovery outcomes in patients undergoing LT.
No financial support or funding has been received from any organization for this study.