A venovenous bypass for transplantation of the liver was developed and evaluated in dogs and applied clinically, with flows that averaged less than 500 milliliters per minute. Fatal pulmonary emboli were seen in two of 40 experiments. The venovenous flow in the four pediatric recipients was 200 to 1,200 milliliters per minute, and there were no complications

Dewolf, A

Ericzon, BG

Jakab, F

Kam, I

Lynch, S

McSteen, F

Starzl, TE

Takaya, S

Todo, S

English

PubMed

D-Scholarship@Pitt

, LOW FLOW VENOVENOUS BYPASSES IN SMALL DOGS AND PEDIATRIC PATIENTS UNDERGOING REPLACEMENT OF THE LIVER Igal Kam, M.D., Stephen Lynch, M.D., Satoru Todo, M.D., Andre Dewolf, M.D., Frank McSteen, B.S., R.N., Ferenc Jakab, M.D., Bo-Goeran Ericzon, M.D., Shunichi Takaya, M.D., and Thomas E. Starzl, M.D., PH.D., F.A.C.S., Pittsburgh, Pennsylvania A venovenous bypass for transplantation of the liver was developed and evaluated in dogs and applied clin-ically, wlthfiows that averaged less than 500 milliliters p,er minute. Fatal pulmonary emboli were seen in two of 40 experiments. The venovenous flow in the four pediatric recijJients was 20() to 1,200 milliliters j)er minute, and there were nu cumplications. ALTHOUGH venovenous bypasses without sys-temic heparinization have revolutionized adult hepatic transplantation, bypasses have not been used for pediatric recipients. Application of the technique has been inhibited by concern that clotting and consequent iatrogenic pulmonary emboli could occur in the low flow bypass circuits of small subjects. In this study, we report our experience with a low flow venovenous bypass that was acquired first witl} replacement of the liver in small dogs and subsequently with four pediatric hepatic recipients. METHODS Dogs. Orthotopic hepatic transplantation was performed upon 40 healthy beagle dogs weighing between 10 and 15 kilograms. General anesthesia was induced with 25 milligrams per kilogram thiopental sodium. The dogs were paralyzed with 0.1 milligram per kilogram pancuronium bro-mide and ventilated through a cuffed endotra-cheal tube. Principles of the transplantation.-The ho-mograft is cooled by infusing it with cold lactated From the Department of SUI'gery, University of Pittsburgh Health Center, Uniwrsity of Pittsburgh, Pittsburgh. Supported by Research Grants from the Veterans Administra-tion; by pfE~ject Grant No. A1\1-2996I from the National Institutes of Health and by Grant No. RR-00084 from the General Clinical Research Centers Program of the Division Research Resources. National Institutes of Health, Bethesda, l\faryland. Reprint requests: Dr. Thomas E, Starzl, 3601 Fifth Avenue, Room 218, Falk Clinic, Pittsburgh, Pennsylvania 15213. Ringer's solution as the donor is exsanguinated. The liver is placed into the fossa which is eva-cuated by the recipient hepatectomy and it is revascularized with a modification of our origi-nally described technique (1). The vena caval anastomoses above and below the liver are per-formed as well as a portal venous anastomosis and an aorta to aorta anastomosis (Fig. 1). Recon-struction of the biliary tract was done with cho-lecystoduodenostomy after ligation of the graft common duct (Fig. 1). Transfusions usually are limited to the donor blood collected during ter-minal exsanguination and hepatic cooling. The bypass.-The technique was similar to that described by Denmark and colleagues (2). The inferior vena caval system was drained through the proximal femoral vein after ligation of the distal vessel. Splenectomy was performed and the central splenic vein was cannulated to drain the splanchnic bed (Fig. 2). Venous re-entry was through the external jugular vein (Fig. 2). All of the cannulas were standard No. 12 chest tubes (Argyle Division of Sherwood Medical). The extracorporeal bypass consisted of a three-eighth inch (internal diameter) Tygon (Norton Industrial Plastics) tubing interrupted with a centrifugal pump (Bio-Medicus, Inc.) and primed with 250 milliliters of Plasmalyte (Fig. 2). An electromagnetic probe on the venous re-turn side was used to measure flow. The venous bypass time was that req uired to complete the recipient hepatectomy, obtain he-mostasis in the hepatic fossa and perform the ve-nous anastomoses. Usually, the suprahepatic ca-val, infrahepatic caval and portal anastomoses were carried out while on bypass before revascu-larizing the portal vein. In a few dogs, the portal vein was revascularized after only the suprahe-patic caval and portal anastomoses. Although this Reprint from SURGERY, Gynecology & Obstetrics, July, 1986, Vol. 163,33-36 Copyright, 1986, by The Franklin H. Martin Memorial Foundation Surgery, Gynecology & Obstetrics' July 1986 . Volume 163 TABLE I.-CLINICAL FEATURES OF PEDIATRIC HEPATIC RECIPIENTS Duration Age, Weight, bypass, OT*, No. yrs. kgm. Diagnosis rnlns. 452 ..... 6 24 Drug induced acute liver failure 95 478 ..... 5 15.5 Biliary atresia 130 475 ..... 9 21 Familial intrahepatic cholestasis 108 494 ..... 2Yz 13 Postnecrotic cirrhosis 232 *OT, Orthotopic transplantation. modification reduced the cold ischemia time, it necessitated a period of even lower venovenous bypass flow since only the vena caval bed was being drained while the third anastomosis was performed. The aortic anastomosis was carried out after the bypass was terminated, after all cannulas had been removed and not until good hemostasis had been obtained. The human experience. Four children, each of whom had a different diagnosis, were two and one-half to nine years old and weighed between 13 and 24 kilograms (Table I). The reasons for resorting to the venovenous bypasses are listed in Table 1. The equipment was the same as in the canine studies except that the chest tubes used for can-nulas ranged from No. 12 to 16. When the chest tubes were inserted, they were flushed and filled with heparin diluted to 1/500, a precaution that was not exercised in dogs. The portal cannula was placed down the transected portal vein (3). The vena cava was decompressed through a can-nula inserted at the saphenofemoral junction and venous return was to the axillary vein (3). Both the splanchnic and systemic venous systems were decompressed during most of the bypass, but during performance of the portal anastomosis, caval flow only was being bypassed. RESULTS In dogs. Bypass flow features.-In the 40 dogs (Table II), the flow range was 200 to 1,500 mil-liliters per minute during the bypass periods of 53.1±12.9 (S. D.) minutes, a range of 34 to 82. The average peak flow as 575.0±229.2 (S. D.) milliliters per minute. The mean minimum flow was 312.3±107.9 (S. D.) milliliters per minute, an average which was kept artifactually high by our policy of discontinuing bypasses when flows fell to less than 200 milliliters per minute. Such discontinuance near the end of the run was ne-cessary in ten of the 40 experiments. The experiments were part of a program to evaluate the new cyclosporine analogue, Cyclo-sporin G. Herein, it need only be noted that 80 Caval plus Caval portal bypass bypass alone mf./min. ml./min. Reason for bypass 1,000 600 Hypotension caused by venous occlusion 1,200 400 to 200 Hepatectomy impossible otherwise 1,200 600 Profound metabolic depletion. Hypotension caused by venous occlusion 800 500 Profound metabolic depletion per cent of the test dogs survived the operation for at least six days postoperatively. If a bypass was maintained during the venous occlusions, the exact amount of flow did not obviously influence either survival or the rate of complications. Thromboembolic complications. The results of extensive clotting studies on six of the dogs were normal before and during the bypass. Two of the 40 dogs died suddenly of pulmonary emboli. In both instances, the bypass was discontinued for several minutes because of technical problems. When pump-driven flow was resumed, clots in the stagnant blood in the tubing were advanced into the right atrium, right ventricle and pulmo-nary artery. In two other experiments, fibrin strands were found in the pump head but these had not caused complications. When the same bypass system was tested under systemic hepa-rinization of 3 milligrams per kilogram, the hep-arin effect could not be reversed and the dogs bled to death. In humans. The bypass flows in the pediatric recipients ranged from 200 to 1,200 milliliters per minute (Table I). The lower flows always were at the end of the run when the portal anastomosis was being performed and when only vena caval blood was entering the bypass system. The dura-tion of the bypasses was one and one-half to four hours (Table I). At their conclusion, fibrin or clots were not found in the extracorporeal cir-cuits. The difficult technical or metabolic situa-tions posed by these patients were dealt with eas-ily, and all of the recipients are alive after one to four months. DISCUSSION The threat of pulmonary emboli from the ex-tracorporeal circuit has been known since the first clinical trials of hepatic transplantation in which passive bypasses were used (4). The risk was well recognized by others (2, 3) who described pre-cautions to prevent this complication. Other au-thors have speculated that bypass flows of less than 1,000 milliliters per minute would be unsafe (5) . Kam et al.: LOW FLOW VENOVENOUS BYPASSES IN DOGS AND PEDIATRIC PATIENTS Cholecysto-duodenostomy , \ , FIG. 1. Completed orthotopic hepatic transplantation in dogs. G.b., Gallbladder; I.v.c., inferior vena cava; H.a., hepatic artery, and P.v., portal vein. In actuality, the safe level of flow is probably much lower than this. In the laboratory experi-ment in which the dogs had normal clotting, bypass flows were almost always below 1,000 milliliters per minute, and the average flow was less than one-half of this. Evidence of extra cor-po rea I clot formation was uncommon, occurring in four of 40 dogs. Pulmonary emboli in two of these four dogs were precipitated by technical misadventures that caused nonflowing blood to be left stagnant in the extracorporeal circuit after which pumping was resumed. The pump presumably propelled the clots in these two dogs. In spite of the probable role of the pump in the embolization, the danger of thromboembolic complications has seemed to be less in the efficient pump driven circuits than it was with the passive bypasses that were used many years ago (4). To our knowledge, pump driven bypasses were first described in dogs (6). Others (6, 7) described a single pump driven femorojugular bypass after putting the splanchnic and systemic venous systems into communication with a temporary portacaval shunt (1). In the clinical situation, the risk of emboli should be substantially less than with normal dogs. Almost all hepatic recipients, including the four children reported upon herein, came to the EXI.jug._ From pump t . , , "Ii II Centrifugol pump FIG. 2. Venovenous bypass used in dogs. Note entry of splanchnic cannula through the splenic vein after splenec-tomy. s.v.c., Superior vena cava; I.v.c., inferior vena cava, and Ext. jug., external jugular vein. operating room with complex abnormalities of coagulation that are caused by end stage hepatic disease. In the four pediatric patients we studied, low flow bypasses were used for one and one-half to almost four hours without a trace of fibrin in the circuit. In the original report of Denmark and co-authors (2), as in our laboratory and clinical ex-perience reported herein, heparin bonded Gott shunts were not used. In one study (3), heparin bonded cannulas were added in the first clinical trials as a safety hedge. However, these cannulas TABLE H.-DATA FROM 40 VENOVENOUS BYPASSES IN DOGS UNDERGOING LIVER REPLACEMENT, PLUS OR MINUS VARIATIONS ARE STANDARD DEVIATION No. dogs .................................... . Mean weight, kgm ............................ . Mean maximum flow, ml./mins ................. . Mean minimum flow, ml./mins ................. . Bypass time, mins ............................. . 40 12.3±I.S S7S±229 312±108 S3±13 Surgery, Gynecology & Obstetrics' July 7986 . Volume 763 are expensive, bulky and often of inappropriate SIze. In 1984, chest tube cannulas of varying sizes were often used in adults as well as in children without any clotting difficulties. If this method is as good as with the heparin bonded cannulas and tubing, the expense of the venovenous bypasses will be substantially reduced. The question of need of the heparin bonded equipment remains to be resolved. SUMMARY A low flow venovenous bypass was used during the anhepatic phase of orthotopic transplantation of the liver in 40 dogs and in four pediatric reci-pients who were two and one-half to nine years old and who weighed between 13 and 24 kilo-grams. In these selected human recipients, the advantages of venovenous bypasses were the same as previously described for adults. REFERENCES 1. STARZL, T., KAUPP, H., BROCK, D., and others. Recon-structive problems in canine liver homotransplantation with special reference to postoperative role of hepatic ve-nous flow. Surg. Gynecol. Obstet., 1960, 111: 733. 2. DENMARK, S. W., SHAW, B. W., JR., GRIFFITH, B. P., and STARZL, T. E. Venovenous bypass without systemic anticoagulation in canine and human liver transplanta-tion. Surg. Forum, 1983, 34: 380-382. 3. GRIFFITH, B. P., SHAW, B. W., JR., HARDESTY, R L., and others. Veno-venous bypass without systemic anti-coagulation for human liver transplantation. Surg. Gynecol. Obstet., 1985, 160: 270-272. 4. STARZL, T. E. Experience in Hepatic Transplantation. With the assistance of C. W. Putnam. Pp. 122-125; 166-167. Philadelphia: W. B. Saunders Co., 1969. 5. SHAW, B. W., JR., MARTIN, D. J., MARQUEZ, J. M., and others. Venous bypass in clinical liver transplantation. Ann. Surg., 1984, 200: 524-534. 6. CUTROPIA, J. C., CORATOLO, F., SPINETTA, A., and others. Trasplante hepatico ortotopico experimental. Rev. Esp. Enferm. Apar. Dig., 1972, 38: 533-570. 7. TOLEDO-PEREYRA, L. H., and MACKENZIE, G. H. Or-thotopic liver transplantation witb the assistance of an external shunt and a non pulsatile perfusion pump. Transplantation, 1983, 35: 102-104. 

Low flow venovenous bypasses in small dogs and pediatric patients undergoing replacement of the liver

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Low flow venovenous bypasses in small dogs and pediatric patients undergoing replacement of the liver

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