The small remnant liver after major liver resection: How common and how relevant?

The Small Remnant Liver After Major Liver Resection: How Common and How Relevant? Cengizhan Yigitler, Olivier Farges, Reza Kianmanesh, Jean-Marc Regimbeau, Eddie K. Abdalla, and Jacques Belghiti The maximum extent of hepatic resection compatible with a safe postoperative outcome is unknown. The study goal was to determine the incidence and impact of a small remnant liver volume after major liver resection in patients with normal liver parenchyma. Among 265 major hepatectomies performed at our institution (1998 to 2000), 138 patients with normal liver and a remnant liver volume (RLV) systematically calculated from the ratio of RLV to functional liver volume (FLV) were studied. Patients were divided into five groups based on RLV-FLV ratio from <30% to >60%. Kinetics of postoperative liver function tests were correlated with RLV. Postoperative complications were stratified by RLV-FLV ratios. Ninety patients (65%) underwent resection of up to four Couinaud segments. The RLV-FLV ratio was <60% in 94 patients (68%) including only 13 (9%) with RLV-FLV <30%. There was no linear correlation between the number of resected segments and the RLV-FLV. Postoperative serum bilirubin but not prothrombin time correlated with extent of resection. The incidence of complications including liver failure was not different among groups. Analysis of the four groups with a RLV-FLV ratio <60% showed a trend toward more complications and a longer intensive care unit stay in patients with the smallest RLVs. After major hepatectomy in patients with normal livers, the proportion of patients with a small remnant liver is low and not directly related to the number of segments resected. Although the rate of postoperative complications, including liver failure, did not directly correlate with the volume of remaining liver, the postoperative course was more difficult for patients with smaller remnants. Therefore preoperative portal vein embolization should be considered in patients who will undergo extended liver resection who have (1) injured liver or (2) normal liver when the planned procedure will be complex or when the anticipated RLV-FLV will be <30%. (Liver Transpl 2003;9:S18-S25.)

From the Department of Hepatopancreatobiliary Surgery, Beaujon Hospital [Assistance Publique-Hoˆpitaux de Paris], University Paris 7, France. Data presented at the International Symposium on the Small-forSize Syndrome, February 4, 2002, in Ghent, Belgium. Address reprint requests to Jacques Belghiti, MD, Department of Hepatopancreatobiliary Surgery, Beaujon Hospital, 92118 Clichy Ce´dex, France. Telephone: 33-1-40-87-58-95; FAX: 33-1-40-87-1724; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0909-0026$30.00/0 doi:10.1053/jlts.2003.50194

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ecent improvement in the safety of liver surgery1 has resulted in the performance of extended hepatic resection in particular for malignancies2,3 or for living-related liver transplantation.4 The maximum extent of resection compatible with a safe postoperative outcome remains unknown, but it is generally believed that the risk for postoperative complications, including liver failure, increases when the remnant liver volume (RLV) is too small. This concept underlies the rationale for preoperative portal vein embolization (PVE) before major liver resections. This technique was initially described in patients with biliary malignancies5or hepatocellular carcinoma6 with liver injured by an underlying process such as viral fibrosis or an obstructive cholestasis. The use of PVE has expanded to patients without underlying liver disease to increase safety and tolerance of major hepatectomy with a small liver remnant. However, the strict criteria for PVE in these patients are not well defined. The indications for PVE in patients with normal liver parenchyma vary among reports, although at hepatobiliary surgery centers, patients are typically selected by liver remnant size. Methods of measurement of the future remnant vary,7 but most investigators propose that preoperative PVE is indicated when the measured future liver remnant volume is expected to be less than 25% to 45% of the preoperative functional liver volume (FLV)8-12 or when the standardized FLV will be less than 1% of the patient’s body weight (BW).13 Recognition that these criteria have been determined empirically7 and that the benefits of PVE may not be as obvious for patients with normal underlying liver as for patients with chronic liver disease14,15 has led to increased interest in better definition of the indications for PVE and clearer determination of the limits of safe resection in patients with normal liver. In this study, patients without underlying liver disease who underwent major liver resection were analyzed. First, liver volumetry using computed tomography (CT) was used to validate liver volumes determined by a formula related to body surface area.16 Next, the incidence of small liver volume after extended resection (RLV-FLV ⬍30%) was determined, the correlation between the RLV and kinetics of postoperative biological liver tests was examined, and the pattern of postop-

Liver Transplantation, Vol 9, No 9, Suppl 1 (September), 2003: pp S18-S25

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Measurement and Estimation of Liver Volumes Table 1. Patient Characteristics Characteristic Age (mean) Gender Weight (mean) Diagnosis Secondary hepatic tumor Primary hepatic tumor Benign hepatic tumor Living related donor

Value 52.8 yr (range, 18-77) 71 male, 67 female 70.2 kg (range, 42-128) Number of patients 47 43 24 24

erative complications in patients stratified by the postresection liver volumes was assessed.

Patients and Methods Patient Selection Among 457 hepatic resections performed at our institution between January 1998 and October 2000, 265 were major hepatectomies (resection of three or more Couinaud segments). Of these major hepatectomies, 138 were included in this study after exclusion of 127 patients for the after reasons: (1) presence of chronic liver disease (Knodell fibrosis scoring grade 3 or 4)17 (n ⫽ 50); (2) association of liver resection with another major abdominal procedure such as a vascular resection (resection of portal vein or vena cava), or resection of another organ (e.g., stomach, colon, kidney, adrenal gland, pancreas) (n ⫽ 45); (3) preoperative portal vein embolization (n ⫽ 13) or prior ligation of the right portal vein (n ⫽ 4); (4) emergency liver resection for abdominal trauma (n ⫽ 8); (5) polyadenomatosis or polycystic liver disease (n ⫽ 7), and (6) repeat hepatectomy (n ⫽ 7). Indications of surgery in the 138 studied patients are summarized in Table 1.

Figure 1. Correlation between the liver volume (abscissa) predicted by formula (see Patients and Methods Section), and the CT volumetry (ordinate). Linear regression, observed volume ⴝ 1.05 ⴛ predicted volume ⴚ 122, r2 ⴝ 0.86, P ⴝ .0000001.

The FLV of all of the included patients was calculated using the Lin et al16 formula as follows: {FLV (mL) ⫽ [13 ⫻ height (cm)] ⫹ [12 ⫻ weight (kg)] ⫺ 1,530}. The tumor volume, when applicable, was calculated using the mean of at least two perpendicular diameters (D) measured on the resected specimen as follows: {Tumor volume ⫽ 4/3 ⫻ ␲ (D/2)3}. To validate Lin’s formula in our population, the previous measurements were compared with 40 patients within the study population who had undergone complete preoperative CT volumetric assessments. There was a strong correlation between CT and formulaic volumetry (Fig. 1, r2 ⫽ 0.86, P ⬍ .0001). Assuming that 1 mL of hepatocytes weighs 1 g,18 the resected liver volume was calculated. Further, there was a linear correlation between RLV-BW ratio and RLV-FLV ratio (Fig. 2). Accordingly, patients were divided into five groups based on the RLV-FLV ratio in increments of 10% from ⱕ30% to ⱖ60%.

Postoperative Endpoints The kinetics of postoperative liver function tests and the occurrence of complications were correlated with the RLV. Prothrombin time (PT, expressed as a percentage of controls, lower limit of normal range, 75%) and serum bilirubin (upper limit of normal range, 17 ␮mol/ L) were measured on postoperative days 1, 3, 5, and 7. All complications were carefully recorded prospectively. Minor complications included mild pleural effusions, asymptomatic perihepatic fluid collections not requiring aspiration or drainage, and wound complications. Major complications included postoperative ascites defined by drainage of ⬎300 mL/d ascitic fluid or detection of free intra-abdominal fluid by ultrasound after postoperative day 2, biliary fistula or biloma, reoperation for sepsis or hemorrhage, pleural effusion requiring aspiration or drainage, atelectasis requiring bronchoscopy, pneumonia or pulmonary embolism, and kidney or liver failure. Liver failure was defined as both a prothrombin ratio ⬍50% and a total serum

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Figure 2. Correlation between the RLV-BW and the RLVFLV ratios.

bilirubin level ⬎50 ␮mol/L after postoperative day 4. Operative mortality was defined as death occurring during the same hospital admission or within 30 days of surgery.

Statistical Analysis Results are expressed as mean ⫾ standard deviation unless otherwise stated. Comparisons between means and percentages were performed by ANOVA and Pearson Chi-squared test. A value of P ⬍ .05 was considered to be statistically significant.

Results Correlation Between RLV and Extent of Resection The number of resected Couinaud segments was three in 18 patients (13%), four in 88 patients (64%), five in 22 patients (16%), and six in 10 patients (7%). The RLV-FLV ratios were not significantly different in patients undergoing the resection of four (52.9% ⫾ 18.0), five (50.6% ⫾ 16.4) or six segments (52.4% ⫾ 23.5). Only patients undergoing the resection of three segments had significantly (P ⬍ .05) larger residual volumes (71.8% ⫾ 14.7). As shown in Figure 3, there was no linear correlation between the number of resected segments and RLV. The RLV-FLV ratio was ⱕ30% in 13 patients (9%), 31% to 40% in 23 patients (17%), 41% to 50% in 29 patients (21%), 51% to 60% in 29 patients (21%) and ⱖ60% in 44 patients (32%).

cations (n ⫽ 50) and/or a perioperative blood and/or frozen plasma transfusion (n ⫽ 37) were excluded from this portion of the analysis. As shown in Figure 4, the PT did not correlate with the RLV-FLV ratio. All patients experienced a decrease of PT on postoperative day 1 that progressively normalized thereafter irrespective of remaining liver volume. In contrast, postoperative serum bilirubin was significantly correlated to the RLV-FLV ratio during the first week (day 1, P ⫽ .005; day 3, P ⫽ .02; day 5, P ⫽ .05; day 7, P ⫽ .005; Fig. 5). Correlation Between RLV and Postoperative Complications Overall, 74 patients (54%) had no postoperative complications, as defined in the Methods section, 25 patients (18%) had a minor complication, and 39 patients (28%) had one or more severe complications.

Postoperative Liver Function Tests To clarify the impact of residual liver volume on postoperative liver function tests excluding known confounding variables, patients with postoperative compli-

Figure 3. Correlation between the number of removed segments and the RLV-FLV ratio.

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Figure 4. Correlation between the RLV-FLV ratio (in abscissa) and the PT (in ordinate) on postoperative days 1, 3, 5, and 7. The horizontal line indicates the lower limit of the normal range.

Major complications included pulmonary complications in 25 patients, abdominal infection, biliary leakage or biloma in 17 patients, ascites in 17 patients, liver failure in seven patients, and postoperative hemorrhage in six patients. As shown in Table 2, the overall rate of complications was not statistically different between patients with small or larger RLV-FLV ratios. The occurrence of ascites and liver failure was not statistically different between groups. Liver failure was transient in seven patients and resolved by postoperative day 7 (five patients), day 11 (one patient), and day 13 (one patient). In the last patient, liver failure was part of a cascade leading to multiple organ failure initiated by a severe lung infection associated with cardiogenic shock that culminated in the patient’s death on postoperative day 18. This single postoperative death occurred in a diabetic patient with chronic obstructive lung disease and an RLV-FLV of 38%. However, because patients with an RLV-FLV ratio ⱖ60% tend to have technical complications such as biliary leak related to the large resected tumors, careful examination of the occurrence of complications for the other groups showed a steady trend toward more complications in patients with the smallest RLVs (see Table 2). Importantly, the ICU stay was twice as long and the hospital stay was 60% longer in the group with the lowest RLV-FLV ratio (⬍30%) compared with the group with ratio of 51% to 60%.

Discussion It is generally assumed that the risk of postoperative complications, and in particular of liver failure, is increased in patients with a small RLV after extended hepatic resection.11,19 Further, the belief that an increase in RLV in patients expected to have a small future RLV has led to the development of preoperative techniques designed to selectively increase the volume of the future liver remnant with the expectation of increased safety and tolerance of major hepatectomy.7 This study shows that in a large series of patients who underwent major hepatic resection, the real percentage of patients with small remaining liver volume (RLVFLV ⱕ30%) that corresponds to a RLV-BW ⬍0.6% is low. The incidence of global postoperative complications including liver failure was not significantly correlated with liver remnant size. However, global indicators of operative outcome, that is durations of ICU stay and hospital stay, were longer in the groups with very small remnants. This series includes major resections performed in a center specialized in hepatobiliary surgery. The proportion of patients with normal liver parenchyma undergoing the resection of four segments and of those undergoing very large resections of five or six Couinaud segments was 64% and 24%, respectively. Importantly,

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Figure 5. Correlation between the RLV-FLV ratio (in abscissa) and the serum bilirubin (in ordinate, upper limit of normal, 17 ␮mol/L) on postoperative days 1, 3, 5, and 7. The line indicates the regression coefficient.

the systematic methodology used to calculate liver volume is comparable with that used by others.11 The functional liver volumes were computed from the patients’ body weights and heights using a formula16 that proved to be very accurate in our patients. As in similar studies, tumor volumes were considered to be nonfunctional liver parenchyma,9,20-22 and patients with multiple tumors that could not be accurately measured were excluded from the analysis.11,20 Our first objective was to determine how often a

major hepatectomy results in a small RLV. A small remnant liver, systematically measured and strictly defined as an RLV-FLV ratio ⱕ30%, was observed in only 9% of our patients. Small postresection volumes were never observed after the resection of three Couinaud segments in this series. There was a trend, although not statistically significant, toward small residual volumes after the resection of six segments. A possible explanation for these observations is that in patients with a large malignant tumor mass, the most

Table 2. Postoperative Outcome Stratified by RLV-FLV Ratio After Major Liver Resection RLV-FLV (%)

Total number of patients Overall complications Pulmonary complications Biliary complications Hemorrhage Ascites Liver failure Intensive care unit stay (days, mean ⫾ SD) In-hospital stay (days, mean ⫾ SD)

30

31-40

41-50

51-60

60

13 (9) 7 (54) 4 (31) 2 (14) 0 2 (16) 1 (8) 12 ⫾ 8 21 ⫾ 9

23 (17) 11 (48) 4 (17) 3 (13) 2 (9) 2 (9) 3 (13) 7⫾4 16 ⫾ 6

29 (21) 11 (38) 9 (31) 3 (10) 1 (3) 2 (7) 3 (10) 6⫾2 14 ⫾ 5

29 (21) 7 (24) 2 (7) 1 (3) 1 (3) 3 (10) 1 (3) 5⫾3 13 ⫾ 5

44 (32) 28 (64) 6 (14) 8 (18) 2 (5) 8 (18) 0 5⫾2 16 ⫾ 8

Abbreviation: RLV/FLV, remnant liver volume expressed as a ratio to functional liver volume.

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frequent indication for major resection, the contralateral liver segments have undergone a progressive compensatory hypertrophy, either because this tumor mass does not represent functional liver parenchyma or because it impairs the adjacent portal blood flow. In any case, these results suggest that a major liver resection, in clinical practice, is relatively rarely associated with a small remnant liver in patients with normal underlying liver. Our second objective was to assess the impact of the RLV on the kinetics of postoperative of liver function tests. We23 and others24 have previously shown that the peak postoperative serum bilirubin level increases with the number of segments removed. However, in those early studies, the volume of the remnant liver was not measured. In addition, a significant proportion of the patients analyzed had received massive blood transfusion, which may have had an effect on postoperative bilirubin levels independent of liver volume. More recently, two studies have reported conflicting results in relatively small groups of patients. Kubota et al failed to show an influence of the extent of resection on postoperative serum bilirubin levels,20 and Vauthey et al reported a significant correlation between the extent of functional resection and peak levels of postoperative bilirubin and PT.11 In the latter study, it is difficult to assess whether the elevated bilirubin and PT was a function of volume-related liver insufficiency that predisposed to complications or rather that the elevated liver function test results were related primarily to postoperative complications. To rule out these biases, our analysis was performed in patients who had no transfusion and no complications.25,26 In this analysis, the volume of the remnant liver was not correlated with the PT. On postoperative day 1, the PT decreased to a comparable extent whatever the extent of resection. This result is consistent with our earlier observation that the early decrease in the PT after a right hepatectomy is comparable in patients with and without chronic liver disease.27 A possible explanation is that although the PT is very sensitive to factor VII,28 which has a short half-life and therefore decreases rapidly after a hepatectomy, it is also influenced by hemodilution29 and patient temperature,30 which may be very variable at the end of a major liver resection. The PT thereafter recovers rapidly in patients with a normal liver27—accordingly, PT had normalized in almost all of the patients in this study by postoperative day 5. This may explain why a correlation between peak PT and remnant liver volume was not found at later time points. In contrast, a significant correlation between the remnant liver volume and the postoperative serum bil-

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irubin levels was found. Bilirubin indeed has a longer half-life than the PT and therefore peaks between postoperative day 3 and 5 after a major hepatectomy.27 At this later point postoperatively, plasma volume is normalizing and has a less significant impact on bilirubin.31 Thus, the finding that serum bilirubin is inversely correlated with the volume of the remnant liver was expected. The serum bilirubin level more reliably reflects the impact of small RLV in normal liver than the PT. This should be considered when assessing postoperative liver function tests in living donors. The final objective of our study was to investigate whether the volume of the remaining liver had any influence on the occurrence of postoperative complications. Previous studies addressing this issue have yielded conflicting results.9-11,22 In the present study, the global incidence of complications (whether minor or major) and the duration of in-hospital stay were not significantly different in patients with the smallest or largest remnant liver volumes. However, a notable trend is recognized when the remnant volume decreases from 51% to 60% to ⬍30%: the length of ICU stay doubles and hospital stay is nearly 50% longer in the small residual volume group. There are several likely explanations for the difference in outcome between the groups with larger postresection volumes, specifically those with RLV-FLV ratios 51% to 60% compared with ⬎60%. Pleural effusion and atelectasis are the most common complications after major resections32 and are more directly related to the incision used,33 technique of vascular clamping,34 abdominal drainage,35 and dissection of the right triangular ligament36,37 than to the volume of the remnant liver. Also, biliary leakage is correlated with the care with which liver transection is performed38 and the location of the transection plane rather than with the extent of resection.39,40 Thus, the increase in the rate of biliary complications and ascites in patients with very large liver remnant volumes (⬎60%) compared with those with liver volumes 51% to 60%, is not likely related to volume but rather to technical issues. The same arguments likely hold true for postoperative bleeding and pulmonary complications. The mechanisms for formation of postoperative ascites observed in these patients may also differ from the mechanisms in patients with small liver remnants. Indeed, it is yet not clear whether the increase in the portal pressure observed after resection of more than 30% of the functional liver volume can generate ascites.41 Surprisingly, the incidence of liver failure was not strictly correlated with the size of the RLV in this study. Accordingly, the true minimum liver volume that must

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be preserved after liver resection in patients with normal liver remains undefined. To assess the impact of liver hypertrophy of the future liver remnant volume induced by PVE on the immediate postoperative complications after a standardized major liver resection, we previously conducted a prospective study comparing two groups of patients with normal livers who underwent an elective right hemihepatectomy.14 Despite an increase in the left liver volume of 45% in the group that underwent preoperative PVE, a similar postoperative course was observed in patients with a RLV-FLV ratio of 31% and those with a post-PVE RLV-FLV ratio of 47%. However, in this study, the important observation was made that patients with RLV-FLV ratio ⬍30% required more attention to their postoperative care manifested as longer stays in the ICU and longer hospital stay than patients with a larger liver remnant. Thus there is growing evidence that although mortality is low after extensive hepatic resection leaving a very small remnant in patients with normal liver, there is a clear trend toward slower recovery, greater need for critical care, and prolonged hospitalization. These are perhaps manifestations of the global physiological importance of sufficient functioning liver in the postoperative patient. A measure of single organ function, such as liver failure, no matter how it is defined, may not be the best measure of the physiological reserve necessary to recover safely from major hepatic surgery.

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Conclusion In conclusion, this study shows that (1) the number of patients with small RLV after major hepatectomy in normal liver is low (⬍10%) even in specialized centers, and (2) although we could not show that the rate of postoperative complications including liver failure is directly correlated with the volume of the remaining liver volume, the postoperative course is clearly more difficult as the remnant gets smaller. Thus preoperative PVE must be considered not only in patients who will undergo extended hepatic resection who have injured liver but also in patients with normal liver when the planned procedure will be complex or when the anticipated RLV will be less than 30% of the FLV.

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