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Percutaneous Treatment of Venous Outflow Obstruction in Pediatric Liver Transplants
Percutaneous Treatment of Venous Outflow Obstruction in Pediatric Liver Transplants Jonathan M. Lorenz, MD, Thuong Van Ha, MD, Brian Funaki, MD, Michael Millis, MD, Jeffrey A. Leef, MD, Andrew Bennett, MD, and Jordan Rosenblum, MD
PURPOSE: To evaluate the efficacy and safety of percutaneous dilation in the treatment of impaired venous outflow in pediatric patients with liver transplants. MATERIALS AND METHODS: Review was undertaken of the records of 35 procedures to dilate impaired venous outflow in 16 consecutive children (aged 11 days to 17.8 years; mean, 7.2 ⴞ 5.8 y) after liver transplantation over a period of 8 years. Patients presented clinically with signs or symptoms of obstruction of the hepatic venous or inferior vena cava anastomosis and/or abnormal noninvasive imaging findings and were referred primarily to the interventional radiology department for treatment. None were excluded. Technical and clinical success rates were calculated. After venoplasty, patients with incomplete venographic resolution or pressure gradients exceeding 5 mm Hg were treated with stents. Seven died or required repeat transplantation during the study period for reasons unrelated to venous outflow obstruction. Patency rates were calculated for all other patients with sufficient follow-up in the pediatric hepatology clinic. RESULTS: The combined technical success rate for venoplasty (12 of 16) and stent placement (three of 16) was 94% (15 of 16), and the clinical success rate was 81% (13 of 16). One minor complication occurred: a transient hypoxic episode. Primary patency rates were 72.7% (eight of 11) at 3 months, 60% (six of 10) at 6 months, 55.6% (five of nine) at 12 months, 50% (four of eight) at 18 months, and 50% (three of six) at 36 months. Primary assisted and secondary patency rates were 90.9% (10 of 11) at 3 months, 90% (nine of 10) at 6 months, 88.9% (eight of nine) at 12 months, 87.5% (seven of eight) at 18 months, and 83.3% (five of six) at 36 months. CONCLUSIONS: Excellent technical and clinical success rates can be achieved with percutaneous dilation of impaired venous outflow after pediatric liver transplantation. Long-term patency may require repeated interventions. J Vasc Interv Radiol 2006; 17:1753–1761 Abbreviation:
IVC ⫽ inferior vena cava
FOR children with end-stage liver disease, hepatic transplantation has become a standard treatment (1–3). Venous outflow obstruction involving the hepatic veins and inferior vena cava (IVC) remains an uncommon but
From the Departments of Radiology (J.M.L., T.V.H., B.F., J.A.L., A.B., J.R.) and Surgery (M.M.), The University of Chicago, 5841 South Maryland Avenue, MC2026, Chicago, Illinois 60637. Received March 17, 2006; revision requested May 29; final revision received July 28; and accepted August 3. Address correspondence to J.M.L.; E-mail: jlorenz@radiology. bsd.uchicago.edu None of the authors have identified a conflict of interest. © SIR, 2006 DOI: 10.1097/01.RVI.0000241540.31081.52
persistent complication of liver transplantation despite advances in surgical technique (1–3). Venoplasty and stent placement are minimally invasive and are often used as first-line treatments at our institution because alternatives include surgical revision or repeat transplantation. Although publications have addressed percutaneous dilation of the portal vein inflow in children with liver transplants (4), few literature series have addressed dilation of impaired venous outflow vessels (5– 8). The purpose of this study was to evaluate the technical and clinical success, long-term patency, and complications associated with percutaneous treatment of venous outflow obstruction resulting
from liver transplantation in children.
MATERIALS AND METHODS This retrospective study was approved by the institutional review board. We performed a chart review of all children with liver transplants who underwent venoplasty with or without stent placement at the transplant venous outflow vessel between January 1, 1996, and December 31, 2003. Patients presented clinically with signs or symptoms of obstruction of the hepatic venous or IVC anastomosis and/or had noninvasive imaging findings suggestive of obstruction. They were referred primarily to the
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Figure 1. Images from a 2-year-old boy with a cadaveric left lateral segment graft. (a) Venogram from femoral approach shows IVC stenosis (arrow) at the level of the hepatic vein/IVC anastomosis. The portal vein stent was placed 5 months earlier to treat stenosis. (b) Venogram shows resolution of stenosis after venoplasty to 9-mm diameter and new reflux into hepatic veins of graft.
interventional radiology unit for venoplasty or stent placement. No cases were excluded. We evaluated operative notes, discharge reports, pathology reports, laboratory data, and all pertinent radiologic studies. In addition to recording the dates of liver transplantation, balloon dilation, stent implantation, and repeat evaluation by ultrasonography (US) or venography, we recorded the causes of liver disease before transplantation, presenting signs and symptoms of venous outflow obstruction, type of liver transplant graft, and type of venous outflow anastomosis. Patients During the study period, strictures or occlusions of the outflow veins were dilated in 16 children. In addi-
tion to the 16 primary procedures, 19 follow-up procedures were required to maintain patency. At the time of liver transplantation, patients (six female, 10 male) ranged in age from 11 days to 17.8 years (mean, 7.2 ⫾ 5.8 y). Venoplasty or stent placement was performed 15 days to 8.6 years (mean, 2 y) after transplantation. Indications for liver transplantation included biliary atresia (n ⫽ 10), ␣-1 antitrypsin deficiency (n ⫽ 2), liver failure of unknown cause (n ⫽ 2), fulminant hepatitis B (n ⫽ 1), and congenital tyrosinemia (n ⫽ 1). Types of liver transplant grafts included left lateral segment (n⫽ 10), whole liver (n⫽ 4), and splitliver left lobe (n ⫽ 2). Grafts included 15 cadaveric organs and one livingrelated organ. Types of venous outflow anastomosis included “piggyback” in 13 cases, including donor
hepatic vein–to–recipient IVC (n ⫽ 6) (Fig 1), donor hepatic vein–to–recipient hepatic vein (n⫽ 5), caval-caval (n ⫽ 1), and donor hepatic vein–to–recipient IVC/right atrial junction (n ⫽ 1) (Fig 2). Conventional technique was used (ie, interposed donor IVC) in three cases (Fig 3). The hepatic vein– to–right atrium anastomosis was created in a patient with absence of IVC (likely congenital) and azygous continuation. The average child had undergone three previous open abdominal operations, including an average of 1.75 liver transplantation procedures and one additional operation. Additional surgical procedures included splenectomy for abscess, hematoma and biloma evacuation, exploratory laparotomy, Kasai procedure, correction of bile leak, and release of abdominal adhesions.
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Figure 2. Images from a 4-year-old girl with cadaveric left lateral segment graft. (a) Venogram from the right femoral vein reveals azygous continuation of IVC, which necessitated creation of an anastomosis from the hepatic vein to the junction of the IVC and right atrium. (b) Venogram from jugular approach shows anastomotic stenosis (arrow). (c) Venogram shows resolution of stenosis.
Patients presenting to the pediatric hepatology service with clinical findings suggestive of outflow obstruction were typically referred for noninvasive imaging of the outflow veins with Doppler sonography, magnetic resonance (MR) venography, or computed tomography (CT). Abnormalities associated with the outflow veins prompted referral for venography. Sonographic findings considered suggestive of outflow obstruction included direct visualization of stenosis or occlusion, monophasic flow or absence of flow in the hepatic veins, focal segments of high flow velocity, collat-
eral veins, ascites, and hepatomegaly. Some patients were referred directly to undergo venography on the basis of strong clinical suspicion, nonspecific sonographic results, and a liver biopsy result that failed to explain the clinical presentation. Venoplasty Before dilation, patients with fever or bacteremia were treated with antibiotics until resolution in anticipation of the need for stent placement. Before all procedures, patients with a prothrombin time greater than 17 seconds
or a platelet count less than 50,000/ mm3 received blood products to correct deficiencies. All patients received ceftizoxime sodium (Cefizox; Glaxo SmithKline, Philadelphia, PA) 1 hour before the procedure. All procedures were performed with the patients under general anesthesia. Successful IVC and hepatic venous dilations were performed from a femoral or jugular venous approach in all but one case, which required a transhepatic approach as a result of complete hepatic venous occlusion not traversable from the IVC. For transhepatic balloon angioplasty, the skin of the right upper
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Figure 3. Images from a 2-year-old boy 1 month after transplantation with a full-size graft with use of conventional technique of interposed donor IVC. (a) Venogram from jugular approach shows stenosis (arrow) at upper caval-caval anastomosis likely caused by torsion of graft. (b) Venogram after venoplasty shows no change. (c) Repeat venogram after stent placement shows resolution of stenosis.
quadrant was cleansed in standard fashion with povidone iodine, and access to an intrahepatic hepatic venous branch was achieved with direct sonographic guidance with a micropuncture system (Cook, Bloomington, IN). In all cases, a vascular sheath was placed over a 0.035-inch guide wire and venography was performed through the sheath. A balloon catheter (VasCath, Mississauga, ON, Canada) was oversized by 10%–20% compared with the normal vein size. Balloon diameters ranged from 7 mm to 16 mm. The balloon was typically inflated to approximately 10 –12 atm, and higherpressure inflation (maximum of 20 atm) was reserved for resistant or recurrent lesions. Venoplasty was repeated until venous patency was verified by venography, which usually required two to three dilations. Judg-
ment of successful venoplasty was made if there was complete venographic resolution of the stenosis or a final pressure gradient of 3 mm Hg or less (9). All patients were observed for at least 23 hours in the hospital, and overnight infusion of intravenous heparin was started 2 hours after the procedure. Clinic follow-up with a pediatric hepatologist was performed approximately 1 month after the procedure and was typically continued every 1–3 months. Patients with symptoms of recurrence underwent US evaluation and were subsequently referred for venography if indicated.
Stent Placement In three cases, a pressure gradient greater than 5 mm Hg remained after
venoplasty alone and a stent was placed. In two additional cases, symptoms of restenosis occurred within 30 days of venoplasty, one after primary venoplasty and one after a second venoplasty. In both cases, a stent was placed. When a stent was required, patients underwent endovascular metallic Wallstent placement (Boston Scientific, Natick, MA). Stent diameters ranged from 8 mm to 12 mm. Definitions and Statistics Technical success was defined as successful traversal of the venous obstruction with a catheter, completion of dilation with full expansion of a balloon or stent, and follow-up venography demonstrating less than 20% residual stenosis. Clinical success was defined as resolution or marked im-
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provement of clinical signs and symptoms of venous obstruction based on laboratory data and clinic notes by the referring pediatric hepatologist. For patients presenting with increased liver enzyme levels, clinical success was verified by clinical notes and laboratory data describing marked improvement between 1 and 2 months after the procedure. Some patients died or required repeat transplantation for reasons unrelated to venous outflow obstruction, as verified by pathologic or imaging findings. Patency rates were calculated for all other patients with sufficient follow-up. Primary patency was defined as the interval between initial dilation and first presentation for outflow obstruction requiring percutaneous hepatic venography. Primary assisted patency was defined as patency after initial dilation until treatment with repeated percutaneous dilation was abandoned. Secondary patency was defined as patency after the treatment of thrombosis with thrombolysis and/or mechanical recanalization until all attempts at maintaining patency were abandoned. The Wilcoxon test was used to compare pressure gradients and serum levels of liver enzymes before and after dilation. P values less than .05 were considered to indicate a statistically significant difference. Kaplan-Meier analysis was used to evaluate patency results.
RESULTS Adequate clinical data were obtained for all 16 children. The clinical presentation of venous outflow obstruction included ascites (n ⫽ 11), hepatomegaly (n ⫽ 1), increased liver enzyme levels (n ⫽ 7), and gastrointestinal bleeding (n⫽ 1). Referral for venography was based on Doppler imaging findings in eight patients, detection of stenosis by MR venography in one patient, detection of stenosis by CT in one patient, detection of hepatic congestion by liver biopsy in one patient, and strong clinical suspicion because of the combination of liver function test results, ascites, hepatomegaly, and a negative liver biopsy result in five patients. Sonographic findings suggestive of obstruction in the study group included sluggish flow, absence of flow, or reversed flow in the out-
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flow veins; accelerated flow at the outflow vein anastomosis; and direct visualization of occlusion or stenosis on grayscale images. Venography demonstrated occlusions in three patients and stenoses in 13 patients. Venographic findings included focal (⬍2 cm) stenosis of the IVC in eight patients, hepatic vein/ IVC anastomosis in three patients, hepatic vein–to– hepatic vein anastomosis in one patient, and hepatic vein–to– right atrium anastomosis in one patient, as well as total occlusion of the hepatic vein/IVC anastomosis in one patient and the IVC in two patients. In 63% of patients (n⫽ 10), moderate stenosis of hemodynamic significance was observed and verified by measurement of an abnormal pressure gradient greater than 5 mm Hg. In 18.7% of patients (n ⫽ 3), severe stenosis was observed, and in 18.7% of patients (n ⫽ 3), complete occlusion was observed. For these six cases, the interventional radiologist believed no pressure measurements were necessary to verify the diagnosis of venous outflow obstruction. The technical success rate 94% (15 of 16). In 75% of patients (n ⫽ 12), venoplasty alone restored outflow, and in 18.7% of patients (n⫽ 3), a stent was required. The Table matches the ages and graft types of the 16 children with the outcomes of percutaneous treatment. Of the 10 cases in which pressure measurements were obtained, the mean pressure gradient measured 12.5 ⫾ 5.8 mm Hg before the procedure and 3.0 ⫾ 1.3 mm Hg after the procedure (P ⫽ .002). The case of technical failure occurred in a 9.5-year-old boy with a left lateral segment graft and occlusion of the IVC anastomosis who presented clinically with ascites, increased blood levels of liver enzymes, and variceal bleeding. Attempts to traverse the occluded IVC from the transjugular, transfemoral, and transhepatic approaches were made with a hydrophilic Glidewire and catheter (Terumo, Tokyo, Japan), but chronic occlusion of the entire suprarenal IVC was encountered, and traversal could not be achieved. The patient later died of hepatic failure related to venous outflow occlusion. Another patient with an interposed donor IVC presented with occlusion of the caudal anastomosis and tight stenosis of the cranial anas-
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tomosis. Although the caudal occlusion could not be traversed for dilation, venoplasty of the cranial stenosis from a jugular vein approach was successful, and venous outflow from the graft was restored to the right atrium. The clinical success rate was 81% (13 of 16). Of the 13 patients who presented with clinical symptoms, improvement or resolution of symptoms was observed in 10. The three cases of clinical failure included the single technical failure described previously and occurred also in a 9.9-year-old boy with no change in marked ascites resulting from acute rejection and a 6.4year-old boy with no change in marked ascites and hepatomegaly resulting from primary graft failure. The latter two patients underwent repeat transplantation within 1 month of the dilation procedure. Of the seven patients who presented increased serum liver enzyme levels, reductions in the levels of serum aspartate aminotransferase and alanine aminotransferase were observed in all patients. In these cases, biopsy results revealed no evidence of hepatitis or rejection to explain the abnormal serum enzyme levels. The mean levels of serum aspartate aminotransferase were 136.3 ⫾ 129 U/L before the procedure and 47.7 ⫾ 10.3 U/L after the procedure (P ⫽ .031). The mean levels of serum alanine aminotransferase were 166.9 ⫾ 129.2 U/L before the procedure and 71.9 ⫾ 37.5 U/L after the procedure (P ⫽ .016). No significant differences in serum levels of total bilirubin, alkaline phosphatase, or albumin were noted before and after dilation. Primary patency rates for surviving patients were 92.9% (13 of 14) at 1 month, 72.7% (eight of 11) at 3 months, 60% (six of 10) at 6 months, 55.6% (five of nine) at 12 months, 50% (four of eight) at 18 months, and 50% (three of six) at 36 months. Patients were removed from the patency analysis if they died or underwent repeat transplantation during the study interval as a result of causes unrelated to venous outflow obstruction (Table). In such cases, patency of the outflow veins at the time of death was verified by autopsy, pathology results for the explanted liver, or Doppler sonography. Primary assisted and secondary patency rates were 92.9% (13 of 14) at 1 month, 90.9% (10 of 11) at 3 months, 90% (nine of 10) at 6 months, 88.9%
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Outcomes in 16 Children Undergoing Percutaneous Dilation of Venous Outflow Obstruction after Liver Transplantation
Case
Type of Transplant
Age at Age at Primary Transplantation Dilation Type of Patency Technical Clinical (y) (y) Dilation (months) Success Success
1 Whole 2 Split (left)
1.0 8.5
3.2 12.6
Balloon Stent
45.0 17.0
Yes Yes
Yes Yes
3 Cadaveric left lateral segment 4 Cadaveric left lateral segment
3.5 1.6
3.7 1.8
Balloon Stent
42.7 8.3
Yes Yes
Yes Yes
5 Whole
6.3
6.4
Balloon
40.9
Yes
Yes
6 Cadaveric left lateral segment
6.6
14.7
Balloon
4.4
Yes
Yes
7 Split (left)
0.03
0.8
Balloon
1.6
Yes
Yes
8 Cadaveric left lateral segment
8.7
8.9
Balloon
2.4
Yes
Yes
9 Whole
9.8
9.9
Balloon
0.4
Yes
No
10 Cadaveric left lateral segment
0.7
1.8
Balloon
1.4
Yes
Yes
11 Cadaveric left lateral segment
6.3
6.4
Balloon
0.4
Yes
No
12 Cadaveric left lateral segment 13 Cadaveric left lateral segment
1.6 1.5
1.7 2.2
Stent Balloon
2.3 3.2
Yes Yes
Yes Yes
14 Living related left lateral segment 15 Whole 16 Cadaveric left lateral segment
10.0
10.2
Balloon
22.9
Yes
Yes
17.8 0.9
22.0 9.3
Balloon Failed
2.2 0.0
Yes No
Yes No
(eight of nine) at 12 months, 87.5% (seven of eight) at 18 months, and 83.3% (five of six) at 36 months. Figure 4 is a Kaplan-Meier plot of patency rates. In eight surviving patients, patency persisted through the end of the study interval. Four patients still showed patency without repeated procedures after a range of 68 days to 3.7 years (mean, 1.5 y). Four required repeat dilation (two venoplasty and two stent placement) at a mean interval between procedures of 146 days, and overall primary assisted patency in this group ranged from 321 days to 4.7 years (mean, 3.1 y). Twelve patients underwent successful venoplasty alone for obstruction of venous outflow. For surviving patients with sufficient follow-up
Figure 4. Kaplan-Meier curve shows patency after percutaneous dilation of venous outflow obstruction after pediatric liver transplantation.
times, primary patency rates after venoplasty alone were 100% (10 of 10) at 1 month, 75% (six of eight) at 3
Outcome Patent, no recurrence Repeat venoplasty (3 times); died of acute hepatitis after 1.7 years No recurrence; died of sepsis Repeat venoplasty once; patent after 1.1 years No recurrence; died of fungal infection No recurrence; died of primary hepatic failure No recurrence; repeat transplantation for chronic rejection Stent implantation once; repeat venoplasty once; patent after 4.7 years No recurrence; repeat transplantation for acute rejection Stent implantation twice; repeat venoplasty 10 times; patent after 3.2 years No recurrence; repeat transplantation for preexisting hepatic arterial thrombosis Patent, no recurrence Repeat venoplasty; patent after 0.9 years Patent, no recurrence Patent, no recurrence Died of hepatic failure related to venous outflow obstruction
months, 66.7% (four of six) at 1 year, 66.7% (four of six) at 18 months, and 60% (three of five) at 3 years. Five patients underwent stent placement across the venous outflow. Three stent placement procedures were primary in nature, and two stents were placed after delayed restenosis after venoplasty. For the surviving stent-implanted patients with sufficient follow-up times, the primary patency rates after stent placement were 100% (five of five) at 1 month, 100% (four of four) at 3 months, 100% (four of four) at 6 months, and 75% (three of four) at 1 year. One patient experienced an episode of transient hypoxia while under general anesthesia. The episode resolved with supportive care during the pro-
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cedure, and there were no further sequelae. There were no other procedure-related complications. The 30day mortality rate was zero, and the 1-year mortality rate was 12.5% (two of 16). In the children who died, the causes of death included acute hepatitis, primary hepatic failure, and sepsis. The rate of repeat transplantation during the study interval was 18.8% (three of 16), and repeat transplantation was performed in those three cases 11, 13, and 50 days after the dilation procedure. In the three children who required repeat transplantation, indications included chronic rejection, acute rejection, and hepatic arterial thrombosis present before the onset of venous outflow symptoms. The cause of death or need for repeat transplantation was unrelated to venoplasty or stent placement in all cases.
DISCUSSION Venous outflow obstruction occurs in 3%– 6% of pediatric liver transplantation cases (3,6). Presentation may include ascites, increased liver function test results, gastrointestinal bleeding, and hepatosplenomegaly. Obstruction can occur at all levels of the reconstructed venous outflow from the donor hepatic veins to the recipient right atrium. Postulated causes and risk factors include cross-clamp injury, interposed venous conduits, partial liver transplantation, a low graft-to-recipient weight ratio, graft migration, graft torsion, and surgical technique. The newer technique of triangulating the recipient IVC to the donor hepatic veins and positioning the graft at the junction of the left and middle hepatic veins has reduced the incidence of venous outflow obstruction compared with earlier results (3,10,11). All types of venous anastomosis were represented in this study. The outflow veins can be drained by variations of two basic surgical techniques: conventional and piggyback. In the conventional technique, the donor retrohepatic IVC is preserved with the graft and interposed into the recipient IVC by means of an upper and lower caval-caval anastomosis. In the piggyback technique, the donor hepatic vein or IVC is anastomosed to the recipient IVC. Occasionally, size match allows for hepatic vein–to– hepatic vein end-to-end anastomosis.
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The piggyback technique can lead to obstruction at all levels from the hepatic vein to the IVC. The conventional technique can lead to obstruction at the upper caval-caval anastomosis, sometimes leading to symptoms of hepatic venous outflow obstruction accompanied by lower-extremity edema. At our institution, patients with clinical signs and symptoms of venous outflow obstruction typically undergo some form of noninvasive imaging, and findings that arouse suspicion prompt referral to the interventional radiology unit for venography with the intent to treat. Color Doppler sonography was the most common modality in this study group because most patients presented before alternative modalities were perfected. Despite newer options, sonography is immediately available, can be performed at the bedside, avoids ionizing radiation, and provides information on flow direction and velocity (12,13). MR venography and CT are excellent alternatives but require scanner availability and sedation in the pediatric population. In this study, venography and dilation were performed with patients under general anesthesia. For adolescents, we consider the option of moderate sedation if the patient is particularly cooperative and the procedure is unlikely to require a transhepatic approach. For all other adolescent and younger patients, we use general anesthesia to maximize the quality of venography and to avoid movement during selective catheterization, venoplasty, and stent placement. All but one patient in our study group were younger than 11 years and required general anesthesia (6). The remaining patient was an adolescent patient who was believed by the pediatric hepatology service to have a low tolerance and limited capacity to cooperate during the procedure. In our patients with outflow stenosis, venography demonstrated a stenosis shorter than 2 cm in length: moderate in 10 cases and severe in three. In all cases, the appearance and focality of the stenosis was believed to be related to fibrosis at the venous anastomosis rather than to pressure from abdominal ascites. A pressure gradient measured across the stenosis may help
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verify the significance of the stenosis, but some variability exists in the literature as to the gradient considered hemodynamically significant; with reports ranging from 3 mm Hg (5,9) to 5 mm Hg (6). Higher gradients may result from measurements over a longer segment of venous outflow (eg, from the hepatic vein to the right atrium) and from the added pressure of abdominal ascites. To minimize the influence of such factors, in the 10 cases of moderate stenosis in our study, pressure gradients were measured below the diaphragm, across the anastomotic stenosis. Not inconsistently with the published reports, we chose 5 mm Hg as a clinically significant gradient and 3 mm Hg as a target gradient after treatment. At our institution, the transjugular or transfemoral approach is chosen as the primary route of access for venography and dilation, depending on the location and severity of the stenosis. As demonstrated by this study, a high rate of technical success can be achieved with this technique. The one technical failure in our study occurred in a patient with complete chronic occlusion of the entire intrahepatic IVC, which could not be traversed from the transjugular, transfemoral, or transhepatic approach. Others advocate more routine use of the transhepatic approach (5), but we use this route if other approaches prove unsuccessful or are deemed unlikely to be successful (eg, complete occlusion of the hepatic vein). Despite the low complication rates described for transhepatic procedures in children (4,5), we believe placement and removal of a transhepatic sheath followed by overnight anticoagulation may carry a greater risk of complications than the transjugular or transfemoral technique. Our clinical success rate of 81% is consistent with the findings of published reports. Ko et al (14) achieved a 73% clinical success at just less than 1 year with repeated interventions. In our experience, clinical failure was related to technical failure or the presence of comorbidities contributing to clinical symptoms, such as rejection, hepatitis, and primary graft failure. Although primary dilation of venous outflow obstruction has not produced the durable results reported after primary dilation of portal vein
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obstruction (4), our results suggest that excellent long-term patency is achievable with repeated interventions. The high rate of primary assisted patency underscores the importance of excellent clinical follow-up with a pediatric hepatologist, Doppler sonography in symptomatic patients, and a low threshold for repeat intervention in cases that arouse suspicion. Successful venoplasty results in normalization of the diminished flow velocity and flattened wave pattern associated with hepatic venous outflow obstruction (12). In patients presenting with altered liver function rather than clinical symptoms of outflow obstruction, the presence of increased serum enzyme levels becomes important for the detection of recurrence during clinical follow-up. In our study, significant changes were found only in the serum aminotransferase levels after dilation, and changes of other liver function test results were insignificant. The changes in aminotransferase levels in our pediatric population were consistent with those of Wang et al (9), who found that decreases in these levels reached significance in younger patients after venous outflow dilation. The lack of significant changes in other liver function test results may reflect the variety of comorbidities in our patient population. Our patency rates are consistent with the results found in the literature (5,6,14). Cheng et al (6) achieved patency in five of six children for a mean follow-up interval of 3.67 years, with a subset of patients requiring repeat interventions. Totsuka et al (15) reported numerous repeated interventions to maintain patency in four children with outflow stenoses and suggested that venoplasty may eventually be successful after multiple attempts, obviating stent placement. In our experience, a subset of patients also responded well to venoplasty alone. For this reason, we reserve metal stent placement for patients with elastic stenoses or numerous recurrences after venoplasty alone. Considering the future growth of the child and the possibility of the need for repeat transplantation, we recommend choosing the largest stent diameter and the shortest stent length possible to achieve resolution of the obstruction. A recent case review (16) demonstrated the feasibility of a new cutting balloon technology in the
treatment of hepatic venous stricture in a child. Further studies are warranted to evaluate the safety of this type of device and the durability of the result. Cutting balloons are unlikely to replace metal stents for certain applications, including the treatment of hepatic venous kinking related to graft position or torsion (16). In our series, no major complications were observed, as was consistent with past reports (6,14,17). The high nonprocedural mortality rate was consistent with that in other series (6) and was likely related to the complexity of this patient population, which tended toward multiple comorbidities and previous operations. One incident of a self-limited, transient hypoxic episode was observed after venoplasty. The cause of this episode was not determined. Although air embolus is a possibility, dramatic increases in hepatic venous flow velocity have been noted by Doppler imaging immediately after percutaneous dilation (16), which could result in transient increases in right heart pressure. To minimize the risk of complications, we avoid percutaneous dilation within 1 month of transplantation if possible to minimize the risk of anastomotic rupture, and we admit patients overnight for intravenous heparin infusion. Despite the risks, early percutaneous dilation is sometimes necessary, especially in cases of stenosis resulting from graft migration or torsion. We avoid longterm anticoagulation with warfarin to minimize the danger of bleeding complications in active children. Despite the lack of long-term anticoagulation, no cases of delayed thrombosis occurred in our patients after dilation of venous outflow obstruction or portal venous obstruction (4). This study was limited by the low patient population, the absence of long-term follow-up in a large group as a result of loss of patients to repeat transplantation or death, and the retrospective collection of data involving several operators across a long time interval. Despite these limitations, the results demonstrate that impaired venous outflow after pediatric liver transplantation can be safely and effectively treated with venoplasty or stent placement. Long-term patency can be achieved in some patients with venoplasty alone, but a subgroup of patients requires repeated interven-
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tions and possible stent placement. Because surgical revision or repeat transplantation is associated with a significant risk of morbidity, percutaneous dilation should be considered the first-line treatment in children with hepatic venous outflow obstruction. References 1. Settmacher U, Nussler NC, Glanemann M, et al. Venous complications after orthotopic liver transplantation. Clin Transplant 2000; 14:235–241. 2. Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993; 217:82–91. 3. Buell JF, Funaki B, Cronin DC, et al. Long-term venous complications after full-size and segmental pediatric liver transplantation. Ann Surg 2002; 236:658–666. 4. Funaki B, Rosenblum JD, Leef JA, et al. Angioplasty treatment of portal vein stenosis in children with segmental liver transplants: long-term results. Radiology 2000; 215:147–151. 5. Kubo T, Shibata T, Kyo I, et al. Outcome of percutaneous transhepatic venoplasty for hepatic venous outflow obstruction after living donor liver transplantation. Radiology 2006; 239: 285–290. 6. Cheng YF, Chen CL, Huang TL, et al. Angioplasty treatment of hepatic vein stenosis in pediatric liver transplants: long-term results. Transpl Int 2005; 18: 556–561. 7. Rerksuppaphol S, Hardikar W, Smith AL, et al. Successful stenting for Budd-Chiari syndrome after pediatric liver transplantation: a case series and review of the literature. Pediatr Surg Int 2004; 20:87–90. 8. Zanotelli ML, Vieira S, Alencastro R, et al. Management of vascular complications after pediatric liver transplantation. Transpl Proc 2004; 36:945–946. 9. Wang SL, Sze DY, Busque S, et al. Treatment of hepatic venous outflow obstruction after piggyback liver transplantation. Radiology 2005; 236: 352–359. 10. Yamaguchi T, Yamaoka Y, Mori K, et al. Hepatic vein reconstruction of the graft in partial liver transplantation from living donor: surgical procedures relating to their anatomic variations. Surgery 1993; 114:976–983. 11. Tannuri U, Mello ES, Carnevale FC, et al. Hepatic venous reconstruction in pediatric living-related donor liver transplantation: experience of a single center. Pediatr Transplant 2005; 9:293– 298.
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12. Huang TL, Chen TY, Chen CL, et al. Hepatic outflow insults in living-related liver transplantation: by Doppler sonography. Transplant Proc 2001; 33: 3464–3465. 13. Chaubal N, Dighe M, Hanchate V, et al. Sonography in Budd-Chiari syndrome. J Ultrasound Med 2006; 25:373–379. 14. Ko GY, Sung KB, Yoon HK, et al. En-
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dovascular treatment of hepatic venous outflow obstruction after livingdonor liver transplantation. J Vasc Interv Radiol 2002; 13:591–599. 15. Totsuka E, Hakamada K, Narumi S, et al. Hepatic vein anastomotic stricture after living donor liver transplantation. Transplant Proc 2004; 36: 2252–2254.
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16. Narumi S, Hakamada K, Totsuka E, et al. Efficacy of cutting balloon for anastomotic stricture of the hepatic vein. Transplant Proc 2004; 36:3093–3095. 17. Egawa H, Tanaka K, Uemoto S, et al. Relief of hepatic vein stenosis by balloon angioplasty after living related liver transplantation. Clin Transplant 1993; 7:306–311.
PURPOSE: To evaluate the efficacy and safety of percutaneous dilation in the treatment of impaired venous outflow in pediatric patients with liver transplants. MATERIALS AND METHODS: Review was undertaken of the records of 35 procedures to dilate impaired venous outflow in 16 consecutive children (aged 11 days to 17.8 years; mean, 7.2 ⴞ 5.8 y) after liver transplantation over a period of 8 years. Patients presented clinically with signs or symptoms of obstruction of the hepatic venous or inferior vena cava anastomosis and/or abnormal noninvasive imaging findings and were referred primarily to the interventional radiology department for treatment. None were excluded. Technical and clinical success rates were calculated. After venoplasty, patients with incomplete venographic resolution or pressure gradients exceeding 5 mm Hg were treated with stents. Seven died or required repeat transplantation during the study period for reasons unrelated to venous outflow obstruction. Patency rates were calculated for all other patients with sufficient follow-up in the pediatric hepatology clinic. RESULTS: The combined technical success rate for venoplasty (12 of 16) and stent placement (three of 16) was 94% (15 of 16), and the clinical success rate was 81% (13 of 16). One minor complication occurred: a transient hypoxic episode. Primary patency rates were 72.7% (eight of 11) at 3 months, 60% (six of 10) at 6 months, 55.6% (five of nine) at 12 months, 50% (four of eight) at 18 months, and 50% (three of six) at 36 months. Primary assisted and secondary patency rates were 90.9% (10 of 11) at 3 months, 90% (nine of 10) at 6 months, 88.9% (eight of nine) at 12 months, 87.5% (seven of eight) at 18 months, and 83.3% (five of six) at 36 months. CONCLUSIONS: Excellent technical and clinical success rates can be achieved with percutaneous dilation of impaired venous outflow after pediatric liver transplantation. Long-term patency may require repeated interventions. J Vasc Interv Radiol 2006; 17:1753–1761 Abbreviation:
IVC ⫽ inferior vena cava
FOR children with end-stage liver disease, hepatic transplantation has become a standard treatment (1–3). Venous outflow obstruction involving the hepatic veins and inferior vena cava (IVC) remains an uncommon but
From the Departments of Radiology (J.M.L., T.V.H., B.F., J.A.L., A.B., J.R.) and Surgery (M.M.), The University of Chicago, 5841 South Maryland Avenue, MC2026, Chicago, Illinois 60637. Received March 17, 2006; revision requested May 29; final revision received July 28; and accepted August 3. Address correspondence to J.M.L.; E-mail: jlorenz@radiology. bsd.uchicago.edu None of the authors have identified a conflict of interest. © SIR, 2006 DOI: 10.1097/01.RVI.0000241540.31081.52
persistent complication of liver transplantation despite advances in surgical technique (1–3). Venoplasty and stent placement are minimally invasive and are often used as first-line treatments at our institution because alternatives include surgical revision or repeat transplantation. Although publications have addressed percutaneous dilation of the portal vein inflow in children with liver transplants (4), few literature series have addressed dilation of impaired venous outflow vessels (5– 8). The purpose of this study was to evaluate the technical and clinical success, long-term patency, and complications associated with percutaneous treatment of venous outflow obstruction resulting
from liver transplantation in children.
MATERIALS AND METHODS This retrospective study was approved by the institutional review board. We performed a chart review of all children with liver transplants who underwent venoplasty with or without stent placement at the transplant venous outflow vessel between January 1, 1996, and December 31, 2003. Patients presented clinically with signs or symptoms of obstruction of the hepatic venous or IVC anastomosis and/or had noninvasive imaging findings suggestive of obstruction. They were referred primarily to the
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Figure 1. Images from a 2-year-old boy with a cadaveric left lateral segment graft. (a) Venogram from femoral approach shows IVC stenosis (arrow) at the level of the hepatic vein/IVC anastomosis. The portal vein stent was placed 5 months earlier to treat stenosis. (b) Venogram shows resolution of stenosis after venoplasty to 9-mm diameter and new reflux into hepatic veins of graft.
interventional radiology unit for venoplasty or stent placement. No cases were excluded. We evaluated operative notes, discharge reports, pathology reports, laboratory data, and all pertinent radiologic studies. In addition to recording the dates of liver transplantation, balloon dilation, stent implantation, and repeat evaluation by ultrasonography (US) or venography, we recorded the causes of liver disease before transplantation, presenting signs and symptoms of venous outflow obstruction, type of liver transplant graft, and type of venous outflow anastomosis. Patients During the study period, strictures or occlusions of the outflow veins were dilated in 16 children. In addi-
tion to the 16 primary procedures, 19 follow-up procedures were required to maintain patency. At the time of liver transplantation, patients (six female, 10 male) ranged in age from 11 days to 17.8 years (mean, 7.2 ⫾ 5.8 y). Venoplasty or stent placement was performed 15 days to 8.6 years (mean, 2 y) after transplantation. Indications for liver transplantation included biliary atresia (n ⫽ 10), ␣-1 antitrypsin deficiency (n ⫽ 2), liver failure of unknown cause (n ⫽ 2), fulminant hepatitis B (n ⫽ 1), and congenital tyrosinemia (n ⫽ 1). Types of liver transplant grafts included left lateral segment (n⫽ 10), whole liver (n⫽ 4), and splitliver left lobe (n ⫽ 2). Grafts included 15 cadaveric organs and one livingrelated organ. Types of venous outflow anastomosis included “piggyback” in 13 cases, including donor
hepatic vein–to–recipient IVC (n ⫽ 6) (Fig 1), donor hepatic vein–to–recipient hepatic vein (n⫽ 5), caval-caval (n ⫽ 1), and donor hepatic vein–to–recipient IVC/right atrial junction (n ⫽ 1) (Fig 2). Conventional technique was used (ie, interposed donor IVC) in three cases (Fig 3). The hepatic vein– to–right atrium anastomosis was created in a patient with absence of IVC (likely congenital) and azygous continuation. The average child had undergone three previous open abdominal operations, including an average of 1.75 liver transplantation procedures and one additional operation. Additional surgical procedures included splenectomy for abscess, hematoma and biloma evacuation, exploratory laparotomy, Kasai procedure, correction of bile leak, and release of abdominal adhesions.
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Figure 2. Images from a 4-year-old girl with cadaveric left lateral segment graft. (a) Venogram from the right femoral vein reveals azygous continuation of IVC, which necessitated creation of an anastomosis from the hepatic vein to the junction of the IVC and right atrium. (b) Venogram from jugular approach shows anastomotic stenosis (arrow). (c) Venogram shows resolution of stenosis.
Patients presenting to the pediatric hepatology service with clinical findings suggestive of outflow obstruction were typically referred for noninvasive imaging of the outflow veins with Doppler sonography, magnetic resonance (MR) venography, or computed tomography (CT). Abnormalities associated with the outflow veins prompted referral for venography. Sonographic findings considered suggestive of outflow obstruction included direct visualization of stenosis or occlusion, monophasic flow or absence of flow in the hepatic veins, focal segments of high flow velocity, collat-
eral veins, ascites, and hepatomegaly. Some patients were referred directly to undergo venography on the basis of strong clinical suspicion, nonspecific sonographic results, and a liver biopsy result that failed to explain the clinical presentation. Venoplasty Before dilation, patients with fever or bacteremia were treated with antibiotics until resolution in anticipation of the need for stent placement. Before all procedures, patients with a prothrombin time greater than 17 seconds
or a platelet count less than 50,000/ mm3 received blood products to correct deficiencies. All patients received ceftizoxime sodium (Cefizox; Glaxo SmithKline, Philadelphia, PA) 1 hour before the procedure. All procedures were performed with the patients under general anesthesia. Successful IVC and hepatic venous dilations were performed from a femoral or jugular venous approach in all but one case, which required a transhepatic approach as a result of complete hepatic venous occlusion not traversable from the IVC. For transhepatic balloon angioplasty, the skin of the right upper
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Figure 3. Images from a 2-year-old boy 1 month after transplantation with a full-size graft with use of conventional technique of interposed donor IVC. (a) Venogram from jugular approach shows stenosis (arrow) at upper caval-caval anastomosis likely caused by torsion of graft. (b) Venogram after venoplasty shows no change. (c) Repeat venogram after stent placement shows resolution of stenosis.
quadrant was cleansed in standard fashion with povidone iodine, and access to an intrahepatic hepatic venous branch was achieved with direct sonographic guidance with a micropuncture system (Cook, Bloomington, IN). In all cases, a vascular sheath was placed over a 0.035-inch guide wire and venography was performed through the sheath. A balloon catheter (VasCath, Mississauga, ON, Canada) was oversized by 10%–20% compared with the normal vein size. Balloon diameters ranged from 7 mm to 16 mm. The balloon was typically inflated to approximately 10 –12 atm, and higherpressure inflation (maximum of 20 atm) was reserved for resistant or recurrent lesions. Venoplasty was repeated until venous patency was verified by venography, which usually required two to three dilations. Judg-
ment of successful venoplasty was made if there was complete venographic resolution of the stenosis or a final pressure gradient of 3 mm Hg or less (9). All patients were observed for at least 23 hours in the hospital, and overnight infusion of intravenous heparin was started 2 hours after the procedure. Clinic follow-up with a pediatric hepatologist was performed approximately 1 month after the procedure and was typically continued every 1–3 months. Patients with symptoms of recurrence underwent US evaluation and were subsequently referred for venography if indicated.
Stent Placement In three cases, a pressure gradient greater than 5 mm Hg remained after
venoplasty alone and a stent was placed. In two additional cases, symptoms of restenosis occurred within 30 days of venoplasty, one after primary venoplasty and one after a second venoplasty. In both cases, a stent was placed. When a stent was required, patients underwent endovascular metallic Wallstent placement (Boston Scientific, Natick, MA). Stent diameters ranged from 8 mm to 12 mm. Definitions and Statistics Technical success was defined as successful traversal of the venous obstruction with a catheter, completion of dilation with full expansion of a balloon or stent, and follow-up venography demonstrating less than 20% residual stenosis. Clinical success was defined as resolution or marked im-
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provement of clinical signs and symptoms of venous obstruction based on laboratory data and clinic notes by the referring pediatric hepatologist. For patients presenting with increased liver enzyme levels, clinical success was verified by clinical notes and laboratory data describing marked improvement between 1 and 2 months after the procedure. Some patients died or required repeat transplantation for reasons unrelated to venous outflow obstruction, as verified by pathologic or imaging findings. Patency rates were calculated for all other patients with sufficient follow-up. Primary patency was defined as the interval between initial dilation and first presentation for outflow obstruction requiring percutaneous hepatic venography. Primary assisted patency was defined as patency after initial dilation until treatment with repeated percutaneous dilation was abandoned. Secondary patency was defined as patency after the treatment of thrombosis with thrombolysis and/or mechanical recanalization until all attempts at maintaining patency were abandoned. The Wilcoxon test was used to compare pressure gradients and serum levels of liver enzymes before and after dilation. P values less than .05 were considered to indicate a statistically significant difference. Kaplan-Meier analysis was used to evaluate patency results.
RESULTS Adequate clinical data were obtained for all 16 children. The clinical presentation of venous outflow obstruction included ascites (n ⫽ 11), hepatomegaly (n ⫽ 1), increased liver enzyme levels (n ⫽ 7), and gastrointestinal bleeding (n⫽ 1). Referral for venography was based on Doppler imaging findings in eight patients, detection of stenosis by MR venography in one patient, detection of stenosis by CT in one patient, detection of hepatic congestion by liver biopsy in one patient, and strong clinical suspicion because of the combination of liver function test results, ascites, hepatomegaly, and a negative liver biopsy result in five patients. Sonographic findings suggestive of obstruction in the study group included sluggish flow, absence of flow, or reversed flow in the out-
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flow veins; accelerated flow at the outflow vein anastomosis; and direct visualization of occlusion or stenosis on grayscale images. Venography demonstrated occlusions in three patients and stenoses in 13 patients. Venographic findings included focal (⬍2 cm) stenosis of the IVC in eight patients, hepatic vein/ IVC anastomosis in three patients, hepatic vein–to– hepatic vein anastomosis in one patient, and hepatic vein–to– right atrium anastomosis in one patient, as well as total occlusion of the hepatic vein/IVC anastomosis in one patient and the IVC in two patients. In 63% of patients (n⫽ 10), moderate stenosis of hemodynamic significance was observed and verified by measurement of an abnormal pressure gradient greater than 5 mm Hg. In 18.7% of patients (n ⫽ 3), severe stenosis was observed, and in 18.7% of patients (n ⫽ 3), complete occlusion was observed. For these six cases, the interventional radiologist believed no pressure measurements were necessary to verify the diagnosis of venous outflow obstruction. The technical success rate 94% (15 of 16). In 75% of patients (n ⫽ 12), venoplasty alone restored outflow, and in 18.7% of patients (n⫽ 3), a stent was required. The Table matches the ages and graft types of the 16 children with the outcomes of percutaneous treatment. Of the 10 cases in which pressure measurements were obtained, the mean pressure gradient measured 12.5 ⫾ 5.8 mm Hg before the procedure and 3.0 ⫾ 1.3 mm Hg after the procedure (P ⫽ .002). The case of technical failure occurred in a 9.5-year-old boy with a left lateral segment graft and occlusion of the IVC anastomosis who presented clinically with ascites, increased blood levels of liver enzymes, and variceal bleeding. Attempts to traverse the occluded IVC from the transjugular, transfemoral, and transhepatic approaches were made with a hydrophilic Glidewire and catheter (Terumo, Tokyo, Japan), but chronic occlusion of the entire suprarenal IVC was encountered, and traversal could not be achieved. The patient later died of hepatic failure related to venous outflow occlusion. Another patient with an interposed donor IVC presented with occlusion of the caudal anastomosis and tight stenosis of the cranial anas-
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tomosis. Although the caudal occlusion could not be traversed for dilation, venoplasty of the cranial stenosis from a jugular vein approach was successful, and venous outflow from the graft was restored to the right atrium. The clinical success rate was 81% (13 of 16). Of the 13 patients who presented with clinical symptoms, improvement or resolution of symptoms was observed in 10. The three cases of clinical failure included the single technical failure described previously and occurred also in a 9.9-year-old boy with no change in marked ascites resulting from acute rejection and a 6.4year-old boy with no change in marked ascites and hepatomegaly resulting from primary graft failure. The latter two patients underwent repeat transplantation within 1 month of the dilation procedure. Of the seven patients who presented increased serum liver enzyme levels, reductions in the levels of serum aspartate aminotransferase and alanine aminotransferase were observed in all patients. In these cases, biopsy results revealed no evidence of hepatitis or rejection to explain the abnormal serum enzyme levels. The mean levels of serum aspartate aminotransferase were 136.3 ⫾ 129 U/L before the procedure and 47.7 ⫾ 10.3 U/L after the procedure (P ⫽ .031). The mean levels of serum alanine aminotransferase were 166.9 ⫾ 129.2 U/L before the procedure and 71.9 ⫾ 37.5 U/L after the procedure (P ⫽ .016). No significant differences in serum levels of total bilirubin, alkaline phosphatase, or albumin were noted before and after dilation. Primary patency rates for surviving patients were 92.9% (13 of 14) at 1 month, 72.7% (eight of 11) at 3 months, 60% (six of 10) at 6 months, 55.6% (five of nine) at 12 months, 50% (four of eight) at 18 months, and 50% (three of six) at 36 months. Patients were removed from the patency analysis if they died or underwent repeat transplantation during the study interval as a result of causes unrelated to venous outflow obstruction (Table). In such cases, patency of the outflow veins at the time of death was verified by autopsy, pathology results for the explanted liver, or Doppler sonography. Primary assisted and secondary patency rates were 92.9% (13 of 14) at 1 month, 90.9% (10 of 11) at 3 months, 90% (nine of 10) at 6 months, 88.9%
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Outcomes in 16 Children Undergoing Percutaneous Dilation of Venous Outflow Obstruction after Liver Transplantation
Case
Type of Transplant
Age at Age at Primary Transplantation Dilation Type of Patency Technical Clinical (y) (y) Dilation (months) Success Success
1 Whole 2 Split (left)
1.0 8.5
3.2 12.6
Balloon Stent
45.0 17.0
Yes Yes
Yes Yes
3 Cadaveric left lateral segment 4 Cadaveric left lateral segment
3.5 1.6
3.7 1.8
Balloon Stent
42.7 8.3
Yes Yes
Yes Yes
5 Whole
6.3
6.4
Balloon
40.9
Yes
Yes
6 Cadaveric left lateral segment
6.6
14.7
Balloon
4.4
Yes
Yes
7 Split (left)
0.03
0.8
Balloon
1.6
Yes
Yes
8 Cadaveric left lateral segment
8.7
8.9
Balloon
2.4
Yes
Yes
9 Whole
9.8
9.9
Balloon
0.4
Yes
No
10 Cadaveric left lateral segment
0.7
1.8
Balloon
1.4
Yes
Yes
11 Cadaveric left lateral segment
6.3
6.4
Balloon
0.4
Yes
No
12 Cadaveric left lateral segment 13 Cadaveric left lateral segment
1.6 1.5
1.7 2.2
Stent Balloon
2.3 3.2
Yes Yes
Yes Yes
14 Living related left lateral segment 15 Whole 16 Cadaveric left lateral segment
10.0
10.2
Balloon
22.9
Yes
Yes
17.8 0.9
22.0 9.3
Balloon Failed
2.2 0.0
Yes No
Yes No
(eight of nine) at 12 months, 87.5% (seven of eight) at 18 months, and 83.3% (five of six) at 36 months. Figure 4 is a Kaplan-Meier plot of patency rates. In eight surviving patients, patency persisted through the end of the study interval. Four patients still showed patency without repeated procedures after a range of 68 days to 3.7 years (mean, 1.5 y). Four required repeat dilation (two venoplasty and two stent placement) at a mean interval between procedures of 146 days, and overall primary assisted patency in this group ranged from 321 days to 4.7 years (mean, 3.1 y). Twelve patients underwent successful venoplasty alone for obstruction of venous outflow. For surviving patients with sufficient follow-up
Figure 4. Kaplan-Meier curve shows patency after percutaneous dilation of venous outflow obstruction after pediatric liver transplantation.
times, primary patency rates after venoplasty alone were 100% (10 of 10) at 1 month, 75% (six of eight) at 3
Outcome Patent, no recurrence Repeat venoplasty (3 times); died of acute hepatitis after 1.7 years No recurrence; died of sepsis Repeat venoplasty once; patent after 1.1 years No recurrence; died of fungal infection No recurrence; died of primary hepatic failure No recurrence; repeat transplantation for chronic rejection Stent implantation once; repeat venoplasty once; patent after 4.7 years No recurrence; repeat transplantation for acute rejection Stent implantation twice; repeat venoplasty 10 times; patent after 3.2 years No recurrence; repeat transplantation for preexisting hepatic arterial thrombosis Patent, no recurrence Repeat venoplasty; patent after 0.9 years Patent, no recurrence Patent, no recurrence Died of hepatic failure related to venous outflow obstruction
months, 66.7% (four of six) at 1 year, 66.7% (four of six) at 18 months, and 60% (three of five) at 3 years. Five patients underwent stent placement across the venous outflow. Three stent placement procedures were primary in nature, and two stents were placed after delayed restenosis after venoplasty. For the surviving stent-implanted patients with sufficient follow-up times, the primary patency rates after stent placement were 100% (five of five) at 1 month, 100% (four of four) at 3 months, 100% (four of four) at 6 months, and 75% (three of four) at 1 year. One patient experienced an episode of transient hypoxia while under general anesthesia. The episode resolved with supportive care during the pro-
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cedure, and there were no further sequelae. There were no other procedure-related complications. The 30day mortality rate was zero, and the 1-year mortality rate was 12.5% (two of 16). In the children who died, the causes of death included acute hepatitis, primary hepatic failure, and sepsis. The rate of repeat transplantation during the study interval was 18.8% (three of 16), and repeat transplantation was performed in those three cases 11, 13, and 50 days after the dilation procedure. In the three children who required repeat transplantation, indications included chronic rejection, acute rejection, and hepatic arterial thrombosis present before the onset of venous outflow symptoms. The cause of death or need for repeat transplantation was unrelated to venoplasty or stent placement in all cases.
DISCUSSION Venous outflow obstruction occurs in 3%– 6% of pediatric liver transplantation cases (3,6). Presentation may include ascites, increased liver function test results, gastrointestinal bleeding, and hepatosplenomegaly. Obstruction can occur at all levels of the reconstructed venous outflow from the donor hepatic veins to the recipient right atrium. Postulated causes and risk factors include cross-clamp injury, interposed venous conduits, partial liver transplantation, a low graft-to-recipient weight ratio, graft migration, graft torsion, and surgical technique. The newer technique of triangulating the recipient IVC to the donor hepatic veins and positioning the graft at the junction of the left and middle hepatic veins has reduced the incidence of venous outflow obstruction compared with earlier results (3,10,11). All types of venous anastomosis were represented in this study. The outflow veins can be drained by variations of two basic surgical techniques: conventional and piggyback. In the conventional technique, the donor retrohepatic IVC is preserved with the graft and interposed into the recipient IVC by means of an upper and lower caval-caval anastomosis. In the piggyback technique, the donor hepatic vein or IVC is anastomosed to the recipient IVC. Occasionally, size match allows for hepatic vein–to– hepatic vein end-to-end anastomosis.
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The piggyback technique can lead to obstruction at all levels from the hepatic vein to the IVC. The conventional technique can lead to obstruction at the upper caval-caval anastomosis, sometimes leading to symptoms of hepatic venous outflow obstruction accompanied by lower-extremity edema. At our institution, patients with clinical signs and symptoms of venous outflow obstruction typically undergo some form of noninvasive imaging, and findings that arouse suspicion prompt referral to the interventional radiology unit for venography with the intent to treat. Color Doppler sonography was the most common modality in this study group because most patients presented before alternative modalities were perfected. Despite newer options, sonography is immediately available, can be performed at the bedside, avoids ionizing radiation, and provides information on flow direction and velocity (12,13). MR venography and CT are excellent alternatives but require scanner availability and sedation in the pediatric population. In this study, venography and dilation were performed with patients under general anesthesia. For adolescents, we consider the option of moderate sedation if the patient is particularly cooperative and the procedure is unlikely to require a transhepatic approach. For all other adolescent and younger patients, we use general anesthesia to maximize the quality of venography and to avoid movement during selective catheterization, venoplasty, and stent placement. All but one patient in our study group were younger than 11 years and required general anesthesia (6). The remaining patient was an adolescent patient who was believed by the pediatric hepatology service to have a low tolerance and limited capacity to cooperate during the procedure. In our patients with outflow stenosis, venography demonstrated a stenosis shorter than 2 cm in length: moderate in 10 cases and severe in three. In all cases, the appearance and focality of the stenosis was believed to be related to fibrosis at the venous anastomosis rather than to pressure from abdominal ascites. A pressure gradient measured across the stenosis may help
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verify the significance of the stenosis, but some variability exists in the literature as to the gradient considered hemodynamically significant; with reports ranging from 3 mm Hg (5,9) to 5 mm Hg (6). Higher gradients may result from measurements over a longer segment of venous outflow (eg, from the hepatic vein to the right atrium) and from the added pressure of abdominal ascites. To minimize the influence of such factors, in the 10 cases of moderate stenosis in our study, pressure gradients were measured below the diaphragm, across the anastomotic stenosis. Not inconsistently with the published reports, we chose 5 mm Hg as a clinically significant gradient and 3 mm Hg as a target gradient after treatment. At our institution, the transjugular or transfemoral approach is chosen as the primary route of access for venography and dilation, depending on the location and severity of the stenosis. As demonstrated by this study, a high rate of technical success can be achieved with this technique. The one technical failure in our study occurred in a patient with complete chronic occlusion of the entire intrahepatic IVC, which could not be traversed from the transjugular, transfemoral, or transhepatic approach. Others advocate more routine use of the transhepatic approach (5), but we use this route if other approaches prove unsuccessful or are deemed unlikely to be successful (eg, complete occlusion of the hepatic vein). Despite the low complication rates described for transhepatic procedures in children (4,5), we believe placement and removal of a transhepatic sheath followed by overnight anticoagulation may carry a greater risk of complications than the transjugular or transfemoral technique. Our clinical success rate of 81% is consistent with the findings of published reports. Ko et al (14) achieved a 73% clinical success at just less than 1 year with repeated interventions. In our experience, clinical failure was related to technical failure or the presence of comorbidities contributing to clinical symptoms, such as rejection, hepatitis, and primary graft failure. Although primary dilation of venous outflow obstruction has not produced the durable results reported after primary dilation of portal vein
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obstruction (4), our results suggest that excellent long-term patency is achievable with repeated interventions. The high rate of primary assisted patency underscores the importance of excellent clinical follow-up with a pediatric hepatologist, Doppler sonography in symptomatic patients, and a low threshold for repeat intervention in cases that arouse suspicion. Successful venoplasty results in normalization of the diminished flow velocity and flattened wave pattern associated with hepatic venous outflow obstruction (12). In patients presenting with altered liver function rather than clinical symptoms of outflow obstruction, the presence of increased serum enzyme levels becomes important for the detection of recurrence during clinical follow-up. In our study, significant changes were found only in the serum aminotransferase levels after dilation, and changes of other liver function test results were insignificant. The changes in aminotransferase levels in our pediatric population were consistent with those of Wang et al (9), who found that decreases in these levels reached significance in younger patients after venous outflow dilation. The lack of significant changes in other liver function test results may reflect the variety of comorbidities in our patient population. Our patency rates are consistent with the results found in the literature (5,6,14). Cheng et al (6) achieved patency in five of six children for a mean follow-up interval of 3.67 years, with a subset of patients requiring repeat interventions. Totsuka et al (15) reported numerous repeated interventions to maintain patency in four children with outflow stenoses and suggested that venoplasty may eventually be successful after multiple attempts, obviating stent placement. In our experience, a subset of patients also responded well to venoplasty alone. For this reason, we reserve metal stent placement for patients with elastic stenoses or numerous recurrences after venoplasty alone. Considering the future growth of the child and the possibility of the need for repeat transplantation, we recommend choosing the largest stent diameter and the shortest stent length possible to achieve resolution of the obstruction. A recent case review (16) demonstrated the feasibility of a new cutting balloon technology in the
treatment of hepatic venous stricture in a child. Further studies are warranted to evaluate the safety of this type of device and the durability of the result. Cutting balloons are unlikely to replace metal stents for certain applications, including the treatment of hepatic venous kinking related to graft position or torsion (16). In our series, no major complications were observed, as was consistent with past reports (6,14,17). The high nonprocedural mortality rate was consistent with that in other series (6) and was likely related to the complexity of this patient population, which tended toward multiple comorbidities and previous operations. One incident of a self-limited, transient hypoxic episode was observed after venoplasty. The cause of this episode was not determined. Although air embolus is a possibility, dramatic increases in hepatic venous flow velocity have been noted by Doppler imaging immediately after percutaneous dilation (16), which could result in transient increases in right heart pressure. To minimize the risk of complications, we avoid percutaneous dilation within 1 month of transplantation if possible to minimize the risk of anastomotic rupture, and we admit patients overnight for intravenous heparin infusion. Despite the risks, early percutaneous dilation is sometimes necessary, especially in cases of stenosis resulting from graft migration or torsion. We avoid longterm anticoagulation with warfarin to minimize the danger of bleeding complications in active children. Despite the lack of long-term anticoagulation, no cases of delayed thrombosis occurred in our patients after dilation of venous outflow obstruction or portal venous obstruction (4). This study was limited by the low patient population, the absence of long-term follow-up in a large group as a result of loss of patients to repeat transplantation or death, and the retrospective collection of data involving several operators across a long time interval. Despite these limitations, the results demonstrate that impaired venous outflow after pediatric liver transplantation can be safely and effectively treated with venoplasty or stent placement. Long-term patency can be achieved in some patients with venoplasty alone, but a subgroup of patients requires repeated interven-
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tions and possible stent placement. Because surgical revision or repeat transplantation is associated with a significant risk of morbidity, percutaneous dilation should be considered the first-line treatment in children with hepatic venous outflow obstruction. References 1. Settmacher U, Nussler NC, Glanemann M, et al. Venous complications after orthotopic liver transplantation. Clin Transplant 2000; 14:235–241. 2. Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993; 217:82–91. 3. Buell JF, Funaki B, Cronin DC, et al. Long-term venous complications after full-size and segmental pediatric liver transplantation. Ann Surg 2002; 236:658–666. 4. Funaki B, Rosenblum JD, Leef JA, et al. Angioplasty treatment of portal vein stenosis in children with segmental liver transplants: long-term results. Radiology 2000; 215:147–151. 5. Kubo T, Shibata T, Kyo I, et al. Outcome of percutaneous transhepatic venoplasty for hepatic venous outflow obstruction after living donor liver transplantation. Radiology 2006; 239: 285–290. 6. Cheng YF, Chen CL, Huang TL, et al. Angioplasty treatment of hepatic vein stenosis in pediatric liver transplants: long-term results. Transpl Int 2005; 18: 556–561. 7. Rerksuppaphol S, Hardikar W, Smith AL, et al. Successful stenting for Budd-Chiari syndrome after pediatric liver transplantation: a case series and review of the literature. Pediatr Surg Int 2004; 20:87–90. 8. Zanotelli ML, Vieira S, Alencastro R, et al. Management of vascular complications after pediatric liver transplantation. Transpl Proc 2004; 36:945–946. 9. Wang SL, Sze DY, Busque S, et al. Treatment of hepatic venous outflow obstruction after piggyback liver transplantation. Radiology 2005; 236: 352–359. 10. Yamaguchi T, Yamaoka Y, Mori K, et al. Hepatic vein reconstruction of the graft in partial liver transplantation from living donor: surgical procedures relating to their anatomic variations. Surgery 1993; 114:976–983. 11. Tannuri U, Mello ES, Carnevale FC, et al. Hepatic venous reconstruction in pediatric living-related donor liver transplantation: experience of a single center. Pediatr Transplant 2005; 9:293– 298.
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12. Huang TL, Chen TY, Chen CL, et al. Hepatic outflow insults in living-related liver transplantation: by Doppler sonography. Transplant Proc 2001; 33: 3464–3465. 13. Chaubal N, Dighe M, Hanchate V, et al. Sonography in Budd-Chiari syndrome. J Ultrasound Med 2006; 25:373–379. 14. Ko GY, Sung KB, Yoon HK, et al. En-
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dovascular treatment of hepatic venous outflow obstruction after livingdonor liver transplantation. J Vasc Interv Radiol 2002; 13:591–599. 15. Totsuka E, Hakamada K, Narumi S, et al. Hepatic vein anastomotic stricture after living donor liver transplantation. Transplant Proc 2004; 36: 2252–2254.
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16. Narumi S, Hakamada K, Totsuka E, et al. Efficacy of cutting balloon for anastomotic stricture of the hepatic vein. Transplant Proc 2004; 36:3093–3095. 17. Egawa H, Tanaka K, Uemoto S, et al. Relief of hepatic vein stenosis by balloon angioplasty after living related liver transplantation. Clin Transplant 1993; 7:306–311.