LONG TERM EVALUATION OF ALLOGENIC VEINS AS ARTERIAL GRAFTS RUSSELL R. KRAEGER, M.D., JULIO A. LAGOS, M.D., HENDRICK B. BARNER, M.D., F.A.C.A.
AND
Despite the fact that long term experimental evaluation of allogenic veins as grafts is lacking this method of arterial reconstruction is being applied clinically. To provide data on the fate of such grafts the following study was undertaken.~ . arterial
’ .
METHOD
’ .
’
&dquo;
&dquo;..
Twenty mongrel dogs weighing nine
to 14 kilograms were operated in pairs. induced with intravenous pentobarbital sodium, 30 milligrams per kilogram. Ventilation was maintained with a Harvard respirator using room air. A six centimeter segment of right femoral vein from Dog A was used as an end-to-side graft to bypass a five centimeter segment of right femoral artery of Dog B. The right femoral vein from Dog B was then used to bypass the right femoral artery of Dog A. Identical procedures were performed on the left side of the pair after completion of the right side. Penicillin, 600,000 units, and streptomycin, 0.750 gram, were administered intramuscularly each day for three days. Each dog was examined weekly for six months, monthly for one year and then every two months. Graft patency was established by the presence of a
Anesthesia
was
TABLE 1 Fate of
allogenic grafts
palpable pulse over the graft. Dogs with patent grafts were followed for 42 months. Dogs were killed with a massive dose of pentobarbital and the grafts excised and inspected. Representative sections were prepared and stained with hematoxylin and eosin or Veerhoff-Van Giesen. From the 63104.
Department of Surgery, St.
Louis
University
1325 So.
Grand, St. Louis, Missouri
Supported by Grant HL-06312 from the United States Public Health Service. Reprint requests to: Hendrick B. Barner, M.D., 1325 So. Grand Blvd, St. Louis, Missouri
63104.
121
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
122 RESULTS
failed in the first two weeks. Subsequent graft failures occurred in pairs in the same dog within two to four weeks of each other at one, one and one-half, two, four, five, six, eight and 15 months. Five dogs died from 15 to 34 months with patent grafts and the remaining five dogs were sacrificed with patent grafts at 42 months (Table 1). Thus, no grafts failed after 15 months and 20 of 40 grafts (50%) remained patent from 15 to 42 months. If the early &dquo;technical&dquo; failures are excluded the patency rate was 56%. Five of 20 patent grafts had segmental increase in internal diameter of one to two millimeters but there was no aneurysm formation. Three grafts had nonocclusive small, mural thrombi. Microscopy revealed fibrotic replacement of the normal elements of the vein so that normal architecture was destroyed and the intimal-medial junction could not be distinguished (Fig. 1). Most grafts contained a few smooth muscle fibers and all had persistent elastic fibers in the adventitia. The inflammatory reaction, when present, was very mild and consisted of focal aggregates of lymphocytes and histiocytes. Five of the 10 veins patent at 42 months had mural microthrombi (Fig. 2 and 3) in various stages of evolution in addition to those with gross thrombus formation. Osseous metaplasia with bone marrow formation was noted in five grafts (Fig. 4). Others had focal calcification unrelated to osseous metaplasia. Atherosclerotic change was not observed although small aggregates of foam cells in relationship to hemosiderin pigment were present in a few grafts (Fig.
Four
grafts
5). DISCUSSION
Because autogenous vein is significantly better for small artery reconstruction than is synthetic material there has been continuing interest in the use of allogenic vein for those patients lacking suitable autogenous vein. Acceptability of an arterial graft is based on long term patency and freedom from the complications of infection, dehiscence and aneurysmal degeneration. This study reveals a 44 percent thrombosis rate of allogenic venous arterial grafts followed 42 months and compares with a 31 percent failure rate in an earlier study’ with a 20 to 30 weeks follow-up. Immunosuppression was associated with a failure rate of 24 percent but 10 of 17 patent grafts had mural thrombi, and the maximal duration of evaluation was 30 weeks.2 The observation that paired grafts tend to thrombose in pairs is not new’ and seems to clearly implicate rejection as the cause for mural thrombus formation which frequently leads to graft failure. Autogenous vein grafts uncommonly exhibit mural thrombi.2, Even at 42 months the endothelium is apparently not completely healed and stable as evidenced by the presence of gross and microscopic mural thrombi. However, no graft failures were recognized after 15 months which suggests that the intensity of rejection at the endothelial level diminished with time.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
123
FIG. 1. Photomicrograph showing vein wall 42 months after grafting.
a
monotonous
pattern with loss of normal architecture of
Clinical experience is limited but in a collected series of 50 operations with a follow-up of one month to four and one-half years the patency was 48 percent.44 In a later report of 46 grafts followed up to three years the patency was 72 percent. Arteriovenous allograft fistulas for chronic hemodialysis have had
extremely
poor
patency6
Graft infection and dehiscence have not been
a
problem
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
with
venous
124
FIG. 2.
FIG. 3.
Photomicrograph
of
Photomicrograph showing
organizing
a
mural thrombus.
well organized mural thrombus.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
125
FIG. 4. Photomicrograph of osseous metaplasia in vein wall marrow and fat spaces.
demonstrating
new
bone forma-
tion, bone
allografts either experimentally or clinically and the present study supports this experience. Aneurysm formation has been reported with some frequency in the clinical 8~ 9 This was a prime reason for use of venous allografts as arterial substitutes the present study as existing experimental observations are short term (30 weeks). Aneurysmal degeneration has not occurred in this study and only one instance has been found in the two large clinical series that have been reported since this study was undertaken. 4, The reasons for the freedom of arterial venous allografts from aneurysmal degeneration despite chronic rejection have been discussed. 1,4 Our microscopic observations confirm those that have been made previously and indicate that there is progressive replacement of the vein with fibrous tissue and persistence of elastic tissue elements in the adventitia. Although we observed smooth muscle cells in the graft wall at 42 months and these have been shown to be of graft origin, at least 119 days after grafting on the basis of sex chromatin, 10 it seems likely that eventually all smooth muscle cells of donor origin will be rejected. An interesting observation that is consonant with continuing rejection and
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
126
FIG. 5. Photomicrograph of foam cells atherosclerosis at 42 months.
near
the lumen which
were
the only evidence of
associated inflammation is the finding of ossous metaplasia which has not been described before. Cartilaginous metaplasia, which may be viewed as a 1 precursor of new bone formation, was noted in grafts followed a shorter time/ Osseous metaplasia is occasionally noted in association with severe atherosclerosis but that is an unlikely relationship here. There continues to be need for a substitute for autogenous vein in arterial reconstruction. The autogenous dacron reinforced tube is an acceptable alternative for femoropopliteal bypass, but has the disadvantage of needing four to six weeks for formation. &dquo; Thus, allogenic vein may be the best alternative for the patient requiring urgent femoropopliteal reconstruction or elective femorotibial bypass and lacking suitable autogenous vein. Although patency is limited this graft is not associated with an undue risk of infection,
hemorrhage
or
aneurysmal degeneration.
One must remain highly critical of the use of allogenic vein for coronary bypass’ because the short segments of autogenous vein that are needed are invariably available, even if the saphenous veins are absent, and the internal mammary artery is an acceptable or even better graft,. 12 SUMMARY
Ten pairs of mongrel dogs had bilateral femoral artery reconstruction using the femoral veins from the other of each pair. Four grafts failed in the first two
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
127 weeks and 16 grafts failed in pairs within two to four weeks of each other up to 15 months. Five dogs died with patent grafts between 15 and 42 months and five dogs were sacrificed at 42 months with patent grafts. Aneurysmal degeneration did not occur. Normal architecture of the vein was destroyed by fibrous replacement, but a few smooth muscle cells and adventitial elastic fibers persisted. Gross and microscopic mural thrombi were present in half the grafts indicating continued endothelial instability at 42 months. Osseous metaplasia was found in five grafts. Allogenic vein is an acceptable substitute when autogenous vein is lacking for femorotibial bypass and urgent femoropopliteal bypass. Hendrick B. Barner, M.D., F.A.C.A.
St. Louis University
Department of Surgery 1325 So. Grand
St. Louis, Missouri 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12.
63104
REFERENCES J. and H. B., DeWeese, Z., Schenk, E. A.: Fresh frozen homologous venous grafts for Barner, arterial repair. Angiology, 17: 389, 1966. Carpenter, E. W., and Lindenauer, S. M.: Immunosuppression in arterial and venous allografts. Arch. Surg., 106: 75, 1973. Phillips, C. E. Jr., DeWeese, J. A., and Campeti, F. L.: Comparison of peripheral arterial grafts. Arch. Surg., 82: 38, 1961. Ochsner, J. L., DeCamp, P. T., and Leonard, G. L.: Experience with fresh venous allografts as an arterial substitute. Ann. Surg., 173: 933, 1971. Tice, D. A., and Zebrino, V.: Clinical experience with preserved human allografts for vascular reconstruction. Surgery, 72: 260, 1972. Adar, R., Siegal, A., Bogokowsky, H., and Mozes, M.: The use of arteriovenous autograft and allograft fistulas for chronic hemodialysis. Surg. Gynecol. Obstet., 136: 941, 1973. Cockett, F.: Quoted by Barner, H. B., DeWeese, J. A., Schenk, E. A. Dye, W. S., Grove, W. J., Olwin, J. H., and Julian, O. C.: Two-to-four year behavior of vein grafts in the lower extremities. Arch. Surg., 72: 64, 1956. Field, P., Matar, A., and Agrama, H.: An assessment of allograft veins for arterial grafting.
Circulation, (Suppl 3), 40: 79, 1969. Schwartz, S. I., Kutner, F. R., Neistadt, A., Barner, H. B., Resnikoff, S., and Vaughn, J.: Antigenicity of homografted veins. Surgery, 61: 471, 1967.
Sparks, C. H.: Silicone mandril method for growing reinforced autogenous femoro-popliteal artery grafts in situ. Ann. Surg., 177, 293, 1973. Barner, H. B.: Double internal mammary-coronary artery bypass. Arch. Surg. 109: 627, 1974.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
AND
Despite the fact that long term experimental evaluation of allogenic veins as grafts is lacking this method of arterial reconstruction is being applied clinically. To provide data on the fate of such grafts the following study was undertaken.~ . arterial
’ .
METHOD
’ .
’
&dquo;
&dquo;..
Twenty mongrel dogs weighing nine
to 14 kilograms were operated in pairs. induced with intravenous pentobarbital sodium, 30 milligrams per kilogram. Ventilation was maintained with a Harvard respirator using room air. A six centimeter segment of right femoral vein from Dog A was used as an end-to-side graft to bypass a five centimeter segment of right femoral artery of Dog B. The right femoral vein from Dog B was then used to bypass the right femoral artery of Dog A. Identical procedures were performed on the left side of the pair after completion of the right side. Penicillin, 600,000 units, and streptomycin, 0.750 gram, were administered intramuscularly each day for three days. Each dog was examined weekly for six months, monthly for one year and then every two months. Graft patency was established by the presence of a
Anesthesia
was
TABLE 1 Fate of
allogenic grafts
palpable pulse over the graft. Dogs with patent grafts were followed for 42 months. Dogs were killed with a massive dose of pentobarbital and the grafts excised and inspected. Representative sections were prepared and stained with hematoxylin and eosin or Veerhoff-Van Giesen. From the 63104.
Department of Surgery, St.
Louis
University
1325 So.
Grand, St. Louis, Missouri
Supported by Grant HL-06312 from the United States Public Health Service. Reprint requests to: Hendrick B. Barner, M.D., 1325 So. Grand Blvd, St. Louis, Missouri
63104.
121
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
122 RESULTS
failed in the first two weeks. Subsequent graft failures occurred in pairs in the same dog within two to four weeks of each other at one, one and one-half, two, four, five, six, eight and 15 months. Five dogs died from 15 to 34 months with patent grafts and the remaining five dogs were sacrificed with patent grafts at 42 months (Table 1). Thus, no grafts failed after 15 months and 20 of 40 grafts (50%) remained patent from 15 to 42 months. If the early &dquo;technical&dquo; failures are excluded the patency rate was 56%. Five of 20 patent grafts had segmental increase in internal diameter of one to two millimeters but there was no aneurysm formation. Three grafts had nonocclusive small, mural thrombi. Microscopy revealed fibrotic replacement of the normal elements of the vein so that normal architecture was destroyed and the intimal-medial junction could not be distinguished (Fig. 1). Most grafts contained a few smooth muscle fibers and all had persistent elastic fibers in the adventitia. The inflammatory reaction, when present, was very mild and consisted of focal aggregates of lymphocytes and histiocytes. Five of the 10 veins patent at 42 months had mural microthrombi (Fig. 2 and 3) in various stages of evolution in addition to those with gross thrombus formation. Osseous metaplasia with bone marrow formation was noted in five grafts (Fig. 4). Others had focal calcification unrelated to osseous metaplasia. Atherosclerotic change was not observed although small aggregates of foam cells in relationship to hemosiderin pigment were present in a few grafts (Fig.
Four
grafts
5). DISCUSSION
Because autogenous vein is significantly better for small artery reconstruction than is synthetic material there has been continuing interest in the use of allogenic vein for those patients lacking suitable autogenous vein. Acceptability of an arterial graft is based on long term patency and freedom from the complications of infection, dehiscence and aneurysmal degeneration. This study reveals a 44 percent thrombosis rate of allogenic venous arterial grafts followed 42 months and compares with a 31 percent failure rate in an earlier study’ with a 20 to 30 weeks follow-up. Immunosuppression was associated with a failure rate of 24 percent but 10 of 17 patent grafts had mural thrombi, and the maximal duration of evaluation was 30 weeks.2 The observation that paired grafts tend to thrombose in pairs is not new’ and seems to clearly implicate rejection as the cause for mural thrombus formation which frequently leads to graft failure. Autogenous vein grafts uncommonly exhibit mural thrombi.2, Even at 42 months the endothelium is apparently not completely healed and stable as evidenced by the presence of gross and microscopic mural thrombi. However, no graft failures were recognized after 15 months which suggests that the intensity of rejection at the endothelial level diminished with time.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
123
FIG. 1. Photomicrograph showing vein wall 42 months after grafting.
a
monotonous
pattern with loss of normal architecture of
Clinical experience is limited but in a collected series of 50 operations with a follow-up of one month to four and one-half years the patency was 48 percent.44 In a later report of 46 grafts followed up to three years the patency was 72 percent. Arteriovenous allograft fistulas for chronic hemodialysis have had
extremely
poor
patency6
Graft infection and dehiscence have not been
a
problem
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
with
venous
124
FIG. 2.
FIG. 3.
Photomicrograph
of
Photomicrograph showing
organizing
a
mural thrombus.
well organized mural thrombus.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
125
FIG. 4. Photomicrograph of osseous metaplasia in vein wall marrow and fat spaces.
demonstrating
new
bone forma-
tion, bone
allografts either experimentally or clinically and the present study supports this experience. Aneurysm formation has been reported with some frequency in the clinical 8~ 9 This was a prime reason for use of venous allografts as arterial substitutes the present study as existing experimental observations are short term (30 weeks). Aneurysmal degeneration has not occurred in this study and only one instance has been found in the two large clinical series that have been reported since this study was undertaken. 4, The reasons for the freedom of arterial venous allografts from aneurysmal degeneration despite chronic rejection have been discussed. 1,4 Our microscopic observations confirm those that have been made previously and indicate that there is progressive replacement of the vein with fibrous tissue and persistence of elastic tissue elements in the adventitia. Although we observed smooth muscle cells in the graft wall at 42 months and these have been shown to be of graft origin, at least 119 days after grafting on the basis of sex chromatin, 10 it seems likely that eventually all smooth muscle cells of donor origin will be rejected. An interesting observation that is consonant with continuing rejection and
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
126
FIG. 5. Photomicrograph of foam cells atherosclerosis at 42 months.
near
the lumen which
were
the only evidence of
associated inflammation is the finding of ossous metaplasia which has not been described before. Cartilaginous metaplasia, which may be viewed as a 1 precursor of new bone formation, was noted in grafts followed a shorter time/ Osseous metaplasia is occasionally noted in association with severe atherosclerosis but that is an unlikely relationship here. There continues to be need for a substitute for autogenous vein in arterial reconstruction. The autogenous dacron reinforced tube is an acceptable alternative for femoropopliteal bypass, but has the disadvantage of needing four to six weeks for formation. &dquo; Thus, allogenic vein may be the best alternative for the patient requiring urgent femoropopliteal reconstruction or elective femorotibial bypass and lacking suitable autogenous vein. Although patency is limited this graft is not associated with an undue risk of infection,
hemorrhage
or
aneurysmal degeneration.
One must remain highly critical of the use of allogenic vein for coronary bypass’ because the short segments of autogenous vein that are needed are invariably available, even if the saphenous veins are absent, and the internal mammary artery is an acceptable or even better graft,. 12 SUMMARY
Ten pairs of mongrel dogs had bilateral femoral artery reconstruction using the femoral veins from the other of each pair. Four grafts failed in the first two
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
127 weeks and 16 grafts failed in pairs within two to four weeks of each other up to 15 months. Five dogs died with patent grafts between 15 and 42 months and five dogs were sacrificed at 42 months with patent grafts. Aneurysmal degeneration did not occur. Normal architecture of the vein was destroyed by fibrous replacement, but a few smooth muscle cells and adventitial elastic fibers persisted. Gross and microscopic mural thrombi were present in half the grafts indicating continued endothelial instability at 42 months. Osseous metaplasia was found in five grafts. Allogenic vein is an acceptable substitute when autogenous vein is lacking for femorotibial bypass and urgent femoropopliteal bypass. Hendrick B. Barner, M.D., F.A.C.A.
St. Louis University
Department of Surgery 1325 So. Grand
St. Louis, Missouri 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12.
63104
REFERENCES J. and H. B., DeWeese, Z., Schenk, E. A.: Fresh frozen homologous venous grafts for Barner, arterial repair. Angiology, 17: 389, 1966. Carpenter, E. W., and Lindenauer, S. M.: Immunosuppression in arterial and venous allografts. Arch. Surg., 106: 75, 1973. Phillips, C. E. Jr., DeWeese, J. A., and Campeti, F. L.: Comparison of peripheral arterial grafts. Arch. Surg., 82: 38, 1961. Ochsner, J. L., DeCamp, P. T., and Leonard, G. L.: Experience with fresh venous allografts as an arterial substitute. Ann. Surg., 173: 933, 1971. Tice, D. A., and Zebrino, V.: Clinical experience with preserved human allografts for vascular reconstruction. Surgery, 72: 260, 1972. Adar, R., Siegal, A., Bogokowsky, H., and Mozes, M.: The use of arteriovenous autograft and allograft fistulas for chronic hemodialysis. Surg. Gynecol. Obstet., 136: 941, 1973. Cockett, F.: Quoted by Barner, H. B., DeWeese, J. A., Schenk, E. A. Dye, W. S., Grove, W. J., Olwin, J. H., and Julian, O. C.: Two-to-four year behavior of vein grafts in the lower extremities. Arch. Surg., 72: 64, 1956. Field, P., Matar, A., and Agrama, H.: An assessment of allograft veins for arterial grafting.
Circulation, (Suppl 3), 40: 79, 1969. Schwartz, S. I., Kutner, F. R., Neistadt, A., Barner, H. B., Resnikoff, S., and Vaughn, J.: Antigenicity of homografted veins. Surgery, 61: 471, 1967.
Sparks, C. H.: Silicone mandril method for growing reinforced autogenous femoro-popliteal artery grafts in situ. Ann. Surg., 177, 293, 1973. Barner, H. B.: Double internal mammary-coronary artery bypass. Arch. Surg. 109: 627, 1974.
Downloaded from ves.sagepub.com at SIMON FRASER LIBRARY on March 16, 2015
