Acute systemic hypotension frequently occurs immediately after reperfusion of the liver graft during orthotopic liver transplantation surgery. If a greater than 30% decrease in the mean arterial pressure (MAP) lasting more than 1 minute is observed within 5 minutes after reperfusion, postreperfusion syndrome (PRS) is diagnosed.1 The reported incidence of PRS varies greatly (12%-81%) with the study design.2-5 Typically, PRS is handled once it occurs instead of being proactively prevented because of its unpredictability and unclear underlying mechanism. However, because of the high incidence of PRS and its associated adverse effects, it seems reasonable to search for preventive measures.2, 4, 6-8
The piggyback technique and liver graft flushing are proven surgical prophylaxis methods for reducing PRS.9-11 Another approach with varying degrees of success is pharmacological pretreatment, which is focused on blocking presumed causes of PRS such as ischemia/reperfusion cascades and their final products.5, 12-15 However, previously tested drugs such as nafamostat mesilate, methylene blue, and aprotinin are neither familiar nor currently available to most anesthesiologists. Therefore, the anticipatory treatment of hypotension with vasoactive agents such as epinephrine and phenylephrine (rather than counteracting specific mediators of PRS) seems more practical.15, 16 Unfortunately, the only published study addressing the prophylactic use of adrenergic agonists to prevent PRS showed that the prophylactic use of atropine prevented the onset of bradycardia but failed to block hypotension.17
Our experience with liver transplantation in the past decade has shown that nearly all patients undergoing reperfusion suffer from various degrees of hypotension and bradycardia. We hypothesized that the appropriate dose of a potent β- or α-adrenergic drug administered before reperfusion would reduce the occurrence of PRS and subsequent vasopressor requirements during adult liver transplantation. The primary objective of the current study was to demonstrate the effects of epinephrine and phenylephrine pretreatments on PRS as well as the accompanying safety profiles.
CO, cardiac output; CVP, central venous pressure; HR, heart rate; ICU, intensive care unit; INR, international normalized ratio; IVC, inferior vena cava; MAP, mean arterial pressure; POD, postoperative day; PRS, postreperfusion syndrome.
PATIENTS AND METHODS
This prospective, randomized, placebo-controlled, double-blinded study was approved by the institutional review board of Seoul National University Hospital (H-0912-050-304) and was registered at ClinicalTrials.gov in March 2010 (National Clinical Trial number 01080625 with C.W.J. as the principal investigator). Written informed consent was obtained from all patients during the preoperative visit.
Patient Selection and Randomization
Adult recipients scheduled for either living or deceased donor liver transplantation were screened for their study eligibility. Patients with cardiac dysfunction, including severe dysrhythmia, pulmonary hypertension, coronary artery disease, and valvular heart disease, were excluded. Patients who were hemodynamically unstable and required additional intravascular volume and vasoactive drugs or had uncorrectable electrolytes and an acid-base imbalance for at least 10 minutes before reperfusion were excluded from the analysis. Enrolled patients were randomly assigned to each group with an Excel program–generated randomization table. The patient enrollment and randomization process is shown in Fig. 1.
Anesthesia and Surgery
Patients were not premedicated before surgery. Anesthesia was induced with 2 mg/kg propofol, 1.2 mg/kg rocuronium, and sevoflurane with oxygen under electrocardiography, noninvasive blood pressure, and pulse oximetry monitoring. Mechanical ventilation was maintained with a volume control mode at a tidal volume of 8 mL/kg, a frequency of 10/minute, and a fraction of inspired oxygen of 0.5. Anesthesia was maintained with sevoflurane and a continuous infusion of atracurium. Arterial lines were inserted into the radial and femoral arteries for frequent sampling and continuous monitoring of the arterial pressure, respectively. A triple-lumen Swan-Ganz introducer and a pulmonary artery catheter were placed into the right internal jugular vein to measure intracardiac pressures and cardiac output (CO).
Anesthetic management during the anhepatic phase was focused on the maintenance of the cardiac preload and the correction of arterial blood gas and electrolyte imbalances. The intravascular volume was managed to maintain the central venous pressure (CVP) between 5 and 10 mm Hg. Minute ventilation was controlled to maintain the arterial carbon dioxide tension at 35 mm Hg. An arterial pH lower than 7.25 that was accompanied by a base deficit greater than 10 mmol/L was treated with sodium bicarbonate. An ionized calcium level less than 1.0 mmol/L was treated with calcium chloride, and hyperkalemia (>6.5 mmol/L) after acidosis correction was immediately treated with insulin and glucose. An intermittent bolus of ephedrine was our first vasopressor choice for hypotension. However, patients who showed persistent hypotension requiring epinephrine or dopamine were excluded.
All donor liver grafts were prepared with a histidine tryptophan ketoglutarate solution (Custodiol, Köhler Chemie GmbH, Germany). Similar surgical techniques were used for living and deceased donor cases. The anastomosis of the liver graft was performed with the piggyback technique. The position of the venous clamp was adjusted to achieve an adequate cardiac preload with a stable arterial pressure. Neither venovenous bypass nor temporary portocaval shunting was used. Just before the hepatic vein anastomosis was completed, the liver graft was perfused with 250 mL of 5% albumin through the portal vein. The portal vein was vented just before the portal vein anastomosis was completed. After the completion of the portal vein anastomosis, the liver graft was reperfused via the consecutive release of the clamps over the hepatic and portal veins. The end-to-end anastomosis of the hepatic artery and the duct-to-duct anastomosis of the bile duct were performed sequentially.
Electrolytes and arterial blood gases were monitored and corrected as required throughout surgery. All patients were transported to the intensive care unit (ICU) after the end of the operation while they were intubated.
All investigators were masked from the randomization throughout the study. The doses of epinephrine and phenylephrine were empirically chosen. According to the allocation group, normal saline (the control group), 10 μg of epinephrine (the epinephrine group), or 100 μg of phenylephrine (the phenylephrine group) was prepared before the reperfusion of the liver graft. All 3 drugs were labeled “study drug,” and the volume of the injectate was adjusted to 10 mL. At the time of reperfusion, the study drug was injected via a side port of the Swan-Ganz introducer just as the surgeon released the portal vein clamp. At the same time, an event marker was added to the anesthesia monitoring system, and the timer was started.
The onset of hypotension was noted when MAP fell more than 30% within 5 minutes after reperfusion versus the baseline level at the time of reperfusion and continued there for more than 1 minute. PRS was treated with 10 mg of ephedrine. Severe hypotension (an abrupt decrease in MAP below 40 mm Hg) was immediately treated with 10 μg of epinephrine. If MAP fell more than 30% versus the baseline level or MAP continued to be <40 mm Hg, repeated doses of ephedrine or epinephrine were administered every minute until MAP ceased to decrease or started to increase. Continued hypotension despite 5 repeated doses of ephedrine or epinephrine required a titrated infusion of dopamine so that MAP would not fall more than 30% versus the baseline value.
All hemodynamic data were stored in the data server of the anesthesia monitoring system and were recorded after the end of the surgery. The heart rate (HR), MAP, CVP, CO, and systemic vascular resistance were recorded at the following time points: reperfusion; the identification of PRS; every minute after the identification of PRS for 5 minutes; and 10, 30, and 60 minutes after the identification of PRS. PRS was diagnosed when MAP met the aforementioned hypotension criteria. In patients who did not develop PRS, 1 minute after reperfusion was considered equivalent to the time of the identification of PRS. The use of vasopressors during the early postreperfusion period (within the first 10 minutes after reperfusion) and the late postreperfusion period (more than 10 minutes after reperfusion through the surgery) was determined from the anesthesia records.
Other data, including patient and donor characteristics and surgery-related information, were obtained from the electronic medical recording system by a physician who was blinded to the study protocol. Perioperative laboratory data [hemoglobin, serum albumin, serum total bilirubin, and serum aminotransferase levels and prothrombin times as international normalized ratios (INRs)] were obtained before surgery, immediately after surgery, and on postoperative days (PODs) 1, 3, 7, and 30.
Sample Size Calculations and Statistical Analyses
Pilot data showed that the incidence of PRS during liver transplantation surgery was 73%, 42%, and 33% for the control, epinephrine, and phenylephrine groups, respectively. With a type I error of 0.05 and a power of 0.8, a sample size of 93 (31 patients per group) was calculated to achieve an effect size of 0.326 (a medium effect size) with 2 degrees of freedom.
Group characteristics were compared with a 1-way analysis of variance, the Kruskal-Wallis test, and the chi-square test. Prereperfusion variables were compared with a 1-way analysis of variance. The incidence of PRS was compared with the chi-square test, and multiple comparisons were made with Bonferroni correction. The characteristics of MAP overshoots were compared with the chi-square test between the 3 groups and with the Mann-Whitney test between the pretreatment groups. The use of vasopressors during the early and late postreperfusion periods was compared between the groups with the Kruskal-Wallis test, the Mann-Whitney test (for multiple comparisons), and the chi-square test. Hemodynamic data from the reperfusion period were compared with a generalized estimating equation analysis, and multiple comparisons were adjusted with the Bonferroni method.
Univariate logistic regressions were performed with patient characteristics (age, sex, body mass index, Model for End-Stage Liver Disease score, diagnosis, history of diabetes mellitus, preoperative use of propranolol, prolonged QT interval in the electrocardiogram, and diastolic dysfunction in the echocardiography), surgery-related factors (anesthesia time, type of donor graft, graft-recipient weight ratio, donor age, donor graft steatosis, and cold and warm ischemia times), and anesthesia-related variables (pretreatments, transfused blood components, CO, systemic vascular resistance, HR, MAP and CVP at the time of reperfusion, and MAP overshoot after reperfusion) as independent variables. The occurrence of PRS was the dependent outcome. Thereafter, selected variables (P < 0.2) were entered into the multivariate logistic regression analysis to produce a multivariate prediction model for PRS occurrence.
Perioperative laboratory test values were compared with a generalized estimating equation. The ICU and hospital lengths of stay of the groups were compared with the Kruskal-Wallis test. A partial correlation test and an analysis of covariance were performed to reveal the correlation between the hospital and ICU lengths of stay and independent risk factors (including the occurrence of PRS).
P values less than 0.05 were considered statistically significant. All statistical analyses were performed with IBM SPSS Statistics 19 (SPSS, Inc., Chicago, IL).
Ninety-six of the 128 eligible candidates were enrolled in this study (Fig. 1). The final analysis included 93 patients (31 patients per group). The patient and donor characteristics of the 3 groups were similar (Table 1). The prereperfusion variables of the groups were also similar (Table 2).
Table 1. Group Characteristics
Control Group (n = 31)
Epinephrine Group (n = 31)
Phenylephrine Group (n = 31)
NOTE: No differences were found between the 3 groups.
The data are presented as medians and interquartile ranges.
The data are presented as means and standard deviations.
Liver grafts from living donors were either right lobes (66/68) or left lobes (2/68); those from deceased donors were exclusively whole livers (25/25).
PRS occurred significantly less frequently in the epinephrine group (39%, P = 0.002) and the phenylephrine group (48%, P = 0.02) versus the control group (77%), and there was no difference between the epinephrine and phenylephrine groups (P = 0.61; Table 3). MAP was significantly higher in the epinephrine and phenylephrine groups versus the control group during the immediate postreperfusion period (P < 0.05; Fig. 2). There were no differences in HR or CVP between the groups during the postreperfusion period.
Table 3. PRS and Vasoactive Drug Requirements
Control Group (n = 31)
Epinephrine Group (n = 31)
Phenylephrine Group (n = 31)
P < 0.05 (Bonferroni-corrected) between the control group and the other groups (no difference was found between the pretreatment groups).
Comparisons were made between the epinephrine and phenylephrine groups; the overshoot frequency was compared between the 3 groups.
The data are presented as medians and interquartile ranges.
An overall difference was apparent; however, multiple comparisons failed to reveal differences between the groups.
In one-third of each pretreatment group, an overshoot of MAP that was similar in incidence, degree, and time to occurrence was observed immediately after reperfusion (Table 3). However, an increase in MAP that was greater than 20% of the baseline value was seen in only 2 of the 31 patients (6%) in each pretreatment group. In patients who showed an overshoot of MAP, the accompanying HR change was minimal.
The use of epinephrine during the early and late postreperfusion periods and the use of dopamine during the late postreperfusion period were significantly lower in the epinephrine and phenylephrine groups versus the control group (P < 0.001; Table 3).
Univariate logistic regression analyses determined that 9 independent variables were risk factors for PRS (Fig. 3). The final model included the use of an epinephrine or phenylephrine pretreatment, the use of a deceased donor graft, and a higher HR at the time of reperfusion as negative predictors of PRS occurrence. The diagnosis of liver cirrhosis was a positive predictor (Table 4). The negative, positive, and overall predictive values of this model were 64.3%, 82.4%, and 74.2%, respectively.
Table 4. Multivariate Model for Predicting the Occurrence of PRS
95% Confidence Interval
Use of deceased donor graft
HR at time of reperfusion (bpm)
Diagnosis of liver cirrhosis
All the perioperative laboratory variables of the groups were similar (Fig. 4). The overall in-hospital mortality rate was 4.3% (4/93), and there were no differences between the 3 groups (P = 0.77; Table 1). Three patients died because of sepsis and subsequent multiorgan failure. One patient in the phenylephrine group suffered from hypoxic brain damage and died on POD 171. The lengths of the hospital and ICU stays were also similar for the 3 groups (P = 0.91 and P = 0.21, respectively), although post hoc power analyses showed low power for both results (55% and 50%, respectively, with a type I error of 0.05). A partial correlation test showed that the length of the postoperative hospital stay was weakly correlated with the amount of red blood cell transfusions (r = 0.278, P = 0.008).
The main finding of our study is that pretreatment with 10 μg of epinephrine or 100 μg of phenylephrine at the time of reperfusion significantly reduced the occurrence of PRS during adult liver transplantation surgery. The need for vasopressors in the postreperfusion period was significantly lower in the groups pretreated with either epinephrine or phenylephrine. Arterial pressure overshooting after the use of an epinephrine or phenylephrine pretreatment was acceptable, and the accompanying HR change was minimal as well. The postoperative courses were similar in the control and pretreatment groups.
Many investigators have tried to attenuate the occurrence and/or degree of PRS during liver transplantation by surgical or pharmacological interventions. A prospective study of the piggyback technique demonstrated better hemodynamic balance and less frequent PRS in comparison with total clamping of the inferior vena cava (IVC) and venovenous bypass.9 Flushing the liver graft with lactated Ringer's solution also provided hemodynamic stability in comparison with IVC venting without flushing.11 In a retrospective study, retrograde reperfusion via the IVC with the piggyback technique lowered the incidence and severity of PRS.10 In contrast, immediate and homogeneous reperfusion of the liver graft resulted in serious cardiovascular instability.18
Another approach to reducing PRS involves pharmacological interventions, most of which have been aimed at interfering with the presumed fundamental mechanism of PRS. Previously, Aggarwal et al.19 suggested that PRS is caused by undefined vasodilating substances. Subsequent studies reporting the relationship between presumed antagonists and reduced PRS occurrence provided clinically applicable methods for pharmacological interventions. Possibly by blocking the kinin system, aprotinin reduced vasoactive drug requirements as well as blood product transfusions and supported hemodynamic stability during liver transplantation.12, 14, 15 A pretreatment with methylene blue was effective in maintaining MAP and reducing epinephrine requirements during ischemia/reperfusion injury, presumably because of guanylate cyclase inhibition.13 Recently, nafamostat mesilate, a serine protease inhibitor similar to aprotinin, was used before reperfusion of the liver graft and significantly reduced PRS and vasopressor requirements.5 However, these drugs are either unfamiliar or unavailable to most anesthesiologists.
A more practical pharmacological approach is to block the postreperfusion hemodynamic changes per se with adrenergic agonists. Bradycardia and hypotension are very common after reperfusion of the liver graft. The only trial using a pharmacological intervention to block these changes was conducted with atropine. Atropine abolished bradycardia even when PRS occurred but failed to block the decrease in MAP.17 In the current study, we have demonstrated that commonly used vasopressors such as epinephrine and phenylephrine are helpful in preventing PRS as well as further hypotension. A drug with a potent alpha effect such as phenylephrine is effective in treating acute hypotension caused by systemic vasodilation, which is the most suspected cause of hypotension in liver transplant recipients, especially during the reperfusion period.16 In addition, frequent bradycardia during reperfusion of the liver graft makes epinephrine an appropriate rescue drug of choice. Our results show that these 2 drugs are equally effective at preventing PRS in terms of maintaining arterial pressure. However, the effect of epinephrine is alpha-mediated only and is similar to that of phenylephrine. This may be due to prevailing chronotropic incompetence, which is a blunted response of the heart to β-adrenergic stimulation. Chronotropic incompetence is a characteristic feature of cirrhosis, which was present in 77% (72/93) of our subjects.20
Our major concern in designing the current study was MAP and/or HR overshooting after the preemptive use of phenylephrine or epinephrine. Because not all patients undergoing liver transplantation develop PRS, an adrenergic pretreatment could result in unintended hypertension and/or tachycardia in a subset of patients at the time of reperfusion. The doses were carefully determined on the basis of the literature and our clinical experience with PRS.15, 17 The timing of drug administration was determined on the basis of the time to the peak effect of each drug and the interval between reperfusion and the peak manifestation of postreperfusion hypotension, which was usually 1 minute after reperfusion. Our results showed that only a small proportion of patients who received either phenylephrine or epinephrine (2 of 31 in each group) experienced an increase in MAP greater than 20%. In addition, there was little change in HR during the reperfusion period. Varying degrees of chronotropic incompetence seem rather protective against unintended tachycardia after epinephrine use.
It is not clear whether PRS in and of itself causes adverse outcomes or is simply a reflection of poor physiological reserves, suboptimal graft protection, or another pathology that might lead to poor long-term results. However, many studies suggest that PRS is associated with adverse postoperative outcomes such as early graft dysfunction,7 prolonged mechanical ventilation, longer hospital and ICU stays, retransplantation,4 postoperative renal failure, and lower early6 and 1-year survival.2 Although the current study failed to reveal a relationship between PRS and postoperative hospital stays or in-hospital mortality, the attenuation of PRS by preventive measures should still be emphasized because hypotension itself may become a critical step to disastrous circulatory collapse during surgery.8
The multivariate analysis in the current study revealed 3 factors associated with the occurrence of PRS in addition to pretreatments. First, the diagnosis of either alcoholic or nonalcoholic cirrhosis was a positive predictor of PRS occurrence. Purported factors related to hemodynamic instability in patients with cirrhosis include central hypovolemia and chronic myocardial dysfunction, which is termed cirrhotic cardiomyopathy and becomes more apparent during liver transplantation surgery or the reperfusion period.21 Second, the use of deceased donor grafts (which were without exception whole livers in the current study) was a negative predictor. The use of whole liver grafts is frequently associated with reduced venous return because of the deeper application of the IVC side clamp in comparison with partial liver grafts and the compression of the IVC by the large graft during the piggyback approach. The volume administered to maintain the cardiac preload during the anhepatic phase accumulates below the IVC clamp; with the release of the IVC clamp, a sudden inflow occurs. This increase in the preload is usually tolerated,22, 23 and higher CO and MAP values result in response to the volume load.24 However, the quantitative relationship between the administered volume and PRS occurrence requires further investigation. Third, a higher HR before reperfusion was protective against the occurrence of PRS. Postreperfusion bradycardia is common and very resistant to chronotropic medications. Such a protective effect is reasonably inferred because MAP is the product of HR and CO.
Finally, the high frequency of PRS in our study versus other reports (even in the pretreatment groups) should be mentioned. This was most likely due to differences in study designs and data collection methods. In comparison with retrospective chart reviews, prospective data collection with beat-to-beat records (as in our study) may result in greater detection of hypotension. Another potential contributor to the high incidence of PRS was the use of a histidine tryptophan ketoglutarate solution for organ preservation.25
In summary, our study shows that the administration of either 10 μg of epinephrine or 100 μg of phenylephrine at the time of reperfusion is an effective measure for significantly reducing the occurrence of PRS and the need for vasoactive support during adult liver transplantation surgery. In addition, the fact that immediate adverse effects such as hypertension and tachycardia were minimal with no additional late complications may serve as a basis for the extensive use of vasopressors in practice to reduce profound hypotension during the reperfusion period.