Introduction
Repair of thoracoabdominal aortic aneurysms (TAAAs) is a highly complex process that
involves interruption of blood flow to vital organs. Despite adjunctive measures,
organ ischemia is unavoidable. Consequently, elevation of hepatopancreaticobiliary
(HPB) laboratory values is common after TAAA repair. It is not clear whether a certain
degree of elevation should trigger further clinical investigation or could provide
information about the degree of ischemic insult. To clarify the clinical significance
of these changes, we elucidated the expected trends in HPB laboratory values after
extensive TAAA repairs.
Materials and Methods
Study Enrollment
The population consisted of 155 patients who underwent Crawford extent II TAAA repair
over a 5-year period and were enrolled in a randomized trial comparing cold crystalloid
and cold blood renal perfusion for renal protection[1 ]. The Institutional Review Board at Baylor College of Medicine approved the randomized
trial and also this retrospective analysis. In accordance with the study protocol,
left heart bypass (LHB), selective visceral perfusion, and cold renal perfusion were
used during all repairs. Patients with preoperative liver dysfunction (conjugated
bilirubin level > 0.3 mg/dL) and preoperative left ventricular dysfunction (ejection
fraction < 20%) were excluded. [Table 1 ] lists additional exclusion criteria for the trial. Baseline laboratory values for
aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase
(GGT), lactate dehydrogenase (LDH), total bilirubin, amylase, and lipase were measured
preoperatively and for 7 days postoperatively. [Table 2 ] shows the patients' preoperative characteristics.
Table 1.
Preoperative Exclusion Criteria
Planned Crawford extent I or IV TAAA repair
Planned repair without left heart bypass
Hypothermic circulatory arrest
Previous TAAA repair
Pseudoaneurysm
Free aortic aneurysm rupture
Inability to monitor left kidney temperature
Impaired renal function (renal failure requiring dialysis, or serum creatinine ≥3
mg/dL)
Impaired left ventricular function (ejection fraction <20%)
Liver disease (conjugated bilirubin >0.3 mg/dL)
Age younger than 18 years
Inability to obtain consent
TAAA, thoracoabdominal aortic aneurysm.
Table 2.
Preoperative Patient Characteristics
Age (years)
62.1 ± 13.1
Male gender (n ; %)
99 (64)
Hypertension (n ; %)
135 (87)
Diabetes mellitus (n ; %)
14 (9)
Smoking history (n ; %)
123 (79)
Peptic ulcer disease (n ; 5%)
13 (8)
Aortic dissection
Acute (n ; %)
2 (1)
Subacute (n ; %)
6 (4)
Chronic (n ; %)
70 (45)
Acute and chronic dissection (n ; %)
2 (1)
AST (IU/L)
23.5 ± 13.9
ALT (IU/L)
21.3 ± 17.7
GGT (IU/L)
43.9 ± 58.8
LDH (IU/L)
252.3 ± 136.5
Total bilirubin (mg/dL)
1.3 ± 4.8
Amylase (U/L)
59.5 ± 6.9
Lipase (U/L)
55.7 ± 92.7
Values are mean ± standard deviation. AST, aspartate transaminase; ALT, alanine transaminase;
GGT, γ-glutamyl transpeptidase; LDH, lactate dehydrogenase.
Surgical Technique
The surgical technique used for TAAA repairs in our practice has been described in
detail elsewhere[1 ]. A standard protocol for selective visceral perfusion was used in all cases. While
the thoracoabdominal aorta was exposed, the patient's body temperature was allowed
to drift to 32-34°C. Left heart bypass was initiated at a flow of 500 mL/min. After
the proximal and mid-thoracic aortic cross-clamps were placed, LHB flow was increased
to 2000 mL/min. The proximal anastomosis was then completed. Left heart bypass was
discontinued, the mid-thoracic aortic clamp was removed, and the ostia of the visceral
arteries were exposed. The celiac and superior mesenteric arteries were perfused via
2 9F Pruitt balloon perfusion catheters (Ideas for Medicine, St Petersburg, Florida),
with isothermic blood from the LHB circuit at a total average flow rate of 400 mL/min.
The intercostal arteries and then the visceral arteries were reattached to openings
in the graft. In 54 patients (35%), a single patch containing the origins of all 4
visceral vessels was reattached to an opening in the side of the graft. [Table 3 ] shows the intraoperative variables.
Table 3.
Intraoperative Variables
Total ischemic time (min)
72.2 ± 22.9
Total celiac artery ischemic time (min)
63.1 ± 13.9
Total SMA ischemic time (min)
62.9 ± 13.8
Unprotected celiac artery ischemic time (min)
41.4 ± 11.3
Unprotected SMA ischemic time (min)
41.2 ± 11.2
Values are mean ± standard deviation. SMA, superior mesenteric artery.
Statistical Analysis
We compared the mean ratios between the postoperative and baseline levels for each
time point with 95% confidence intervals. The maximum postoperative laboratory value
was determined for each patient for each of the 7 laboratory tests of interest ([Table 4 ]
[2 ]). We defined total ischemic time as the period during which an artery is not receiving
blood flow directly from the heart, and unprotected ischemic time as total ischemic
time minus left heart bypass time. To determine the effect of total ischemic times
on the maximum laboratory value, multiple linear regression models were constructed
for each laboratory test. For each model, the age, sex, and preoperative baseline
laboratory value were always included for covariate adjustment. In addition, smoking
status, hypertension, diabetes mellitus, and packed red blood cell (PRBC) transfusion
were tested for potential confounding effects. The total ischemic times were then
tested for a unique effect on the maximum laboratory value, adjusted for the baseline
levels (age, sex, preoperative laboratory value, smoking status, hypertension, diabetes,
PRBC). All of the maximum laboratory test values were extremely skewed, violating
the assumption of normality of residuals for linear regression. A log transformation
was conducted for each of the maximum laboratory tests; this measure showed improved
normality and was the variable modeled. All analyses were conducted with Statistical
Analysis Software, Version 9.3 (SAS, Cary, NC). In multiple regression models testing
for potential factors, backward selection was used with a threshold of P = 0.20 to enter the model and P = 0.10 to stay in the model.
Table 4.
Postoperative Hepatopancreaticobiliary Values
Median ± SD
Normal values[2 ]
AST (IU/L)
86.5 ± 105
12–38
ALT (IU/L)
52 ± 94.5
7–41
GGT (IU/L)
72 ± 104.5
9–58
LDH (IU/L)
543 ± 634.7
115–221
Total bilirubin (mg/dL)
1.8 ± 1.51
0.3–1.3
Amylase (U/L)
169.5 ± 361.4
20–96
Lipase (U/L)
85 ± 591.2
3–43
AST, aspartate transaminase; ALT, alanine transaminase; GGT, γ-glutamyl transpeptidase;
LDH, lactate dehydrogenase.
Results
The temporal patterns of the laboratory values were highly variable ([Fig. 1 ]). The AST levels showed significant early increases, then decreased toward baseline
([Fig. 2 ]). The ALT levels continued to increase during the postoperative period ([Fig. 2 ]). The GGT levels remained near baseline through postoperative day 4, and then increased
significantly to more than 2 times baseline ([Fig. 2 ]). Similarly, the LDH levels also increased immediately and remained significantly
elevated throughout the week before trending downward ([Fig. 2 ]). The amylase levels increased initially but then trended downward toward baseline
([Fig. 3 ]). The lipase levels increased initially, returned to near baseline levels, and then
slowly increased again ([Fig. 3 ]). The total bilirubin levels were highly variable and showed no definite trend.
Figure 1. Overall summary of changes in hepatopancreaticobiliary values after thoracoabdominal
aortic aneurysm repair. AST, aspartate transaminase; LDH, lactate dehydrogenase; ALT,
alanine transaminase; GGT, γ-glutamyl transpeptidase.
Figure 2. Changes in aspartate transaminase (AST) values, alanine transaminase (ALT) values,
γ-glutamyl transpeptidase (GGT) values, and lactate dehydrogenase (LDH) values after
thoracoabdominal aortic aneurysm repair.
Figure 3. Changes in amylase values, lipase values, and total bilirubin values after thoracoabdominal
aortic aneurysm repair.
In the adjusted analysis, the total ischemic times were not predictive of maximum
laboratory values for amylase, ALT, or total bilirubin. Ischemic times were predictive
of maximum AST, lipase, GGT, and LDH values. After adjusting for age, sex, and preoperative
baseline AST levels, we found that smoking [β = 0.347; standard error (SE) = 0.109;
P = 0.0019], PRBC (β = 0.035; SE = 0.013; P = 0.0064), and the total ischemic time (β = 0.005; SE = 0.002; P = 0.0133) were significantly associated with the maximum AST value. Therefore, an
increase of 1 min in the total ischemic time was associated with an approximate increase
of 0.005 unit in the log of the maximum AST value (10 min would raise the log of the
maximum AST by 0.05, 100 min would raise the log of the maximum AST value by 0.5).
After adjusting for age, sex, and the preoperative baseline lipase level, we found
that the total celiac artery ischemic time (β = 0.027; SE = 0.008; P = 0.0011) was significantly associated with the maximum lipase value. None of the
other potential confounders were significant.
After adjusting for age, sex, and the preoperative baseline GGT level, we found that
the total ischemic time (β = 0.005; SE = 0.0027; P = 0.0612) was significantly associated with the maximum GGT value. None of the other
potential confounders were significant.
Furthermore, after adjusting for age, sex, and the preoperative baseline LDH level,
we found that smoking (β = 0.225; SE = 0.100; P = 0.0264) and the total ischemic time (β = 0.0055; SE = 0.0016; P = 0.0011) were significantly associated with the maximum LDH value.
Eight patients (5.2%) died within the first 30 days. Five patients (3.2%) developed
paraplegia or paraparesis. No patients developed clinically significant hepatic, pancreatic,
or gastrointestinal complications.
Discussion
Hepatosplanchnic hypoperfusion and ischemia are rare, but severe, complications after
cardiac surgery, and even transient hepatosplanchnic hypoperfusion can lead to severe
postoperative complications[3 ]. In TAAA repair, hepatosplanchnic ischemia is unavoidable, and patients undergoing
repair of extent II TAAAs can have unprotected ischemic times of greater than 40 min.
In the postoperative period, an alarming elevation of HPB enzymes is common, but the
clinical significance of this elevation is not clear. We found that, in the absence
of significant heart and liver dysfunction, patients undergoing elective repair of
extent II TAAAs had substantial variations in their HPB laboratory values.
Hepatic dysfunction is difficult to measure in the postoperative period because commonly
performed laboratory measurements reflect only gross functional abnormalities and
are more indicative of cell damage than of dysfunction[4 ]
[5 ]. This is particularly evident in the liver, which has regional variations in the
number of hepatocytes and in the ability of different hepatic cell types to withstand
hypoxia. We know from metabolic studies of visceral organs protected by adjunctive
measures that the resulting flow is not physiologic[6 ]. Although normal liver blood flow may resume as early as 4-6 h after surgery, the
change in hepatocyte metabolism resulting from diminished flow may persist for longer
periods[1 ]. Increases in liver enzyme levels can indicate only hepatocyte damage, not regional
perfusion or functional defects. Nevertheless, we chose to use the results of commonly
performed liver function tests as markers for liver injury and not liver dysfunction.
Because cytoplasmic enzymes are present in liver parenchymal cells, AST and ALT are
indicators of parenchymal injury; however, cardiac, skeletal muscle, and hematologic
disorders can also cause elevation of these enzymes. In our series, we found that,
despite a continued increase in ALT values throughout the 7-day postoperative period,
maximal ALT values were not associated with the total ischemic time, even after adjusted
analysis. In contrast, after adjusting for age, sex, and preoperative baseline values,
we found that maximal AST values were associated with a history of tobacco use, PRBC
transfusion, and the total ischemic time. Because ALT is more sensitive than AST as
an indicator of liver damage, elevations of AST may reflect systemic damage resulting
from ischemia rather than ischemic damage to the liver. For instance, smoking is known
to increase oxidative stress in the body, and differences between ALT and AST after
adjusted analysis may relate to differences in the susceptibility of multiple organs
to ischemic damage[7 ]. Elevation of ALT and AST levels has also been correlated with changes in the iron
concentration after transfusion[8 ]. Transfusion of blood products leading to changes in the chelatable iron pool may
exceed the hepatocellular iron-chelating capacity and lead to a greater increase in
AST than in ALT levels. Because we did not measure the preoperative and postoperative
iron levels, we cannot comment further about this association.
GGT and LDH are also widely distributed in the liver and other tissues. In this study,
we found that both enzymes became increasingly elevated with time and also were associated
with the total ischemic time. However, elevations of these enzymes can be caused by
other disorders in the absence of liver disease or dysfunction and are not specific
indicators of liver ischemia or injury. Similarly, elevations of the total bilirubin
level can be caused by factors other than liver injury. Cholestasis secondary to impaired
bile flow may be due to intrahepatic causes (hepatocellular dysfunction resulting
from ischemia) or extrahepatic causes, such as biliary obstruction. In this series,
we did not find any pattern for changes in the total bilirubin level.
Although the synthetic function of the liver is best assessed by analyzing coagulation
factors, we did not do this because (1) there was little variation in these laboratory
values, (2) patients often received blood products in the immediate postoperative
period to correct coagulopathy, and (3) because of the blood's interaction with the
Dacron graft, patients were often in a mild state of disseminated intravascular coagulation
after surgery. Moreover, albumin levels depend on a number of factors, including nutritional
status and renal dysfunction, and because of its long half-life, albumin is not a
marker of acute hepatic dysfunction. Therefore, the interpretation of abnormal laboratory
values depends on the type of abnormality that predominates: hepatocellular damage,
abnormal synthetic function, or cholestasis. In this instance, patients with underlying
liver dysfunction (e.g., hepatitis C), as diagnosed by preoperative liver function
tests, were excluded from our study.
Elevations in amylase and lipase levels in the postoperative period are indicative
of pancreatic ischemia. However, in this study, we found that only a postoperative
increase in lipase was associated with the total ischemic time. This insult was manifested
by the immediate elevation of pancreatic enzymes on postoperative day 1, followed
by a later increase in lipase levels during the ensuing postoperative period. However,
depending on the extent of dissection and bowel manipulation, it is common practice
to resume enteral nutrition after the return of bowel function, usually around postoperative
day 4. The resulting increase in lipase levels may reflect an exacerbation of pancreatic
damage induced by the surgery. All patients in our series with elevation of amylase
or lipase levels tolerated feeding without abdominal pain or other sequelae, indicating
that, despite evidence of ischemic pancreatitis, total metabolic function might not
have changed.
To assess the degree of ischemic insult, we compared the ratios between postoperative
values and baseline laboratory results for each postoperative day. We did not perform
a frequency analysis to further stratify risk factors associated with specific organ
dysfunction. Analyzing these risk factors would have been inconsequential because
patients with preoperative liver or renal dysfunction were excluded, few patients
had diabetes (9%), and most patients smoked (79%). Instead, we used a multiple linear
regression model with generalized estimating equations, which allowed us to adjust
for the correlated nature of the laboratory values measured. Because the study's main
goal was to establish generalized trends in the postoperative period, we did not perform
a statistical analysis examining all the different variables that correlated with
extreme postoperative laboratory values.
The primary determinant of whether a patient will develop postoperative multiple organ
dysfunction (MOD) is visceral ischemia lasting for longer than 40 min[9 ]
[10 ]. In our series, the mean total ischemic time was 72.2 min, with a mean unprotected
celiac artery ischemic time of 41.4 min and mean superior mesenteric artery ischemic
time of 41.2 min. However, none of our patients developed MOD. Use of adjunctive measures
such as LHB significantly reduces the duration of visceral ischemia. Although our
patients had a mean ischemic time of >40 min, selective visceral perfusion may have
offered a protective effect against MOD, even in the presence of elevated postoperative
HPB laboratory values.
Despite improved surgical techniques, spinal cord ischemia and renal failure remain
the most devastating complications associated with repair of TAAA. The rate of paraplegia
in our series was 3.2%. There was no correlation between significant elevations in
HPB laboratory values and the development of either paraplegia or renal failure. However,
in paraplegia patients, this may have been due to a small sample size. Most importantly,
none of the patients in our series developed clinically significant postoperative
HPB dysfunction. This may have been due to the fact that patients had relatively normal
preoperative liver function and moderate-to-good left ventricular function, and most
often underwent elective TAAA repair. Safi et al.[11 ] have shown that a history of hepatitis, extent II aortic aneurysm, ruptured aortic
aneurysm, and emergency presentation are significant predictors of elevated postoperative
liver function values. Therefore, patients with borderline liver function or prolonged
ischemic times may be pushed into liver failure and perhaps even multisystem organ
failure.
Limitations
This study has a number of limitations. First, although data were collected prospectively
in accordance with a randomized clinical trial protocol, the secondary analysis of
HPB enzyme levels was retrospective and, thus, consequently can provide only a descriptive
picture of the metabolic changes that occur in patients who undergo elective repair
of extent II TAAAs. Second, use of a longitudinal analysis model over a 7-day period
limits the amount of information that can be gained. Third, we acknowledge that providing
400 mL/min through balloon-perfusion catheters may not provide optimal visceral flow.
The 9F catheters have been used in our practice in part to facilitate safe catheter
placement in vessels that often have small ostia and atherosclerotic plaques and to
avoid vessel injury and dislodgement of atherosclerotic debris. Although we have been
satisfied with the clinical results achieved when using these catheters (an extremely
low incidence of overt hepatic, pancreatic, and gastrointestinal ischemic complications),
the current study suggests that substantial subclinical organ injury occurs and that
use of larger catheters warrants consideration. The study leaves several significant
questions unanswered, such as (1) whether there is a relationship between the duration
of visceral ischemia and injury to the liver or other organs, (2) whether any of the
abovementioned preoperative HPB laboratory values are more or less specific in predicting
organ dysfunction postoperatively, (3) whether there is a relationship between HPB
injury and dysfunction of other organs (as indicated by elevated laboratory values)
or development of multisystem organ failure, and (4) whether adjunctive measures are
significantly protective in patients who have preoperative hepatic dysfunction or
cirrhosis to allow safe repair of TAAAs. Moreover, in some instances proximal aortic
clamping is not possible; the trends revealed by this study can not be applied to
patients in whom circulatory arrest is used.
Conclusion
In patients undergoing TAAA repair, HPB enzyme levels are expected to be elevated
postoperatively in the absence of liver dysfunction or multisystem organ dysfunction.
In this study, we established the normal expected patterns for HPB laboratory values
in the postoperative period after TAAA repair. In some cases, the degree of elevation
correlated with the duration of ischemia. We hope that our findings may be useful
for evaluating laboratory results in similar cases and for interpreting the results
of future studies related to visceral protection.
