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Corresponding author. I. Matia, Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21 Prague, Czech Republic.
Affiliations
Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
To assess the outcome of cold-stored venous allografts in critically ischemic limbs in patients with no ipsilateral autogenous greater saphenous vein.
Design
A non-randomised, retrospective, single-center study.
Methods
From September 2000 to June 2006, 46 cold-stored venous allografts obtained during multiorgan harvest were implanted into 44 critically ischaemic limbs of 43 patients. The indication for reconstructions was rest pain (24%) or tissue lost (76%). Sixty-seven percent of procedures were performed as secondary reconstructions, and 61% of veins were anastomosed to tibial or pedal arteries. Thirty-seven percent of patients received prednisone, and 46% tacrolimus as postoperative immunosuppressive therapy. Mean patient follow-up period was 13.3 months (range 1 week to 60 months).
Results
The secondary patency rate for the cohort was 83±5.6% at 1 month, 64±8.2% at 6 months, 57±10.0% at 12 months and 46±10.7% at 24 months. Limb salvage rate was 96±3.1% at 1 month, 78±6.9% at 6 months, 71±8.1% at 12 months and 50±11.8% at 24 months.
Conclusion
Cold-stored venous allografts are an alternative conduit for limb salvage procedures when ipsilateral autogenous vein is unavailable.
Comparative decades of experience with glutaraldehyde-tanned human umbilical cord vein graft for lower limb revascularization: an analysis of 1275 cases.
However, arterial as well as venous allografts are antigenic and the process of chronic rejection is a limiting factor in long-term patency rates of these by-pass conduits.
At our Institute, the Vascular Surgery Unit is integrated closely with the Transplant Center, so it is possible to obtain allogenic blood vessels for vascular reconstruction during regular multi-organ harvests.
Over the past six years we have used cold-stored venous allografts in patients with no suitable ipsilateral greater saphenous veins and critically ischemic limbs. This present paper reports our results.
Material and Methods
The work was approved by the Ethical Committee of the Institute for Clinical and Experimental Medicine in Prague. The work is a retrospective study dealing with the critically ischaemic lower limbs treated by cold-stored venous allograft reconstructions. Ipsilateral autogenous greater saphenous vein was unavailable in all patients.
Patient population
From September 2000 to June 2006, 46 cold-stored venous allografts were implanted into 44 critically ischaemic limbs of 43 patients (men 21, women 22). Mean patient age at primary graft implantation was 66.8 years (range 46 to 85 years). Demographic data for all 43 patients are shown in Table 1.
Table 1Demographic data for 43 patients in whom cold-stored venous allografts were used
The indication for the 46 reconstructions was either rest pain (n=11, 24%) or tissue lost (n=35, 76%). Suitable ipsilateral autogenous greater saphenous vein was not available in these patients. The most frequent reason for lack of ipsilateral vein was it's use as conduit for a prior leg bypass (43%) (Table 2). Sixty-seven percent of 46 cold-stored venous allograft reconstructions were secondary or even tertiary procedures, performed after a previous failed infrainguinal reconstruction. In 59 percent of venous allograft reconstructions, there was no contralateral autogenous greater saphenous vein available, mainly because of it's previous harvest (20%) (Table 2). In the remaining 41 percent of patients with a suitable contralateral vein we elected not to utilise this because of the high risk that it would be required for future intervention in that leg.
All patients underwent preoperative arteriography. The quality of the peripheral outflow tract distal to the graft was outlined by using Rutherford's run-off-index.
The mean value of the index for the 46 reconstructions was 4.9 (range 2 to 8, SD±1.8).
Harvest and preservation of venous grafts
All venous allografts (greater saphenous veins) were obtained from donors with the diagnosis of brain death in the course of a multiorgan harvest. The mean age of the donors was 32 years (range 17 to 54 years).
After removal, the venous grafts were flushed with heparinised conservation solutions commonly used in multiorgan harvests, i.e. Custodiol or University of Wisconsin. The grafts were stored at a temperature of about 4 degrees Centigrade using the same types of solutions as those used for flushing, with no additional antibiotics. The mean cold ischemic time of venous grafts was 5 days (range 5 hours to 13 days). The patients indicated for the use of venous allograft were integrated into a waiting list similar to that used for potential recipients in solid organ transplantation. The ABO compatibility, but no HLA compatibility, was maintained between donors and recipients of venous allografts. Similarly, no cross-match was performed. In all organ donors bacteriological and serological tests (for HIV, hepatitis C, hepatitis B, cytomegalovirus, syphilis, Epstein-Barr virus) were performed before the multiorgan harvest.
Characteristics of procedures
Characteristics of the operative procedures of the 46 venous allograft are shown in Table 3.
Table 3The sites of proximal and distal anastomosis of 46 venous allografts reconstructions
From September 2000 to September 2004 a variety of immunosuppresive protocols including prednisone, azathioprime, cyclosporine A were used in patients after the allovenous reconstructions (Table 4). Drug dosages and the duration of administration were not standardized. In September 2004, we started using an immunosuppressive protocol consisting of orally administered FK 506 (tacrolimus, Prograf®, Astellas Pharma Ltd.), with the drug blood level generally ranging between 4 and 7 ng/ml. Tacrolimus was administered throughout the entire period of allograft patency and blood levels were determined periodically. This type of immunosuppression was used in 21 (46%) patients (Table 4).
Table 4Type of immunosuppression in 46 venous allografts reconstructions
We defined three follow up periods, namely for the patient, for the limb, and for the vascular procedure. Each of them started on the day of the operation. The death of the patient or the date when the patient was last known to be alive were the end points of the patient follow-up period. The follow-up period for the patency rate ended when the graft was confirmed to be occluded or last known to be patent. The graft patency was evaluated only by a vascular surgeon or diagnostic tests. The follow-up period for the limb salvage rate ended when a major limb amputation was done, the patient died, or the patient was last known to have an affected limb. A major limb amputation was defined as an amputation which was unable to preserve a sufficiently functional foot remnant to allow standing and walking without a prosthesis.
From September 2004 we employed along with the standard immunosuppressive protocol a standard protocol for duplex ultrasound surveillance of patients after the allovenous reconstructions. The patients were seen in three-monthly intervals to check the graft patency and the FK 506 blood levels as well. The patency of reconstructions was verified by clinical examinations as well as ultrasonography at identical time intervals. If signs of bypass stenosis were observed with duplex ultrasonography, angiography (conventional or computed) was performed.
Statistical analysis
Patient survival rates, graft patency rates, and limb salvage rates were determined by the Kaplan–Meier method. Differences between groups were tested for significance using Wilcoxon's signed rank test. Differences between groups were considered significant for P values less than 0.05.
Results
The mean patient follow-up period was 13.3 months (range 1 week to 60 months), the mean limb salvage follow-up period was 13.4 months (range 1 day to 58 months) and the mean graft patency rate follow-up period was 10 months (range 1 day to 56.5 months), respectively.
There were no deaths during the thirty-day perioperative period. The overall thirty-day morbidity was 24%. Systemic complications included acute GIT hemorrhage in 1 patient (2%). Local complications included wound infection (11%), wound hemorrhage without surgical intervention (4%), wound hemorrhage that necessitated surgical intervention (2%), vein allograft bypass rupture (2%), and graft thrombosis with limb amputation (2%). Patients survival rate was 100% at 1 month, 92±4.6% at 3 months, 88±5.7% at 6 months, 88±5.7% at 12 months, 88±5.7% at 24 months and 74±15.4% at 36 months (Fig. 1).
Fig. 1Patients survival curve. Kaplan–Maier method. Number at rist (% SEM).
The primary patency rate for the cohort was 83±5.6% at 1 month, 70±7.1% at 3 months, 47±8.3% at 6 months, 35±9.4% at 12 months, 31±9.0% at 24 months and 15±8.1% at 36 months (Fig. 2).
Fig. 2Primary patency curve for 46 revascularizations procedures with cold-stored venous allografts. Kaplan–Maier method. Number at rist (% SEM).
Six endovascular procedures (5 PTA, 1 PTA/stent) were needed to maintain the primary patency of venous allografts. The primary assisted patency rate for the cohort was 83±5.6% at 1 month, 73±6.9% at 3 months, 61±8.3% at 6 months, 57±10.0% at 12 months, 46±10.7% at 24 months and 23±10.1% at 36 months.
Six surgical thrombectomies and two local usages of tissue plasminogen activator were needed to maintain the secondary patency of venous allografts. The secondary patency rate for the cohort was 83±5.6% at 1 month, 73±6.9% at 3 months, 64±8.2% at 6 months, 57%±10.0% at 12 months, 46±10.7% at 24 months and 31±11.4% at 36 months (Fig. 3).
Fig. 3Secondary patency curve for 46 revascularizations procedures with cold-stored venous allografts. Kaplan–Maier method. Number at rist (% SEM).
Limb salvage rate was 96±3.1% at 1 month, 81±6.3% at 3 months, 78±6.9% at 6 months, 71±8.1% at 12 months, 50±11.8% at 24 months and 43±12.2% at 36 months (Fig. 4).
Fig. 4Limb salvage curve for 44 critically ischaemic limbs treated by cold-stored venous allografts reconstructions. Kaplan–Maier method. Number at rist (% SEM).
To compare the influence of FK 506 immunosuppression, the cohort of patients was divided into a group with standard FK 506 immunosupression (N=21) and one with other types or no immunosuppression (N=25). The primary patency rate for the FK 506 group was 76±9.3% at 1 month, 65±10.8% at 3 months, 59±11.5% at 6 months and 16±14.0% at 12 months. The primary patency rate for the group of patients with other type or no immunosuppresion was 88±6.5% at 1 month, 75±8.9% at 3 months, 42±10.5% at 6 months and 42±10.5% at 12 months, respectively. The secondary patency rate for the FK 506 immunosuppressed group was 76±9.3% at 1 month, 65±10.8% at 3 months, 65±10.8% at 6 months and 44±19.1% at 12 months, and for the other group 88±6.5% at 1 month, 79±8.3% at 3 months, 65±9.9% at 6 months and 60±10.5% at 12 months, respectively.
No statistical differences in patient survival, limb salvage rate, primary and secondary patency rates were observed between the groups using Wilcoxon's signed rank test.
Discussion
In this study, the greater saphenous veins obtained from brain-dead donors in the course of a multi-organ harvest were used in 43 patients with critical lower limb ischaemia. All vascular reconstructions were performed as limb-salvage procedures. The ipsilateral autogenous greater saphenous vein was not available in any of presented patients, and almost 70% of them had diabetes mellitus.
Venous allografts are used in patients with no suitable autogenous vein when polytetrafluoroethylene (PTFE) grafts are not recommended. This concerns mainly patients with gangrene or poor run-off.
There are various types of venous allografts that can be used, which differ in how they are preserved. The most frequently used ones are glutaraldehyde venous allografts, followed by cryopreserved and cold-stored venous allografts.
However, a direct comparison between various allografts or preservation techniques is not possible because of the heterogeneity of individual studies and the absence of a study directly comparing various types of allografts.
suggests that there are probably no statistically significant differences between the various types of allografts.
Currently, only four studies describing the use of venous allografts preserved at 4° for infrainguinal bypasses have been published: Van Reedt Dortland et al.,
(Table 6) Nevertheless, all of these studies were undertaken on venous allografts that were harvested during varicose vein surgery. The grafts were stored in a saline solution containing antibiotics. Because of the difficult assembly of venous allografts, most of them were used as a part of composite grafts made with either polytetrafluoroethylene or polyurethane prostheses,
and no immunosuppressive drugs were used in postoperative protocols (Table 6). Diabetes was the only factor independently associated with a worse outcome in one study of cryopreserved venous allografts.
Table 6Main features of cold-stored venous allografts series published since 1990 compared with the most largest cohort of cryopreserved venous allografts published by Farber et al.
Our cohort of patients differs from that in the previously mentioned studies of venous allograft reconstructions. Most of our patients suffered from diabetes (70%) and ischaemic heart disease (61%), all of them have had critical ischaemia of the legs, 67% of allovenous bypasses were performed as the secondary procedure and the site of distal anastomosis were crural or pedal arteries in 61% of the total reconstructions. Nevertheless, the 1-year limb salvage (71%) and secondary patency rates (57%) presented in this study are comparable to that of cryopreserved (78%, 48%) or cold-stored venous allografts (76%, 64%) presented in the Meta-Analysis by Albers et al.
Fresh venous allografts in peripheral arterial reconstruction in dogs. Effects of histocompatibility and of short-term immunosuppression with cyclosporine A and mycophenolate mofetil.
Early results of infrageniculate arterial reconstruction using cryopreserved homograft saphenous conduit (Cadvein) and combination low-dose systemic immunosuppression.
evaluated a combination of low-dose cyclosporine, azathioprime, prednisone, warfarin, aspirin and vasodilators on the patency of cryopreserved vein bypasses in humans and found a significantly improved patency (59% vs. 17%) at 1 year. Carpenter and Tomaszewski,
however, were unable to show any benefit to low-dose immunosuppression with azathioprime when compared to controls in regard to graft patency or limb salvage.
The drug used most frequently as an immunosuppressant in the beginning of our study was prednisone. From September 2004 we started to use an immunosuppressive protocol composed of oral FK 506 (tacrolimus, Prograf®, Astellas Pharma Ltd.) with drug blood level between 4 to 7 ng/ml. FK 506 is a modern immunosuppressant used widely after solid organ transplantations. Tacrolimus- when compared to cyclosporine-based immunosuppressive therapy in kidney transplantations, resulted in a significantly reduced risk of graft failure, without an increase in the incidence of adverse events.
Moreover, the inhibition of the transforming growth factor – beta (TGF-beta) production by FK 506 could make the drug eligible for use in vascular surgery.
TGF-beta is an important cytokine involved in the process of fibrosis. Increased expression of TGF-beta mRNA is associated with saphenous vein bypass graft disease and with postangioplasty stenosis.
Persistently increased expression of the transforming growth factor-β1 gene in human vascular restenosis: analysis of 62 patients with one or more episode of restenosis.
FK 506 was administered as a monotherapy in low dosages to our patients and no adverse effects have so far been observed. In comparison to other studies, no aneurysmal dilatation occurred in any of the patients (Table 6). This may have resulted from immunosuppression of the immune system, the short duration of the cold-stored preservation period, as well as the properties of preservation solution used. However, these observations need to be studied more consistently to be confirmed. The study reflects all the disadvantages associated with non-randomised, retrospective, single-center studies. The small sample size and the short follow-up period are other limitations.
In conclusion, femoral-infrapopliteal bypass using cold-stored saphenous vein allograft is an acceptable alternative for limb salvage when an autogenous vein is unavailable and the use of a prosthetic graft is not recommended. Only a vascular surgery unit closely integrated with a Transplant Center has the opportunity to use this type of allogenous material.
Acknowledgement
The work was supported by Grant No. MZO 00023001 awarded by Ministry of Health of the Czech Republic.
Comparative decades of experience with glutaraldehyde-tanned human umbilical cord vein graft for lower limb revascularization: an analysis of 1275 cases.
Fresh venous allografts in peripheral arterial reconstruction in dogs. Effects of histocompatibility and of short-term immunosuppression with cyclosporine A and mycophenolate mofetil.
Early results of infrageniculate arterial reconstruction using cryopreserved homograft saphenous conduit (Cadvein) and combination low-dose systemic immunosuppression.
Persistently increased expression of the transforming growth factor-β1 gene in human vascular restenosis: analysis of 62 patients with one or more episode of restenosis.
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