Hemodynamic changes during reperfusion of the graft in an animal model of liver xenotransplantation.

UNLABELLED: Our goal was to determine the hemodynamic changes that are witnessed during the initial minutes of reperfusion of the graft in liver xenotransplantation from pig to baboon. METHOD: We studied a group of 12 baboons undergoing transplantation of a pig liver via the classic technique with arterial anastomosis to the aorta. The anesthesia technique was similar to that used in humans. Hemodynamic monitoring, due to the size of the recipient, consisted of heart rate (HR), mean arterial pressure (MAP), and central venous pressure (CVP) recorded at the beginning and end of each of the three phases: preanhepatic (A1, A2), anhepatic (B1, B2), and neohepatic (C1 and C2). We aimed to maintain the following values by means of crystalloids, colloids, and blood derivates: HR >50 beats/minute; MAP >60 mm Hg; and CVP >10 mm Hg. RESULTS: Both HR and CVP remained unchanged throughout the procedure. MAP droped briefly after vascular clamping (B1) but not on reperfusion (C1). CONCLUSION: In cirrhotic patients there is an autonomic dysfunction, demonstrated as cardiovascular instability at times like the clamping of major vessels and reperfusion of the graft. On the other hand, the intact baboon has an intact nervous system. After vascular clamping, the sharp decrease in venous return lead to an adequate vasopressor response. Likewise, the extreme vasodilatation involved with reperfusion managed to maintain MAP above 70 mm Hg.

Hemodynamic assessment during auxiliary heterotopic liver transplantation with portal vein arterialization in a Swine model: preliminary report of 10 transplants.

UNLABELLED: Portal vein arterialization (PVA) is a technical variation of auxiliary heterotopic liver transplantation (AHLT) that is rarely studied but that simplifies the AHLT surgical technique because it does not act on the portal area. The objective of this study was to analyze the hemodynamic consequences of this auxiliary transplant in an experimental model. MATERIALS AND METHODS: Ten AHLT-PVA were analyzed in a pig model. A PiCCO (Pulsion) monitor was used for the hemodynamic study of the recipient. The following were measured: cardiac index, (CI), systemic vascular resistance index, (SVRI), mean arterial pressure (MAP), global end-diastolic volume, central venous pressure, and intrathoracic blood volume. The measurements were taken at four times during transplant: at baseline, after inferior vena cava clamping, after graft reperfusion, and at closure. RESULTS: After graft reperfusion there was a reduction in SVRI (968 +/- 168.03 vs 1686.25 +/- 290.66; P < .05) and in MAP, and there was an increase in CI. At the end of the transplant MAP and SVRI recovered (1254.2 +/- 225.79 vs 968 +/- 168.03; P < .05) but CI remained slightly high. The end-diastolic volume showed greater variation than central venous pressure, although this was only statistically significant at the inferior vena cava clamping phase (244.75 +/- 52.05 vs 333.37 +/- 170.13; P < .05). DISCUSSION: Heterotopic liver transplantation with portal arterialization is well-tolerated hemodynamically. Graft reperfusion decreases SVRI and increases CI to compensate for this. This behavior, which in healthy recipients like ours is not a problem, could imply a contraindication in patients with a prior hyperdynamic state.

Portopulmonary hypertension and liver transplantation: hemodynamic consequences at reperfusion.

BACKGROUND: The absence of portopulmonary hypertension (PH) upon preoperative evaluation for liver transplantation (OLT) does not exclude the occasional occurrence of an acquired PH while awaiting a graft. We sought to estimate hemodynamic changes and right ventriculoarterial coupling during reperfusion. METHODS: We studied 11 cirrhotic patients diagnosed with mild PH, according to the current classification: mean pulmonary artery pressure (MPAP)-25 to 34 mm Hg. These patients underwent OLT, using the piggyback technique (group PH). None of them had exhibited criteria for PH on preoperative echocardiography. This cohort was compared with 20 consecutive cirrhotic patients with normal MPAP at OLT. We performed a complete hemodynamic profile using a pulmonary artery catheter (RVEF, Baxter-Edwards, Calif, USA) before and 5 minutes after reperfusion. The variables were MPAP and right ventricular (RV) end-diastolic volume index (RVEDVI). Using standard formulas we calculated RV stroke work index (RVSWI), RV end-systolic elastance (Ees), pulmonary effective elastance (Ea), and RV-arterial coupling efficiency as the Ees/Ea ratio. Systolic ventricular function was expressed as RVSWI versus RVEDVI. RESULTS: During the anhepatic phase, MPAP, Ees, Ea, and RVSWI were higher in the PH group; but RVEDVI was lower. After reperfusion the pressure (MPAP), contractility (RVSWI) and preload (RVEDVI) increased in both groups. However, afterload (Ea) decreased in the non-PH group; accordingly, Es/Ea increased only in these patients. DISCUSSION: At reperfusion, the expansion in preload and cardiac output, without a similar afterload decrease, is responsible for the steady increase in pressure. Our results have shown that in the PH patient group, systolic ventricular function improves during reperfusion by a Frank-Starling mechanism; however, ventricular-arterial uncoupling is maintained (Ees/Ea < 1) because ventricular contractility is not appropriately balanced by simultaneous declines in afterload.

Effects of rapid paracentesis on right ventricular-arterial coupling in liver transplantation.

BACKGROUND: In cirrhotic patients intra-abdominal pressure (IAP) changes markedly modify splanchnic and systemic hemodynamics. Previous studies have evaluated the effects of increased IAP on steady-state cardiac performance, showing that right ventricular (RV) function becomes more depressed than that of the left ventricular. We sought to evaluate the effects of paracentesis on RV function and ventricular-arterial coupling among cirrhotics undergoing liver transplantation (OLT). METHODS: Twelve cirrhotic patients undergoing OLT underwent hemodynamic profiles before and 5 minutes after paracentesis, employing a right ventricular ejection fraction catheter in the pulmonary artery. We studied heart rate, systolic pulmonary artery pressure, central venous pressure (CVP), stroke volume index (SVI), RV end-diastolic volume index (RVEDI), and RV ejection fraction. In addition RV stroke work index (RVSWI), RV end-diastolic compliance (RVEDC), RV end-systolic elastance (Ees), pulmonary artery effective elastance (Ea), and RV coupling efficiency (Ees/Ea ratio) were calculated employing standard formulas. RESULTS: After removal of mean ascites volume of 5.6 +/- 2.2 L (range 4.0 to 8.04 L), SVI, RVEDI, RVSWI, and RVEDC were significantly increased and conversely CVP, Ees, and Ea were decreased with an ea/ea ratio unchanged. CONCLUSIONS: Before paracentesis Ees/Ea is preserved by increased of RV contractility; after paracentesis the coupling was maintained.

Effects of dobutamine on right ventricular function and pulmonary circulation in pulmonary hypertension during liver transplantation.

INTRODUCTION: In the setting of orthotopic liver transplantation (OLT), pulmonary hypertension (PH) affects right ventricular (RV) function. When RV failure occurs, reducing RV afterload, optimizing RV preload, and preserving coronary perfusion through maintenance of systemic blood pressure are the primary goals of intraoperative treatment. PATIENTS AND METHODS: To verify the effect of dobutamine on RV function and RV-arterial coupling, we compared a group of 9 cirrhotic patients with mild PH treated with OLT to a group of 20 patients with normal mean pulmonary artery pressure (MPAP). All patients received dobutamine (5-10 microg/kg/min) to maintain a cardiac index (CI) >3 L/min/m(2), during the anhepatic phase. Hemodynamic profile, using a pulmonary artery catheter, was performed before and during dobutamine infusion, studying MPAP, CI, and RV end-diastolic volume index (RVEDVI). RV stroke work index (RVSWI), RV end-systolic elastance (Ees), pulmonary effective elastance (Ea), and RV-arterial coupling efficiency as the Ees/Ea ratio were also calculated. RESULTS: RV contractility (Ees and RVSWI) and afterload (Ea) were significantly higher among the PH group. In both groups, all the studied variables improved with dobutamine: RV contractility increased, afterload decreased, and thus Ees/Ea coupling markedly increased. CONCLUSION: Cirrhotic patients with mild PH who were undergoing OLT still have a reserve of RV contractile performance and pulmonary vasodilation.

Differential response of the systemic and pulmonary circulation related to disease severity of cirrhosis.

BACKGROUND: In cirrhotic patients, the degree of hepatic insufficiency has been related to a physiological landmark: arterial vasodilatation. We sought to assess how the severity of disease, which was stratified according to the Child-Pugh criteria, influences the pulmonary and systemic circulation among patients undergoing liver transplantation. METHODS: We studied 86 cirrhotic patients in three groups: grade A (n = 10), grade B (n = 54), and grade C (n = 22). The outurnes were classified based upon a complete hemodynamic profile obtained using a pulmonary artery catheter (RVEF, Baxter-Edwards, Calif, USA) after induction of anesthesia. The variables were mean arterial and pulmonary artery pressures and cardiac index (CI). Using standard formulae, afterload was calculated as elastance of systemic (Es) and pulmonary (Ep) arterial beds, expressed by the ratio of end-systolic pressure to stroke volume. The relation between pulmonary and systemic circulation was also evaluated by the ratio (Ep/Es). RESULTS: Es was significantly lower in each class than in previous one. Also, Ep was smaller in class B than in class C patients. In addition, CI was significantly higher with disease severity. CONCLUSION: We observed that the hyperdynamic circulation in cirrhosis is directly related to severity of disease. Nevertheless Ep/Es was progressively higher among each group; these data suggest that the hyperdynamic circulation is mainly due to circulatory alterations in the splanchnic area. We conclude that pulmonary vasodilatation is directly related to the severity of cirrhosis, although its evolution is independent of other vascular areas.

Prevention of hyperacute rejection in a model of orthotopic liver xenotransplantation from pig to baboon using polytransgenic pig livers (CD55, CD59, and H-transferase).

INTRODUCTION: The search for alternative sources for transplant organs leads us to the search for animals as an inexhaustible source of organs. The objective of this study was to analyze whether livers from polytransgenic pigs expressing the human complement regulatory proteins CD55 (hDAF), CD59, and alfa alpha1,2-fucosyltransferase (H-transferase), protected against hyperacute rejection after orthotopic liver xenotransplantation to a baboon and also to study pig liver function in a nonhuman primate. MATERIALS AND METHODS: Nine liver transplants from pig to baboon were divided into two groups: a control group (n = 4) of genetically unmodified pigs and an experimental group (n = 5) of pigs transgenic for CD55, CD59, and H-transferase as donors. All the donating piglets obtained through hysterectomy were maintained in specific pathogen-free conditions. The selection of transgenic pig donors followed demonstration of transgene expression using monoclonal antibodies (antiCD55, antiCD59) and immunohistological studies on liver biopsies. RESULTS: All animals in the control group developed hyperacute rejection with survival rates less than 16 hours without function of transplanted livers. In the experimental group none of the animals suffered hyperacute rejection. Survival in this group was between 13 and 24 hours. The livers were functional, producing bile and maintaining above 35% prothrombin activity. Only in one case was there primary dysfunction of the xenograft. CONCLUSION: Polytransgenic livers for complement regulatory proteins prevent hyperacute rejection when xenotransplanted into a baboon.

Ventricular function during liver reperfusion in hepatic transplantation. A transesophageal echocardiographic study.

Postreperfusion syndrome (PRS) is the most dramatic and acute hemodynamic alteration that occurs in OLT. Our aim was to determine heart function by hemodynamic monitoring and transesophageal echocardiography during PRS. We studied 24 nonconsecutive patients allocated to 2 groups: group A (n = 8), patients with PRS, and group B (n = 16), patients without PRS. Usual hemodynamic data were obtained simultaneously with transesophageal echocardiography recording of the left ventricular imaging in 4 different stages: after induction of anesthesia, 5 min before the end of the anhepatic phase, between 2 and 5 min after reperfusion, and 5 min after graft reperfusion. The hemodynamic and echocardiographic findings during reperfusion were (group A vs. group B patients): mean arterial pressure, 50.0 +/- 15.2 vs. 74.7 +/- 13.9 mmHg (P < 0.01); pulmonary capillary wedge pressure, 12.7 +/- 6.1 vs. 13.9 +/- 5.7 mmHg (NS); left ventricular ejection fraction, 79.6 +/- 9.3 vs. 83.4 +/- 9.4% (NS); left ventricular end diastolic volume index, 35.5 +/- 12.7 vs. 54.7 +/- 21.3 ml/m2 (P < 0.05); and stroke volume index, 27.9 +/- 8.9 vs. 45.5 +/- 15.9 ml/m2 (P < 0.01). There was a mild decrease in left ventricular compliance in group A. We found no alteration in left ventricular function that can justify PRS. The hemodynamic changes during PRS seemed to be caused by an insufficient increase in preload after unclamping.

Serum ionized magnesium monitoring during orthotopic liver transplantation.

During orthotopic liver transplantation (OLT) citrate accumulates and magnesium can be chelated, which can lead to ionized hypomagnesemia and cardiovascular dysfunction. Our aim was to study the serum ionized magnesium (Me2+) evolution and establish its relation to serum total Mg and citrate levels during OLT. We studied 58 adult patients undergoing OLT. The serum Me2+ level dropped significantly at the end of the preanhepatic phase, and remained low until the end of the procedure. Furthermore, the Me2+ levels remained below the range of reference from the beginning of the anhepatic phase onward. There was an inverse correlation between Me2+ and citrate for all patients. Me2+, like ionized calcium (Ca2+), is chelated by citrate and its evolution is a mirror image of that of citrate. In our patients, we did not observe any significant dysrhythmias that could be directly attributed to ionized hypomagnesemia. In conclusion, low preoperative levels, together with the massive transfusion of blood products and the increase in renal losses, cause progressive ionized hypomagnesemia in OLT patients. We propose that it he routinely monitored and treated accordingly, as is already done with Ca2+.

Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days.

BACKGROUND: It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates. METHODS: Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs. FINDINGS: The three control animals transplanted with livers from unmodified pigs survived for less than 12 hr. Baboons transplanted with livers from h-DAF transgenic pigs survived for 4 and 8 days. Hyperacute rejection was not detected in the baboons transplanted with hDAF transgenic pig livers; however, it was demonstrated in the three transplants from unmodified pigs. Baboons transplanted with livers from h-DAF transgenic pigs were extubated at postoperative day 1 and were awake and able to eat and drink. In the recipients of hDAF transgenic pig livers the clotting parameters reached nearly normal levels at day 2 after transplantation and remained normal up to the end of the experiments. In these hDAF liver recipients, porcine fibrinogen was first detected in the baboon plasma 2 hr postreperfusion, and was present up to the end of the experiments. One animal was euthanized at day 8 after development of sepsis and coagulopathy, the other animal arrested at day 4, after an episode of vomiting and aspiration. The postmortem examination of the hDAF transgenic liver xenografts did not demonstrate rejection. INTERPRETATION: The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.

Does the standard vs piggyback surgical technique affect the development of early acute renal failure after orthotopic liver transplantation?

The objective of this study was to evaluate the effect of the surgical technique on postoperative renal function during the first week after liver transplantation (OLT). We performed a retrospective study of 184 consecutive OLT. Criteria for acute renal failure were: serum creatinine >1.5 mg/dL, an increase by 50% in the baseline serum creatinine, or oliguria requiring renal replacement therapy. The distribution of patients according to the surgical technique was: standard (n=84), venovenous bypass (n=20), and piggyback (n=80). Other variables analyzed were: intraoperative requirement for blood products, treatment with adrenergic agonists, intraoperative complications, and postreperfusion syndrome. Univariate analysis showed the following parameters to be significantly related to postoperative renal failure: intraoperative fresh frozen plasma and cryoprecipitate requirements, intraoperative complications, postreperfusion syndrome, need for noradrenaline or dobutamine, standard surgical technique versus piggyback (39% vs 18%, P<.01) and venovenous vs piggyback (50% vs 18%, P<.01). Logistic regression analysis identified the following variables as having independent prognostic value: (1) Standard surgical technique vs piggyback (OR=3.3, P=.01); (2) venovenous vs piggyback (OR=4.7, P=.02); and (3) >20 U cryoprecipitate requirement (OR=1.04, P=.01). In conclusion, compared with the piggyback technique, the standard surgical technique appears to be an independent risk factor for postoperative acute renal failure. When venovenous bypass is used in patients who do not tolerate trial clamping of inferior vena cava, it does not reduce the incidence of postoperative renal failure. Finally, the piggyback technique significantly reduces the probability of acute renal failure after liver transplantation.