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Preliminary report on continous cold perfusion during vascular anastomosis in liver transplantation
Preliminary Report on Continous Cold Perfusion During Vascular Anastomosis in Liver Transplantation M. Haberal, R. Emiroglu, H. Karakayali, G. Moray, G. Arslan, N. Bilgin, and B. Demirhan
P
RESERVATION injury continues to be a serious problem in transplantation, including damage during rewarming.1,2 Human liver transplantation involves a rewarming period of at least 30 to 60 minutes,3,4 namely the time the liver is removed from the cold to the moment of reperfusion via the portal vein. Substantial organ damage may occur during this period. Our goal in this preliminary study was to determine whether injury from warm ischemia may be reduced by maintaining continuous cold perfusion during the hepatic vein anastomosis. We also sought to clarify how cold perfusion affects hepatic function in the early posttransplant period, and to assess the histopathologic changes that occur during rewarming. PATIENTS AND METHODS Six liver transplantation cases were studied in two groups. Group I including two men and one women of mean age 33.7 years; (range 7 to 51 years) underwent continuous perfusion and Group II (two men and one women of mean age 38.7 years (range, 21 to 48 years) did not have this treatment. Among Group I, two patients underwent orthotopic whole liver cadaveric donor transplantation and one individual received a left lobe from a living donor. In all three cases, the graft was continuously perfused with histidine-tryptophane-ketoglutarate (HTK) via the portal vein during the hepatic vein anastomosis. Once this was complete, portal vein blood flow was restored and the hepatic artery anastomosis was performed. Wedge biopsies were collected from the cold-preserved liver tissue immediately before the operation and after reperfusion. Histopathologic findings were compared with those in liver biopsies obtained at the same time as in the Group I versus the Group II cases.
RESULTS
In Group I, the three patient’s serum aspartate aminotransferase and alanine aminotransferase (AST/ALT) levels at 24 hours after surgery were 59/56 IU/L, 849/507 IU/L, and 282/56 IU/L, respectively. The corresponding total bilirubin levels were 9.4 mg/dL, 6.1 mg/dL, and 13.7 mg/dL, and the prothrombin times were 13 seconds, 39 seconds, and 19 seconds. On postoperative day 7, the AST/ALT levels were 78/124 IU/L, 110/210 IU/L, and 25/18 IU/L. The corresponding total bilirubin levels were 7.8 mg/dL, 4 mg/dL, and 2 mg/dL, and the prothrombin times were 29 seconds, 19 seconds, and 17 seconds. At 3 weeks, the AST/ALT findings were 34/39 IU/L, 45/208 IU/L, and 20/19 IU/L. The corre-
Fig 1.
Postoperative ALT levels in Groups I and II.
sponding total bilirubin levels were 5.3 mg/dL, 3 mg/dL, and 1 mg/dL, and the prothrombin times were 13 seconds, 13 seconds, and 12 seconds. In the first week postsurgery, the mean AST levels in Group I fell from 397 IU/L to 71 IU/L, whereas those in Group II dropped from 285 IU/L to 141 IU/L. The mean ALT levels in Group I fell from 206 IU/L to 117 IU/L, whereas those in Group II dropped from 206 IU/L to 150 IU/L The AST and ALT levels in Group I dropped more than those in Group II during the first week. ALT results are shown in Fig 1. Histopathologic examination of the biopsies collected presurgery and immediately upon reperfusion revealed that the Group II specimens had a higher number of neutrophils in the sinusoids, perivenular spaces, and subcapsular spaces after reperfusion. The group findings were similar with respect to hydropic degeneration, sinusoidal dilatation, and cellular necrosis. DISCUSSION
Several factors contribute to graft failure after liver transplantation. Surgical technique and/or poor quality of the donor organ are two problems that can result in primary nonfunction. Substantial organ damage may occur during the rewarming period. The rising temperature in this stage activates enzyme systems and increases metabolic activity. From the Baskent University Faculty of Medicine, Department of General Surgery and Transplantation (M.H., R.E., H.K., G.M., N.B., B.D.) and Department of Pathology (B.D.), and Department of Anesthesiology (G.A.), Ankara, Turkey. Address reprint requests to M. Haberal, Baskent University Faculty Medicine, 1. Cadde No: 77 Bahcelievler, Ankara 06490, Turkey. E-mail: [email protected]
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.09.041
Transplantation Proceedings, 35, 2775⫺2776 (2003)
2775
2776
Increased energy demand triggers the reactivation of anaerobic metabolism, which leads to cellular damage. During liver transplantation, the temperature of the graft rises while the anastomoses are being performed. To reduce the impact of this higher temperature, most surgeons try to protect the liver by wrapping it in cold gauze. However, it is impossible to impede the temperature rise by surface cooling alone, and the graft always begins to rewarm in spite of these efforts. Because is extremely important to minimize postischemic hepatic injury in liver transplantation, various preservation methods have been investigated, including continuous cold perfusion versus cold storage, as well as the optimal way to begin reperfusion (portal vein versus hepatic artery).5,6 However, few reports have focused on the impact of rewarming. It is generally accepted that the liver can maintain its integrity for up to 45 minutes of warm ischemia; however, no in-depth studies have examined whether this ischemia makes the liver cell more vulnerable to hypoxia; increases inflammatory cell infiltration of the graft jeopardizes the recovery of the graft or aggravates the reperfusion injury. One group of investigators showed that ischemia during rewarming exacerbates reperfusion injury, and that the use of leukocyte-depleted blood for reperfusion ameliorates this injury.7 In our study, biopsies from grafts that had not been continuously perfused (Group II) showed severe inflammatory reactions, in contrast to minimal neutrophil infiltration in the continuous-perfusion cases (Group I). We observed
HABERAL, EMIROGLU, KARAKAYALI ET AL
no morphologic differences in cell structure between the two groups. Interestingly, liver enzyme levels in Group I normalized more rapidly than Group II, which may be related to the deleterious effects of the activated inflammatory cells in the second group. CONCLUSION
Our preliminary results indicate that continuous perfusion of liver transplants during the hepatic vein anastomosis may facilitate slightly faster recovery. We believe that the more rapid normalization of liver enzyme levels observed in the postoperative period may reflect a protective effect of continuous perfusion. REFERENCES 1. Clavien PA, Harvey PR, Strasberg SM: Transplantation 53: 957, 1992 2. Vajdora K, Smrekova R, Mislanova C, et al: Hepatology 32:289, 2000 3. Massarollo PC, Mies S, Raia S: Transplant Proc 30:2883, 1998 4. Sankary HN, McChesney L, Frye E, et al: Hepatology 21:63, 1995 5. Sadler KM, Walsh TS, Garden OJ, et al: Transplantation 72:1680, 2001 6. Imber CJ, St Peter SD, de Cenarruzabeitia IL, et al: Transplantation 73:701, 2002 7. Shiraishi Y, Lee JR, Laks H, et al: J Heart Lung Transplant 17:250, 1998
P
RESERVATION injury continues to be a serious problem in transplantation, including damage during rewarming.1,2 Human liver transplantation involves a rewarming period of at least 30 to 60 minutes,3,4 namely the time the liver is removed from the cold to the moment of reperfusion via the portal vein. Substantial organ damage may occur during this period. Our goal in this preliminary study was to determine whether injury from warm ischemia may be reduced by maintaining continuous cold perfusion during the hepatic vein anastomosis. We also sought to clarify how cold perfusion affects hepatic function in the early posttransplant period, and to assess the histopathologic changes that occur during rewarming. PATIENTS AND METHODS Six liver transplantation cases were studied in two groups. Group I including two men and one women of mean age 33.7 years; (range 7 to 51 years) underwent continuous perfusion and Group II (two men and one women of mean age 38.7 years (range, 21 to 48 years) did not have this treatment. Among Group I, two patients underwent orthotopic whole liver cadaveric donor transplantation and one individual received a left lobe from a living donor. In all three cases, the graft was continuously perfused with histidine-tryptophane-ketoglutarate (HTK) via the portal vein during the hepatic vein anastomosis. Once this was complete, portal vein blood flow was restored and the hepatic artery anastomosis was performed. Wedge biopsies were collected from the cold-preserved liver tissue immediately before the operation and after reperfusion. Histopathologic findings were compared with those in liver biopsies obtained at the same time as in the Group I versus the Group II cases.
RESULTS
In Group I, the three patient’s serum aspartate aminotransferase and alanine aminotransferase (AST/ALT) levels at 24 hours after surgery were 59/56 IU/L, 849/507 IU/L, and 282/56 IU/L, respectively. The corresponding total bilirubin levels were 9.4 mg/dL, 6.1 mg/dL, and 13.7 mg/dL, and the prothrombin times were 13 seconds, 39 seconds, and 19 seconds. On postoperative day 7, the AST/ALT levels were 78/124 IU/L, 110/210 IU/L, and 25/18 IU/L. The corresponding total bilirubin levels were 7.8 mg/dL, 4 mg/dL, and 2 mg/dL, and the prothrombin times were 29 seconds, 19 seconds, and 17 seconds. At 3 weeks, the AST/ALT findings were 34/39 IU/L, 45/208 IU/L, and 20/19 IU/L. The corre-
Fig 1.
Postoperative ALT levels in Groups I and II.
sponding total bilirubin levels were 5.3 mg/dL, 3 mg/dL, and 1 mg/dL, and the prothrombin times were 13 seconds, 13 seconds, and 12 seconds. In the first week postsurgery, the mean AST levels in Group I fell from 397 IU/L to 71 IU/L, whereas those in Group II dropped from 285 IU/L to 141 IU/L. The mean ALT levels in Group I fell from 206 IU/L to 117 IU/L, whereas those in Group II dropped from 206 IU/L to 150 IU/L The AST and ALT levels in Group I dropped more than those in Group II during the first week. ALT results are shown in Fig 1. Histopathologic examination of the biopsies collected presurgery and immediately upon reperfusion revealed that the Group II specimens had a higher number of neutrophils in the sinusoids, perivenular spaces, and subcapsular spaces after reperfusion. The group findings were similar with respect to hydropic degeneration, sinusoidal dilatation, and cellular necrosis. DISCUSSION
Several factors contribute to graft failure after liver transplantation. Surgical technique and/or poor quality of the donor organ are two problems that can result in primary nonfunction. Substantial organ damage may occur during the rewarming period. The rising temperature in this stage activates enzyme systems and increases metabolic activity. From the Baskent University Faculty of Medicine, Department of General Surgery and Transplantation (M.H., R.E., H.K., G.M., N.B., B.D.) and Department of Pathology (B.D.), and Department of Anesthesiology (G.A.), Ankara, Turkey. Address reprint requests to M. Haberal, Baskent University Faculty Medicine, 1. Cadde No: 77 Bahcelievler, Ankara 06490, Turkey. E-mail: [email protected]
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.09.041
Transplantation Proceedings, 35, 2775⫺2776 (2003)
2775
2776
Increased energy demand triggers the reactivation of anaerobic metabolism, which leads to cellular damage. During liver transplantation, the temperature of the graft rises while the anastomoses are being performed. To reduce the impact of this higher temperature, most surgeons try to protect the liver by wrapping it in cold gauze. However, it is impossible to impede the temperature rise by surface cooling alone, and the graft always begins to rewarm in spite of these efforts. Because is extremely important to minimize postischemic hepatic injury in liver transplantation, various preservation methods have been investigated, including continuous cold perfusion versus cold storage, as well as the optimal way to begin reperfusion (portal vein versus hepatic artery).5,6 However, few reports have focused on the impact of rewarming. It is generally accepted that the liver can maintain its integrity for up to 45 minutes of warm ischemia; however, no in-depth studies have examined whether this ischemia makes the liver cell more vulnerable to hypoxia; increases inflammatory cell infiltration of the graft jeopardizes the recovery of the graft or aggravates the reperfusion injury. One group of investigators showed that ischemia during rewarming exacerbates reperfusion injury, and that the use of leukocyte-depleted blood for reperfusion ameliorates this injury.7 In our study, biopsies from grafts that had not been continuously perfused (Group II) showed severe inflammatory reactions, in contrast to minimal neutrophil infiltration in the continuous-perfusion cases (Group I). We observed
HABERAL, EMIROGLU, KARAKAYALI ET AL
no morphologic differences in cell structure between the two groups. Interestingly, liver enzyme levels in Group I normalized more rapidly than Group II, which may be related to the deleterious effects of the activated inflammatory cells in the second group. CONCLUSION
Our preliminary results indicate that continuous perfusion of liver transplants during the hepatic vein anastomosis may facilitate slightly faster recovery. We believe that the more rapid normalization of liver enzyme levels observed in the postoperative period may reflect a protective effect of continuous perfusion. REFERENCES 1. Clavien PA, Harvey PR, Strasberg SM: Transplantation 53: 957, 1992 2. Vajdora K, Smrekova R, Mislanova C, et al: Hepatology 32:289, 2000 3. Massarollo PC, Mies S, Raia S: Transplant Proc 30:2883, 1998 4. Sankary HN, McChesney L, Frye E, et al: Hepatology 21:63, 1995 5. Sadler KM, Walsh TS, Garden OJ, et al: Transplantation 72:1680, 2001 6. Imber CJ, St Peter SD, de Cenarruzabeitia IL, et al: Transplantation 73:701, 2002 7. Shiraishi Y, Lee JR, Laks H, et al: J Heart Lung Transplant 17:250, 1998