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The Effect of General Anesthesia on Aminotransferase Levels in Patients with Elevated Aminotransferase Levels: A Single-Center 5-Year Retrospective Study

Cho, Youn Joung MD; Park, Young Jae MD; Min, Se Hee MD; Ryu, Ho-Geol MD, PhD

doi: 10.1213/ANE.0000000000001030
Patient Safety: Research Report

BACKGROUND: The effect of commonly used anesthetics on postoperative aminotransferase levels in patients with preoperatively elevated values is unclear.

METHODS: The medical records of 25,567 adult patients undergoing elective general anesthesia were retrospectively reviewed. Patients were classified into normal (≤40 IU/L), mild (41–119 IU/L), moderate (120–199 IU/L), and marked elevation (200+ IU/L) groups according to their preoperative alanine aminotransferase levels. Changes in these levels before and after general anesthesia were compared according to the anesthetics used.

RESULTS: Among the patients with preoperative mild or moderate elevation, 97.8% (2589/2647) did not show a higher alanine aminotransferase level after surgery. Compared with total IV anesthesia (TIVA), sevoflurane showed adjusted odds ratios (95% confidence interval) of 1.27 (1.10–1.46) for mild, 1.33 (0.86–2.05) for moderate, and 3.35 (1.58–7.04) for marked postoperatively elevated levels of alanine aminotransferase versus normal levels. Similarly, compared with TIVA, desflurane showed adjusted odds ratios (95% confidence interval) of 1.21 (0.96–1.53) for mild, 1.44 (0.70–2.94) for moderate, and 3.18 (1.14–8.89) for marked postoperatively elevated levels of alanine aminotransferase versus normal levels (P = 0.05).

CONCLUSIONS: In most cases, postoperative alanine aminotransferase levels did not worsen even in patients with preoperatively elevated levels. Sevoflurane was associated with increased odds for postoperative elevation of these levels after general surgery compared with TIVA.

From the Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, South Korea.

Accepted for publication August 12, 2015.

Funding: Departmental.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Ho-Geol Ryu, MD, PhD, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. Address e-mail tohogeol@gmail.com.

Serum aminotransferases, the most commonly used surrogate markers of liver injury, are sometimes measured as part of preoperative evaluation in patients undergoing elective surgical procedures. The reported incidence of serum elevated aminotransferases ranges between 0.5% and 7.9%, depending on the population studied.1–3 Surgical procedures requiring general anesthesia may be postponed or cancelled for further evaluation when the serum aminotransferases are elevated without a clear cause. Additional evaluation may range from repeated measurements of aminotransferases to liver biopsy, depending on the patient’s medical history and the clinical situation.4,5

Apart from halothane, which is no longer in use in most parts of the world, modern day volatile anesthetics do not appear to affect serum aminotransferase levels after general anesthesia in patients with normal preoperative values.6–9 However, the effect of volatile anesthetics on aminotransferase levels in patients with preoperatively elevated levels is unclear. Thus, there is no consensus about the level of preoperatively elevated aminotransferase that can be tolerated (with regard to postoperative hepatocellular injury) after general anesthesia with commonly used volatile anesthetics.

The purpose of this study was to evaluate the effect of the commonly used volatile anesthetics, sevoflurane and desflurane, on postoperative serum aminotransferase levels and to compare these with total IV anesthesia (TIVA) in patients with preoperatively elevated aminotransferase values.

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METHODS

This retrospective observational study was approved by the IRB of Seoul National University Hospital (1107-072-369). Informed consent from patients was waived by the IRB because of the retrospective observational nature of the study.

Adult patients (≥18 years) who underwent elective surgery under general anesthesia using sevoflurane, desflurane, or TIVA as their primary anesthetic between January 1, 2006, and December 31, 2010, at Seoul National University Hospital were screened for eligibility. Data stored in the electronic medical record system from 2006 were available for the study. Therefore, data from all patients who underwent general anesthesia before 2011 (the year the study was initiated) were collected. TIVA was performed using continuous infusions of propofol and remifentanil with target-controlled infusion pumps. Patients whose anesthetic was converted to general anesthesia after regional anesthesia, or who received >1 type of anesthetic, were excluded. Patients without preoperative (within 60 days before surgery) or postoperative (within 10 days after surgery) liver function test results were also excluded.

Types of surgery/procedures included upper and lower abdominal, thoracic, and orthopedic surgery, gynecologic and obstetric procedures, ophthalmic surgery, head and neck procedures, neurosurgery, plastic surgery, and urologic procedures. Hepatic, biliary, and cardiovascular surgery without cardiopulmonary bypass and surgery using cardiopulmonary bypass were excluded because of their potential effect on postoperative liver function test results.

Patient characteristics, including sex, age, anesthesia time, type of anesthetics used, type of surgery, and use of vasopressors during surgery, were obtained from the electronic medical records.

Alanine aminotransferase (ALT) levels were chosen as the representative surrogate marker of liver injury. Unlike aspartate aminotransferase, which is found in both hepatic and extrahepatic sites, ALT is concentrated in the liver, making it a more sensitive and specific indicator of hepatocellular injury.10,11 Laboratory values within 2 months of scheduled surgery were considered valid for preanesthetic assessment per the Anesthesiology Department policy. Preoperative ALT was defined as ALT measured most adjacent to surgery within the 60 days preceding the operation and postoperative ALT as most adjacent within the 10 days after the operation.

The upper limit of normal (ULN) aminotransferase level is 40 IU/L in our institution. Preoperative and postoperative ALT values were classified into 4 groups: normal (≤40 IU/L), mild (up to 3× ULN, 41–119 IU/L), moderate (3×–5× ULN, 120–199 IU/L), and marked elevation (5>× ULN, 200+ IU/L) groups.

The primary outcome was change in ALT levels compared between the different anesthetics used. The risk of ALT elevation after surgery depending on preoperative ALT level, age, sex, anesthesia time, use of vasopressors, and transfusion was also assessed. Factors associated with increased levels of postoperative ALT were also investigated.

Statistical analysis was performed using SAS statistical software (SAS system for Windows, version 9.2; SAS institute, Cary, NC) and R software (R for Windows, version 3.0.1/R package—pmlr).

Patient characteristics and perioperative variables between preoperative ALT groups were compared using Kruskal-Wallis test for continuous variables and Pearson χ2 or Fisher exact test for categorical variables. To evaluate risk factors associated with postoperative ALT elevation, multinomial logistic regression was performed, and the adjusted odds ratio of each factor was calculated. When separation was detected because of low-frequency cells, penalized maximum likelihood was used to estimate the odds ratio. The linearity assumption in continuous variables (age and anesthesia time) was examined using restricted cubic spline.12 On the basis of the restricted cubic splines and clinical relevance that increased age and anesthesia time would result in elevation of postoperative ALT, they were assumed as linear in the model. Factors with a P value of <0.2 were included in the multivariate multinomial logistic regression, and stepwise selection was used to derive the final model. The interaction terms between each variable in the model and anesthetics used were examined. The overall significance of the factors in the model was reported using type III P value, the significance level after adjusting the other factors in the model. A P value of <0.05 was considered significant.

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RESULTS

Figure 1 illustrates the process for screening and identifying patients for analysis. After screening 72,456 patients for eligibility, 46,889 patients met the exclusion criteria.

Figure 1

Figure 1

Baseline characteristics of the remaining 25,567 patients who had undergone elective surgery with general anesthesia are summarized in Table 1. There were no differences in the frequency of anesthetics used or the duration of anesthesia between groups classified according to preoperative ALT levels. Preoperatively, 89.5% (22,883/25,567) of patients showed a normal ALT and 93.4% (2508/2684) of the abnormal ALT showed mild elevations (Table 2).

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

In patients with mild or moderate preoperative ALT elevation, 97.7% and 98.6% of patients showed either no change or improved postoperative ALT, respectively (Table 2). In patients with marked preoperative ALT elevation, 10.8% remained in the same category after surgery (Table 2). Multivariable analysis showed that sevoflurane was associated with increased odds for elevated postoperative ALT compared with TIVA after adjusting for other factors (Table 3). Statistically, being a male, age, and anesthesia time were also identified as factors associated with increased postoperative ALT (Table 3).

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DISCUSSION

Our study results show that 96.4% (2587/2684) of patients undergoing elective surgery under general anesthesia with preoperatively elevated ALTs show normal or mild elevation of ALT postoperatively. Even in patients with markedly elevated preoperative ALT levels, most of patients showed improved ALT levels after surgery. Only 2.2% (58/2647) of patients showed worse postoperative ALT levels compared with those before surgery. There was a small increased adjusted odds for ALT elevation with anesthesia using sevoflurane when compared with TIVA. As expected, patients who had elevated ALT before surgery showed greater odds of increased postoperative ALT.

Currently, preoperative liver function testing is not recommended in asymptomatic patients.13,14 The caveat of the recommendations is that all recommendations are based on low-quality evidence.13 After reports suggesting association between anesthesia with halothane and postoperative hepatic necrosis,15–17 many institutions (including ours) have continued to routinely screen for hidden liver dysfunction in patients scheduled for elective surgery, despite the evidence that volatile anesthetics used today have no effect on hepatocellular injury.18,19 As shown in our results (Table 1), 99.3% of the patients undergoing surgery had either normal or mildly elevated preoperative ALT levels (<120 IU/L), which can be used as a justification of the current guidelines/practice advisory that do not recommend routine testing for liver dysfunction.

Our study shows that 10.5% of our patients show elevated preoperative serum ALT values, which is more than the 2.5% inherent in the “reference” value. This is relatively consistent with previous observations, in which the prevalence of elevated aminotransferase levels was 4.1% to 11.0% in the general Korean population during regular health checkup.20,21 This can be explained by multiple factors, including limitations inherent in the reference range, relatively high prevalence of hepatitis B virus carriers in Korea (3%–4% of general population),21,22 and the bias because of analyzing hospitalized patients requiring surgery.23

Currently, there is no consensus regarding the classification of elevated aminotransferase levels. Studies have used arbitrary categories based on multiples (commonly ×2, ×3, or ×5) of ULN.24,25 Similarly, patients in our study were classified into 4 groups using multiples (×3 and ×5) of ULN (40 IU/L).

There are only a few studies in the literature that evaluate the effect of anesthetics on hepatocellular injury using aminotransferases as surrogate markers. In a study that compared desflurane with isoflurane in 40 patients with either hepatic or renal disease, there was no change in serum aminotransferases or serum creatinine levels after surgery.26 In a randomized trial of 70 living liver donors undergoing right hepatectomy, there was no difference in ALT levels between donors who received desflurane and TIVA using propofol and remifentanil.27 In a similar randomized trial of 74 living liver donors undergoing right hepatectomy, donors who received sevoflurane for anesthesia showed higher ALT levels compared with those who received desflurane.28 Although the results were in patients undergoing liver resection, the findings were similar to ours.

Our results showed slightly increased postoperative ALT levels in patients who received sevoflurane as the main anesthetic. Possible explanations may include hepatotoxic potential of compound A, a degradation product of sevoflurane in reaction with carbon dioxide absorbent during closed-circuit general anesthesia.29 However, the increments were small, and the clinical importance is likely to be minimal. Therefore, preexisting hepatic injury does not seem to increase the risk of further hepatocellular injury because of anesthetic selection.

Considering the retrospective nature of the study, selection bias of patients with elevated ALTs toward selecting anesthetics was considered. Our anesthesiology department does not have an anesthesia protocol concerning patients with elevated aminotransferases, and the type of anesthetic agents chosen is at the discretion of the attending anesthesiologist. Consequently, as shown in Table 1, there were no differences in the distribution of anesthetics used between the groups.

The following limitations should be considered when interpreting our results. First, >35,000 patients were excluded because of the absence of a postoperative liver function test. Because 93% of these patients had normal preoperative ALT, it can be speculated that these patients were considered unlikely to benefit having postoperative ALT levels checked, undergoing low-risk surgery, or both. Second, clinical outcomes, such as mortality, morbidity, and hospital length of stay, were not addressed. The focus of our study was to evaluate the effect of anesthetics during surgery on hepatocellular injury. Consequently, we can draw no conclusions regarding clinical outcomes. Third, we excluded patients undergoing biliary, hepatic, or cardiovascular surgery because of the expected effects on liver function tests inherent to the surgical procedure. Therefore, our results have limited value for patients undergoing these procedures. Fourth, there is a potential for selection bias owing to the distribution of patients included in our retrospective study. Approximately 80% of the included patients received sevoflurane during general anesthesia compared with 5% who received desflurane, whereas 15% of patients received TIVA. Sevoflurane and desflurane showed similar odds ratios for postoperative ALT levels compared with TIVA. However, statistical significance was found with sevoflurane but not desflurane. It is possible that had there been more patients receiving desflurane for general anesthesia, the results may have been similar to those of the patients who received sevoflurane.

In conclusion, our study suggests that most ALT levels in patients with preoperatively elevated ALT will either improve or remain unchanged after surgery under general anesthesia. Compared with TIVA, sevoflurane seems to be associated with slightly greater odds for elevated postoperative ALT levels.

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DISCLOSURES

Name: Youn Joung Cho, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and statistical work.

Attestation: Youn Joung Cho has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Young Jae Park, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Young Jae Park has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Se Hee Min, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Se Hee Min has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ho-Geol Ryu, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Ho-Geol Ryu has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Sorin J. Brull, MD.

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ACKNOWLEDGMENTS

The authors greatly acknowledge the skillful assistance of the Medical Research Collaborating Center concerning the statistical analysis.

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