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1 Imaging Diagnosis Center, Clinic Hospital, Villarroel 170, 08036 Barcelona,
Spain.
2 Gastrointestinal Diseases Unit, Clinic Hospital, 08036 Barcelona, Spain.
Received December 19, 2002;
accepted after revision March 31, 2003.
Address correspondence to A. García-Criado
(magarcia{at}clinic.ub.es).
Abstract
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MATERIALS AND METHODS. We retrospectively studied the transplanted livers of 90 patients who had been examined on Doppler sonography within the first 3 days after grafting. Seventeen variables from organ donors, transplant recipients, graft characteristics, and surgical procedures were investigated. Early clinical evolution was also analyzed. Follow-up was performed for 5 years.
RESULTS. Forty-one (45.6%) of the 90 patients showed a high resistive index at the hepatic artery during the first 72 hr after transplantation. Two factors showed a statistically significant effect on the occurrence of a high resistive index at the hepatic artery immediately after transplantation: an older liver donor (p = 0.008) and extended preservation time (p = 0.005). No relation with early graft function was detected. The incidence of bile duct complications, retransplantation, or death was not higher at follow-up in patients with high-resistance flow than in those with normal flow.
CONCLUSION. High-resistance flow at the hepatic artery detected on Doppler sonography during the period immediately after transplantation is a frequent finding and is related to older donor age and prolonged period of ischemia. This finding has neither significant clinical repercussions nor prognosis implications for early and long-term follow-up.
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The aim of this study was to investigate the contributing factors and the clinical repercussions of high-resistance flow at the hepatic artery immediately after transplantation. For this reason, we analyzed donor and recipient characteristics, preservation, and surgery-related factors that were correlated with early and late graft function in a series of consecutive liver transplant recipients.
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All Doppler sonography studies were performed by staff radiologists working in the sonography section. The studies were performed on sonography equipment with color Doppler capability (SSH 140 A, Toshiba, Nasu, Japan) and a 3.75-MHz transducer. Real-time imaging was used to assess the echogenicity of graft parenchyma, focal liver lesions, intra- and extrahepatic bile ducts, and the presence of intraabdominal fluid collections. Doppler examinations were used to study blood flow patency in the portal vein, the hepatic veins, the vena cava, and the hepatic artery.
Hepatic artery flow was studied at an extrahepatic level (hepatic hilum,
near the porta hepatis) and an intrahepatic level (right or left arteries
following the course of the main intrahepatic portal vein branches). The
resistive index (RI) [12] was
calculated at both levels using the following formula:
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Only patients with a patent hepatic artery seen on baseline Doppler sonography or on arteriography performed when no flow was found on Doppler sonography were included in the study.
Four patients were excluded from the study because of hepatic artery thrombosis, and one patient was excluded because of hepatic artery stenosis detected during the immediate postoperative period. The diagnosis for each of these five excluded cases was proven on arteriography. Baseline sonography showed an absence of flow in the four patients with hepatic artery thrombosis. For the patient with hepatic artery stenosis, baseline sonography showed an RI of 1 at the hilum with low-resistance intrahepatic flow (RI < 0.55) and tardus-parvus morphology.
Patients with a low RI (< 0.55) on initial Doppler sonography (n = 3) were not considered because the aim of the study was to analyze the cases of high-resistance flow, comparing them with normal cases.
Therefore, the study group was composed of the remaining 90 liver transplant patients: 57 men and 33 women who ranged in age from 16 to 65 years (mean age, 48.5 years). The blood group of the donor was compatible with that of the recipient in all cases except one, a patient with fulminant hepatitis that required emergency transplantation. Livers explanted were preserved in University of Wisconsin solution (Bristol-Myers Squibb, Madrid, Spain) only or University of Wisconsin solution combined with Euro-Collins solution (Lab Estevez, Madrid, Spain) [13]. The liver transplantation procedure in the recipient was performed with standard surgical techniques [14]. All patients had similar perioperative intensive care and immunosuppression therapy.
Patients were divided in two groups according to the hepatic artery waveforms seen on baseline Doppler sonography. Group 1 consisted of patients with a normal RI (0.55-0.80) [9, 15] (Fig. 1), and group 2 was composed of patients with a high RI (> 0.80). In patients with a high RI, the findings were subsequently categorized into four waveforms: the type 1 waveform was a normal systolic velocity peak with continuous but decreased diastolic flow (0.8 < RI < 1) (Fig. 2); type 2, a normal systolic velocity peak with an absence of diastolic flow (RI = 1) (Fig. 3); type 3, a Doppler signal constituted only by low systolic velocity peaks (Fig. 4); type 4, an absence of flow (Fig. 5) on sonography with a patent artery but with sluggish flow on arteriography. Cases of type 4 waveform were included in the analysis because they represent extreme cases of high-resistance arterial flow. In these patients, arterial flow was so attenuated on the Doppler study that an arteriographic study was required to confirm hepatic artery patency.
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To determine their possible influence on the presence of a high RI on the posttransplant study, 17 variables from liver donors, we analyzed transplant recipients, graft characteristics before the implant, and surgical procedures (Tables 1 and 2). Donor factors analyzed were sex, age, and cause of brain death (traumatic, vascular, or other). Recipient factors analyzed were age, sex, Child-Pugh classification before transplantation, viral serology before transplantation (hepatitis A virus, hepatitis B virus, hepatitis C virus, or no virus), and indication for transplantation. Diagnosis was grouped in five categories: liver cirrhosis (alcohol-induced, hepatitis B virus, hepatitis C virus, cryptogenic cause, or hemochromatosis), chronic cholestatic liver disease (primary biliary cirrhosis or sclerosing cholangitis), metabolic diseases (amyloidosis or hyperoxaluria), fulminant liver failure, and retransplantation.
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Graft and surgical factors analyzed included the type of arterial anastomosis, graft ischemia time, surgery time, and transfusion of RBCs and platelets. Findings on the intraoperative liver biopsy performed after reperfusion were also studied for the presence of ischemic changes (absent, mild, or moderate) and steatosis (absent, mild, moderate, or severe). With the aim to obtain indirect information about portal flow, we also analyzed cardiac output after reperfusion and the increase of this postreperfusion cardiac output in relation to the pretransplantation cardiac output.
Factors related to the early clinical evolution were investigated to find a possible relationship between the Doppler finding and graft function: alanine aminotransferase level 72 hr after transplantation, early postoperative graft function grade based on a scoring system previously described [16], results of a needle biopsy 3-15 days after liver transplantation when it was performed (normal, mild or moderate rejection, ischemia, cholestasis, or other), and duration of stay in the intensive care unit and time until discharge from the hospital (Table 3).
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Both clinical and Doppler sonography followups after transplantation were performed for a period of 5 years. The sonography follow-up was performed at the first and third month after transplantation and every 6 months thereafter. Deaths, bile duct complications, and retransplantations during this period were analyzed.
Univariate analyses (Mann-Whitney test for quantitative variables and chi-square test for qualitative variables) were used to compare the parameters investigated in the two groups of patients classified according to the findings on the baseline sonography study of the hepatic artery. A Pearson's correlation analysis was analyzed for the variables that presented a statistically significant difference (p < 0.05) in the univariate analyses to discard a relation between them.
The variables with a statistically significant difference in the univariate study were also subsequently analyzed (Kruskal-Wallis test) for the four previously described types of high-resistance arterial flow on Doppler sonography.
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In 34 of the 41 patients, a second Doppler study performed during the 7 days after the baseline study showed recovery of the diastolic blood flow (RI < 0.8). In the remaining seven patients, the flow remained altered on the second sonography examination. In six of them, a third sonography study performed in the first 15 days after transplantation disclosed that blood flow at the hepatic artery had normalized. The RI in the remaining patient remained high (0.85).
Only one of the study group patients developed hepatic artery thrombosis. In a patient with a high RI (type 1 waveform) on the baseline study that recovered during the follow-up, an absence of flow was seen on a Doppler study performed the 19th day after transplantation because hypertransaminasemia was detected.
Data from organ donors, transplant recipients, and surgical variables are
summarized in Tables 1 and
2. When statistical analyses
were performed with both discrete and continuous variables, two factors showed
a statistically significant effect on the occurrence of high-resistance flow
at the hepatic artery immediately after transplantation: older (
50 years
old) donor age (p = 0.008) and extended preservation time (p
= 0.005). Both factors acted independently in the increase of the RI (a
Pearson's correlation index, r = 0.175). The analysis correlating
these two factors with the degree of arterial Doppler waveform impairment
(types 1-4) did not show statistically significant differences
(Table 4).
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A third factor that showed a statistically significant effect on the occurrence of high-resistance flow at the hepatic artery immediately after transplantation was the presence of chronic cholestatic disease as the indication for transplantation (p = 0.038).
No influence was detected from the remaining donor and recipient factors evaluated, such as sex of the donor and recipient, the cause of brain death in the donor, the age of liver recipient, Child-Pugh classification before liver transplantation, or existence of hepatic viral infection. No correlation was found with the results of intraoperative hepatic needle biopsy, and neither more ischemia nor steatosis was seen more often in the group with a high RI than in the group with a normal RI.
Surgical factors such as the type of arterial anastomosis, surgery time, or blood products required for transfusions were not associated with the elevation of the RI. No differences in cardiac output after reperfusion or in the increase of output in relation with pretransplantation cardiac output were seen between patients with a normal RI and those with a high RI.
No correlation between Doppler findings and the early clinical course after liver transplantation was found. There was no association between high-resistance hepatic artery flow and early postoperative graft function and the duration of hospital or intensive care unit stay as an indirect indicator of early evolution. The findings of percutaneous hepatic needle biopsy performed 3-15 days after liver transplantation because of the presence of graft dysfunction did not show statistically significant differences between the group with normal flow and the group with a high RI (RI > 0.8). Data about early graft function are shown in Table 3.
On follow-up examinations, which were performed for 5 years, no more bile duct complications were found in the group with a high RI. Only one case of intrahepatic bile duct stenosis was detected in each group. Neither more deaths nor a higher incidence of graft loss was seen in the group with a high RI when compared with the group with a normal RI. Six (12.2%) of the 49 patients in the group with a normal RI underwent a second transplantation, and 12 (24.5%) died. In the group with high-resistance arterial flow, three (7.3%) of 41 patients received a second graft and eight (19.5%) died.
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Recently, a group of researchers suggested that portal flow is inversely related to arterial flow [21]. After reperfusion, there is portal hyperflow that is related to elevated cardiac output. In our study, we analyzed cardiac output after reperfusion and also the increase in cardiac output after reperfusion in relation to the pretransplantation cardiac output. No differences were found between the groups with a high versus a normal RI.
Our results suggest that a high RI might be related to graft and donor conditions. We found cold ischemia time of the graft is longer in patients with a high RI.
However, factors that assessed hepatocyte injury such as alanine aminotransferase level and liver biopsy after reperfusion showed no correlation with a high RI. This finding is in accordance with previous works, mostly in vitro studies, that analyzed the effect of hypothermic storage using factors such as oxygen uptake, ATP content, and histologic evaluation. These studies showed that hepatocyte function is relatively well preserved after 24 hr of cold preservation, being more resistant to ischemic insult than sinusoidal endothelial cells [22]. Nowadays, evidence points to nonparenchymal cell damage or activation during cold preservation and reperfusion as the key events of hepatic injury. Hypothermia during the preservation period causes morphologic changes in the sinusoidal endothelial cells, which become rounded, detached, and slough into the sinusoidal lumen [23, 24]. Liver sinusoids also contain tissue macrophages (Kupffer's cells) that under ischemic conditions produce a number of angiogenic mediators and other cells (sinusoidal endothelial, stellate, hepatocytes) that may participate in the microcirculatory disturbance. Furthermore, endothelial cells are the targets of reperfusion injury [23].
Reperfusion injury occurs to liver grafts even in cases in which the damage caused by the reperfusion has no clinical repercussions [25]. These changes caused by the ischemic and reperfusion damage could increase arterial resistance and explain the high RI found immediately after transplantation.
Microcirculatory disturbance after cold preservation is reported to be higher in the fatty liver than in the nonfatty liver [26]. However, we found no relation between the RI and the presence of steatosis in the nine fatty livers in our study, suggesting that steatosis alone is not enough to cause an elevation of the arterial resistance in the liver.
A similar alteration in the arterial resistance during the immediate postoperative period has been observed in the transplanted kidney. In kidney transplantation, prolonged cold ischemia time causes acute tubular necrosis. In these cases, the Doppler study usually discloses an elevated RI that reflects the altered vascular compliance that results from interstitial edema [27]. This high-resistance flow can also be observed in cases of acute graft rejection due to interstitial edema or endovasculitis. In an experimental study with renal transplantation in dogs, Pozniak et al. [28] found an elevation of the RI, peaking on postoperative day 2, during the immediate postoperative period in normal transplanted kidneys. Biopsy in these cases showed vacuolation in the distal tubules, which is consistent with mild ischemic tubular injury. Similar changes could be occurring in liver transplants and could lead to an increase in liver vascular resistance, in spite of the absence of detectable ischemic changes at the intraoperative biopsy performed immediately after reperfusion.
A relationship between high-resistance flow and older donor age was also
observed in our analysis. Eighty-three percent of the transplant patients who
received an older liver (age of donor 50 years) had a high RI on routine
Doppler sonography. This finding could also be related to ischemic damage
because the use of older liver grafts has been reported to be associated with
more extensive ischemic damage immediately after graft reperfusion
[29].
Although ischemia time and older liver donor were independently associated with the elevated RI seen after transplantation in our study, we did not find any correlation between the degree of waveform alteration and the duration of the ischemia period or the age of the liver donor. The patients with the type 4 waveform (absence of flow) had an older donor age and more extended preservation time, but this group was composed of only two cases, so it was not possible to obtain conclusions. Therefore, Doppler sonography does not seem useful for predicting the severity of ischemia. Likewise, in the case of the transplanted kidney, in spite of the capability of Doppler sonography in disclosing the arterial changes due to acute tubular necrosis, this technique is not useful for assessing its severity [30].
In spite of the association of high-resistance flow with ischemia time and donor age, not all patients with a high RI in our study received a liver that had a long ischemia time or that was from an older donor. Therefore, other factors probably affect the resistance of arterial flow in the liver. In our study, the third factor that affected the occurrence of high-resistance flow at the hepatic artery was the presence of chronic cholestatic disease as the indication for transplantation. However, chronic cholestatic disease was an infrequent indication for liver transplantation in our series, only in 10 cases; thus, the relevance of these diseases on the development of high RI is not clear and needs further assessment.
We did not find any relation between the increase in RI and the early clinical evolution of findings or the findings at early needle biopsy. An absence of a correlation between the degree of high-resistance flow and the presence of initial poor graft function has already been shown in a previous work [3]. That study analyzed the value of Doppler sonography in differentiating the cause of initial poor graft function (vascular vs primary) in 47 of 216 consecutive liver transplant recipients with initial poor graft function. Thirty-four patients had preserved diastolic blood flow in the study performed immediately after liver transplantation. Hepatic artery occlusion was present in five patients. However, in the eight patients with initial poor graft function and an RI of 1, arterial stenosis was diagnosed in four; thus, the contribution of Doppler sonography in establishing the cause of initial poor graft function in these specific patients was not adequate. Therefore, although the detection of high-resistance flow (RI > 0.80) at the hepatic artery during the immediate postoperative period on routine Doppler sonography does not have any significant clinical repercussions at early or long-term followup, this finding must be evaluated together with the clinical status of the patient. If hepatic artery thrombosis is suspected on the basis of clinical findings, arteriography to rule out hepatic artery alterations must be performed. In the only patient who developed hepatic artery thrombosis in our study, the high RI had normalized on the second sonography examination. On the 19th postoperative day, the patient developed hypertransaminasemia, so another sonography examination was performed. The findings revealed hepatic artery thrombosis.
Follow-up Doppler sonography must be performed when an absence of diastolic flow (RI = 1) at the hilum without intrahepatic flow is observed because hepatic artery thrombosis could develop [31]. In addition, other diagnostic studies, such as arteriography or MR angiography, are mandatory when a complete absence of flow is shown on sonography in an asymptomatic patient. Hepatic artery thrombosis in asymptomatic patients is not an unusual finding when patients are enrolled in follow-up Doppler sonography, and prompt treatment might prevent the development of bile duct complications and graft loss [7].
In conclusion, high-resistance flow at the hepatic artery during the period immediately after transplantation is a frequent finding that is probably related to an injury caused by ischemia and reperfusion. A high RI at the hepatic artery but with Doppler flow has no clinical relevance. The radiologist should be aware of this finding so that false-positive diagnoses of hepatic artery abnormalities can be avoided.
Acknowledgments
We thank J. M. Carrasco of the Department of Statistics, University of
Barcelona, for his technical and statistical assistance.
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