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Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis

Jung, Kyeo-Woon MD*; Kim, Wan-Joon MD; Jeong, Hye-Won MD*; Kwon, Hye-Mee MD*; Moon, Young-Jin MD*; Jun, In-Gu MD, PhD*; Song, Jun-Gol MD, PhD*; Hwang, Gyu-Sam MD, PhD*

doi: 10.1213/ANE.0000000000002756
Perioperative Medicine: Original Clinical Research Report
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SDC

BACKGROUND: Although desflurane and sevoflurane, the most commonly used inhalational anesthetics, have been linked to postoperative liver injury, their impact on liver regeneration remains unclear. We compared the influence of these anesthetics on the postoperative liver regeneration index (LRI) after living donor hepatectomy (LDH).

METHODS: We conducted a retrospective chart review of 1629 living donors who underwent right hepatectomy for LDH between January 2008 and August 2016. The patients were divided into sevoflurane (n = 1206) and desflurane (n = 423) groups. Factors associated with LRI were investigated using multivariable logistic regression analysis. Propensity score matching analysis compared early (1 postoperative week) and late (within 1–2 months) LRIs and delayed recovery of hepatic function between the 2 groups.

RESULTS: The mean early and late LRIs in the 1629 patients were 63.3% ± 41.5% and 93.7% ± 48.1%, respectively. After propensity score matching (n = 403 pairs), there were no significant differences in early and late LRIs between the sevoflurane and desflurane groups (early LRI: 61.2% ± 41.5% vs 58.9% ± 42.4%, P = .438; late LRI: 88.3% ± 44.3% vs 94.6% ± 52.4%, P = .168). Male sex (regression coefficient [β], 4.6; confidence interval, 1.6–7.6; P = .003) and remnant liver volume (β, –4.92; confidence interval, –5.2 to –4.7; P < .001) were associated with LRI. The incidence of delayed recovery of hepatic function was 3.6% (n = 29) with no significant difference between the 2 groups (3.0% vs 4.2%, P = .375) after LDH.

CONCLUSIONS: Both sevoflurane and desflurane can be safely used without affecting liver regeneration and delaying liver function recovery after LDH.

From the *Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.

Published ahead of print December 15, 2017.

Accepted for publication November 13, 2017.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

K.-W. Jung and W.-J. Kim contributed equally to this study.

Reprints will not be available from the authors.

Address correspondence to Jun-Gol Song, MD, PhD, Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. Address e-mail to jungol.song@amc.seoul.kr.

The unique ability of the liver to regenerate to a predetermined size after resection or transplantation makes adult-to-adult living liver donation possible.1 Fortunately, complete and prompt liver regeneration after living liver donation and transplantation occurs in both the donor and recipient under most circumstances.2 However, if liver regeneration after hepatectomy is compromised for any reason, it can cause harm to the patient. Recent studies have suggested that a barrier to remnant liver regeneration may be the main cause of liver failure after massive hepatectomy3 and that early regeneration of the liver is a good predictor of clinical course in hepatectomized patients.4

Donor safety is considered the primary concern because living donor surgery is performed on healthy people in living donor liver transplantation (LDLT). Since right hepatectomy became widely accepted in LDLT, there has been considerable interest in liver regeneration due to concerns about small-for-size syndrome after donor hepatectomy.5 Accordingly, many studies have been conducted to identify the factors affecting liver regeneration.6,7 In previous studies, liver regeneration was reported to be poorer in older donors and in patients with higher steatosis.8,9 In addition, women have been found to show better liver regeneration than men.10

Halogenated anesthetics have been linked to liver injury, and the mechanisms were thought to be immune-allergic reactions caused by metabolites.11 Sevoflurane and desflurane, relatively new forms of halogenated anesthetics, are the most commonly used inhalation agents in several operations, including living donor hepatectomy (LDH).12 Both inhalation agents also produce metabolites and have been suggested to be hepatotoxic.13,14 Although these unusual hepatotoxic cases may not be applicable to a LDLT situation, safety issues regarding inhalation agents in LDH remain to be resolved.

Little is known about the effects of anesthetic agents, especially sevoflurane and desflurane, on liver regeneration after LDH. In this study, therefore, we compared the association of the inhalational anesthetics sevoflurane and desflurane on the postoperative liver regeneration index (LRI) after LDH. We also compared the incidence of delayed recovery of hepatic function (DRHF) after LDH.

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METHODS

Patients

Figure 1.

Figure 1.

This study was approved by the institutional review board of the Asan Medical Center, and the requirement for written informed consent was waived by the Institutional Review Board. A flowchart of the study patients is provided in Figure 1. We retrospectively analyzed the medical records of 2847 patients who underwent hepatectomy for LDLT from January 2008 to August 2016 in Asan Medical Center. The selection criteria for living liver donors at our institution have previously been described in detail.15 Briefly, the sum of macro- and microvesicular hepatic steatosis had to be <30% and the left liver volume had to be >35% of the whole liver volume for right lobe donation. Among the remaining cases, we only included donors who underwent right hepatectomy and excluded all others (eg, left lobectomy [n = 339], right posterior segmentectomy [n = 9], and left lateral segmentectomy [n = 110]). We also excluded donors without computed tomography (CT) volumetry results (n = 760). We ultimately analyzed 1629 donors. The donors were divided into 2 groups according to anesthetic agent: a sevoflurane group (n = 1206) and a desflurane group (n = 423).

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Clinical Data

After reviewing the electronic medical records of the remaining 1629 patients in the study population, we obtained preoperative and intraoperative data and postoperative outcomes. The standard protocol used at our institution was applied to every living liver donor before the operation.15,16 As a preoperative evaluation, series of tests were performed, including electrocardiography, chest x-rays, complete blood counts, liver and renal function tests, coagulation profiles, and viral serology assessments including hepatitis A, B, and C and human immunodeficiency virus. Imaging workups for donors included triphasic liver CT, magnetic resonance cholangiography, abdominal Doppler ultrasound, and percutaneous liver biopsy. An indocyanine green retention test (ICG R15) was also performed for 4 peripheral blood samples taken at 0, 5, 10, and 15 minutes after a bolus injection of ICG 0.5 mg/kg. The test was repeated if the initial ICG R15 values appeared too high (>15%) due to a possible sampling time error.17 We also collected electronic medical records from the anesthesia database and postanesthetic care data from the computerized database.

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Anesthetic Technique

Standard American Society of Anesthesiologists monitoring was applied before anesthesia. During the induction period, thiopental sodium (5 mg/kg), fentanyl (1–2 µg/kg), and rocuronium (0.6 mg/kg) were administered. Endotracheal intubation was performed, and donors were mechanically ventilated with a constant tidal volume of 8–10 mL/kg to maintain an end-tidal carbon dioxide tension of 30–35 mm Hg. The respiratory rate was adjusted to 10–12 cycles/min to achieve target end-tidal carbon dioxide tension. General anesthesia was maintained with volatile agents, sevoflurane or desflurane, a 50% nitrous oxide/oxygen mixture, and intermittent boluses of esmeron and fentanyl. End-tidal concentrations of 1.5%–2.0% sevoflurane and 6%–8% desflurane were maintained to ensure a bispectral index between 40 and 60. Crystalloid (Plasma solution A; CJ Pharmaceutical, Seoul, Korea) and colloid solutions (Voluven; Fresenius Kabi Korea, Seoul, Korea) were administered during the operation. Systolic blood pressure ≥90 mm Hg was maintained during anesthesia. Incremental doses of ephedrine and additional fluids were administered intravenously if the systolic blood pressure was found to be 20% below the baseline blood pressure. A hemoglobin concentration ≥7.0 g/dL and urine output of ≥0.5 mL/kg/h were maintained during the operation.

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Surgical Technique

A J-shaped incision was made, and a cholecystectomy and intraoperative cholangiography were performed. A Cavitron Ultrasonic Surgical Aspirator (CUSA Excel; Valleylab Inc, Boulder, CO) and electrocautery were used in the operation. Vascular structure flow was not interrupted during surgery. All donors were transferred to a postanesthetic care unit for appropriate postoperative management after the operation.

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Definitions of Outcomes

Liver volume was calculated by CT volumetry using 3-mm–thick dynamic CT images, and total liver volume, future liver remnant, and liver remnant at 1 week and within 1–2 months after the operation were assessed. The graft weight was subtracted from the total liver volume to define the future liver remnant. A Picture Archiving and Communication System (Petavision2, Asan Medical Center, Seoul, Korea), which is capable of image processing and various measurements, was used to calculate the liver volume. The LRI, defined as , where VLR is the volume of the liver remnant and VFLR is the volume of the future liver remnant, was calculated. Early and late LRIs were defined as LRI at 1 postoperative week and within 1–2 months, respectively.

Immediately after the graft was obtained, the graft was flushed with preservative solution and the graft weight was measured. The graft-to-donor weight ratio (GDWR) was calculated as follows18: The degree of fatty change in the liver graft was determined by a histological examination in the operating room before hepatectomy. Wedge resections were performed for biopsy, 1 from the right lobe and the other from the left lobe, from which frozen sections were made for the analysis.19

DRHF was defined based on a proposal by the International Study Group of Liver Surgery.20 The International Study Group of Liver Surgery designated DRHF as follows: an impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased international normalized ratio (INR) of prothrombin time (PT) and concomitant hyperbilirubinemia (considering the normal limits of the local laboratory) on or after postoperative day 5. The normal upper limits of PT and bilirubin in our institutional laboratory were 1.30 INR and 1.2 mg/dL, respectively. If the INR of PT or serum bilirubin concentration was preoperatively elevated, DRHF was defined by an increasing PT INR and increasing serum bilirubin concentration on or after postoperative day 5 (compared with the values of the previous day).

The Kidney Disease: Improving Global Outcomes classification system definition of postoperative acute kidney injury was used, which is a change in the serum creatinine from baseline on postoperative days 1–7. The baseline serum creatinine was the concentration measured just before surgery. Acute kidney injury was defined as an increase in serum creatinine above baseline of ≥0.3 mg/dL within 2 days or ≥50%–99% within 7 days.21

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Statistical Analysis

Continuous variables were compared using the Mann-Whitney rank sum test or t test to assess differences between the sevoflurane and desflurane groups and are expressed as medians (first quartile and third quartile). Categorical data were compared using the χ2 test or Fisher exact test to assess differences between the 2 groups. The propensity score (PS) method was used to reduce the effect of potential confounding factors, and intergroup differences between the sevoflurane and desflurane groups were adjusted. We subsequently used the derived PS to match patients at a ratio of 1:1 using greedy matching algorithms with a caliper of 0.2 standard deviations of the logit of the PS. Linear regression and logistic regression were performed to identify variables significantly associated with the LRI and DRHF, respectively. Multivariable analyses were performed by backward selection of covariates with a cutoff univariate P value of .1. The variables entered into the propensity model were gender, age, body mass index (BMI), duration of operation, remnant liver volume (RLV), GDWR, degree of steatosis, intraoperative volume of crystalloid, and total dose of ephedrine. Model discrimination and model calibration were evaluated with C statistics (0.749) and Hosmer–Lemeshow statistics (χ2 = 7.5555, df = 8, P = .48), respectively. After all PS matches were completed, McNemar test was used to compare the intergroup difference for categorical variables. A paired t test or Wilcoxon signed rank test was adopted for continuous variables. The comparison of binary outcomes was tested with logistic regression generalized estimating equations that accounted for the clustering of the matched pairs. A P value of <.05 was considered statistically significant. Analyses were performed using IBM SPSS Statistics version 23.0 (IBM Corp, Armonk, NY).

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RESULTS

Analysis Before PS Matching

A total of 1629 patients were reviewed in this study. The average total liver volume of the 1629 patients was 1196.9 cm3 (1050.8–1334.3 cm3), and the average RLV was 38.9% (34.5%–42.9%). The mean GDWR (%) of total donors was 1.1% (1.0%–1.2%). Of the 1629 patients, the mean early and late LRIs were 63.3% ± 41.5% and 93.7% ± 48.1%, respectively. The incidence of DRHF was 3.7% ± 0.2%.

Table 1 lists the preoperative and intraoperative variables of the 2 groups categorized by anesthetic agent. Before matching, there was heterogeneity between the 2 groups. Compared with the desflurane group, the sevoflurane group had a lower RLV (P = .004), larger GDWR (P < .001), higher ICG R15 ratio (P = .001), more fatty change (P < .001), lesser intraoperative crystalloid use (P < .001), more intraoperative colloid use (P = .005), more intraoperative ephedrine use (P = .002), lower PT INR (P < .001), higher albumin (P < .001), and lower glucose (P < .001).

Table 1.

Table 1.

Table 2.

Table 2.

Figure 2.

Figure 2.

Table 2 presents the clinical outcomes of the 2 groups. The sevoflurane group had a higher early LRI than the desflurane group (65.1 ± 40.8 vs 58.2 ± 41.8, P < .001), but late LRI was not significantly different between the 2 groups (93.7 ± 46.8 vs 93.6 ± 51.8, P = .445). In addition, the incidences of DRHF (3.6% vs 4.0%, P = .730) were not significantly different between the 2 groups. Postoperative laboratory variables are shown in Figure 2. By postoperative day 7, the maximum PT INR was significantly higher in the desflurane group than in the sevoflurane group (1.58 ± 0.7 vs 1.53 ± 0.2, P = .021) (Figure 2B). In contrast, the sevoflurane group had a significantly lower maximal alanine aminotransferase (ALT) level than the desflurane group (153.5 ± 73.6 vs 163.2 ± 82.9, P = .025) (Figure 2D).

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Analysis After PS Matching

The demographic and perioperative characteristics of PS-matched patients (n = 403 pairs) are also listed in Table 1. A mirrored histogram of PS distribution in the 2 groups before and after matching is shown in Supplemental Digital Content 1, Figure 1, http://links.lww.com/AA/C186. After PS matching for all parameters indicated in Table 1 (except colloid use and urine output), there were no statistically significant differences found between the sevoflurane and desflurane groups. After PS matching, there were no significant differences in either the early or late LRI between the sevoflurane and desflurane groups (early LRI: 61.2 ± 41.5 vs 58.9 ± 42.4, P = .438; late LRI: 88.3 ± 44.3 vs 94.6 ± 52.4, P = .168) (Table 2). Furthermore, there was no difference in the maximum PT INR (Figure 2B). The desflurane group had a significantly higher maximal ALT level than the sevoflurane group (167.4 ± 83.4 vs 156.7 ± 70.2, P = .049) (Figure 2D).

Figure 3.

Figure 3.

Figure 4.

Figure 4.

Multivariable logistic regression analysis revealed that male sex (regression coefficient [β], 4.6; 95% confidence interval [CI], 1.6–7.6; P = .003) and RLV (β, –4.92; 95% CI, –5.2 to –4.7; P < .001) were significantly associated with early LRI after LDH (Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/C187). Early LRI (%) was inversely correlated with the RLV (r = –0.725, P < .0001) (Figure 3). In addition, male sex (odds ratio [OR], 3.31; 95% CI, 1.5–7.1; P = .002), BMI (OR, 0.89; 95% CI, 0.8–1.0; P = .019), and ICG R15 (%) (OR, 1.03; 95% CI, 1.0–1.1; P = .025) were associated with DRHF after multivariable logistic regression analysis (Supplemental Digital Content 3, Table 2, http://links.lww.com/AA/C188). Donors who experienced DRHF tended to have a higher preoperative ICG R15 (%) than donors who did not develop DRHF (Figure 4).

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DISCUSSION

In our present study, the sevoflurane group had a higher early LRI than the desflurane group. However, after PS matching, no significant differences were found between the 2 groups in early and late LRIs. Male sex and RLV were associated with LRI. In addition, there was no significant difference in the incidence of DRHF between the 2 groups after LDH.

According to a previous study by Pomfret et al,22 liver volume regenerated 59.8% ± 7.4% in women and 61.5% ± 7.4% in men from its original size after LDH at 7 postoperative days. Our result shows that the liver regenerated by an average 61.7% ± 11.6%, which is comparable with previous results. In addition, the incidence of DRHF was not significantly different between the 2 groups. However, the sevoflurane group showed lower maximal ALT levels until postoperative day 7 compared to the desflurane group.

Sevoflurane and desflurane are the most commonly used halogenated inhalation agents in several surgeries, including LDH.12 The pathophysiology of liver injury after exposure to halogenated inhalation anesthetics is mainly due to their metabolism to hepatotoxic trifluoroacetylated hepatic protein adducts.23 Nevertheless, sevoflurane and desflurane are usually considered safe because their biotransformation to trifluoroacetic acid is minimal.11 In particular, sevoflurane has not been shown to result in the formation of trifluoroacetic acid; hence, the hepatotoxic potential of sevoflurane is considered to be even lower than that of desflurane.24,25 Sevoflurane has also shown advantages in liver surgery regarding anesthetic preconditioning, with sevoflurane preconditioning preventing hepatic injury, defined by transaminase levels, and improving clinical outcome.26 Although the mechanism of hepatocyte protection due to sevoflurane preconditioning is still unclear, it is thought to involve preservation of mitochondrial function27 and increased nitric oxide synthase.28 Desflurane also has a preconditioning effect on the myocardium, but studies have shown conflicting results regarding the preconditioning effects of desflurane and sevoflurane.29–31 In our present study, neither sevoflurane nor desflurane showed any differences with regard to LRI or the incidence of DRHF. The postoperative maximal ALT values did show a statistically significant difference but could not assure clinical relevance.

Liver regeneration is one of the factors reflecting surgical stress and recovery, and many studies have tried to determine the independent factors associated with LRI. Our results showed that the type of anesthetic agent was not associated with LRI, but that male sex and RLV were risk factors for LRI. A negative correlation was shown between RLV and early LRI (Figure 3), with the results indicating that the more liver is resected, the more rapidly liver regeneration occurs. Although the exact mechanism remains to be elucidated, according to Pagano and Gruttadauria,32 larger resections may lead to a higher concentration of cytokines and may induce the liver to grow faster.

Some reports have suggested that there is increased regeneration in younger donors4,8 and female patients, possibly secondary to estrogen.10,33 However, other studies reported that age34 and sex35 did not influence the LRI. We also found no association between age and LRI. Donors who underwent LDH were usually young in our center, with an average age of 27.4 ± 7.9 years; only 8.7% were >40 years. Therefore, a selection bias might have affected the interpretation of these results. Regarding sex, there have been reports of the beneficial role of estrogen in liver regeneration.36,37 As expected, females might have better liver regeneration than males.8 However, studies have also shown the opposite results.22,34 Thus, further studies are needed to determine whether sex affects liver regeneration.

In our study, male sex, BMI, and ICG R15 (%) were associated with DRHF. However, the type of anesthetic agent did not affect DRHF incidence. A previous study determined that age, male sex, and steatosis were risk factors for DRHF.38 In our present study cohort, the male patients had a higher incidence of DRHF. Generally, steatosis affects hepatocyte function and impairs regeneration after major hepatectomy.39 However, in our study, age and steatosis did not affect the incidence of DRHF. In contrast, a high BMI showed a protective effect on the incidence of DRHF.

ICG is a synthetic dye that is eliminated by the liver without extrahepatic metabolism or excretion because it is not reabsorbed in the intestine and therefore avoids enterohepatic recirculation. ICG elimination has been proposed to identify perturbations in liver function that might lead to postoperative failure.40 Our study also revealed the usefulness of the ICG R15 test to predict the DRHF in LDH (Figure 4).

The present study had several limitations of note. First, as our analysis was retrospective, we used PS matching to mitigate selection bias. However, not all potentially confounding factors could be controlled. A disparity between sevoflurane and desflurane use was noted as time period differences existed between the 2 study groups. This was mainly due to the use of sevoflurane in LDH until 2013 when desflurane was adopted as the main inhalational agent for this procedure. However, no significant changes in anesthetic management or surgical technique were noted in these periods that might have affected the results. Second, we were unable to identify specific biomarkers, such as α-fetoprotein, retinol-binding protein, or γ-glutamyl transferase for LRI, or cytokines such as interleukin-1 or glutamate dehydrogenase for hepatic injury, to elucidate the molecular effects of each anesthetic agent. Therefore, the precise mechanisms underlying the actions of each anesthetic agent on LRI and hepatic injury could not be determined. Third, our study patients were from a single center and may have had different outcomes from cases treated at other institutions.

In conclusion, our current findings suggest that both anesthetic agents—sevoflurane and desflurane—can be safely used in LDH without affecting liver regeneration and DRHF after LDH.

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DISCLOSURES

Name: Kyeo-Woon Jung, MD.

Contribution: This author helped provide substantial contribution to the concept and design; acquisition, analysis, and interpretation of the data; drafting of the manuscript; and study supervision.

Name: Wan-Joon Kim, MD.

Contribution: This author helped provide substantial contribution to the concept and design; acquisition, analysis, and interpretation of the data; drafting of the manuscript; and study supervision.

Name: Hye-Won Jeong, MD.

Contribution: This author helped provide substantial contribution to the acquisition, analysis, and interpretation of the data.

Name: Hye-Mee Kwon, MD.

Contribution: This author helped provide substantial contribution to the acquisition, analysis, and interpretation of the data.

Name: Young-Jin Moon, MD.

Contribution: This author helped provide substantial contribution to the acquisition, analysis, and interpretation of the data.

Name: In-Gu Jun, MD, PhD.

Contribution: This author helped provide substantial contribution to the acquisition, analysis, and interpretation of the data.

Name: Jun-Gol Song, MD, PhD.

Contribution: This author helped provide substantial contribution to the concept and design; acquisition, analysis, and interpretation of the data; drafting of the manuscript; and study supervision.

Name: Gyu-Sam Hwang, MD, PhD.

Contribution: This author helped provide substantial contribution to the study design and supervision.

This manuscript was handled by: Tong J. Gan, MD.

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