Development of an in situ isolated porcine liver perfusion model for tightly controlled physiologic and pharmacologic studies.

Several types of isolated perfused porcine liver models have been proposed for the study of hepatic assist, preservation injury, and specific physiologic or pharmacologic mechanisms. The development of a more general in situ isolated perfused model applicable to a broad range of studies is presented. This model eliminates or minimizes the shortcomings of previous models including ischemic injury prior to perfusion, limited range of vascular pressures and flows, nonphysiologic sources of portal and hepatic artery perfusion, and coupling of the liver to uncontrolled whole-body homeostatic mechanisms. Essentially the model as presented can be described as an autologous transplanted liver without preservation or ischemic injury, functioning within an adrenalectomized, cardiac output and temperature-controlled animal. Independent control of the dual hepatic vascular supply is maintained with pulsatile perfusion of the hepatic artery from the left atrium and nonpulsatile perfusion of the portal vein via the portal system. Oxygenators are not required. Hepatic vein pressure can be controlled independently of hepatic blood flow and systemic hemodynamics. Pharmacologic studies are not restricted to drugs whose termination of action is limited to hepatic metabolism because normal routes of drug redistribution, metabolism, and excretion are present. The model exhibits normal oxygen metabolism and classic control of hepatic artery resistance by portal vein blood flow. There are rather obvious significant advantages inherent in this model for tightly controlled hepatic physiologic and pharmacologic studies.

Danger of amiodarone therapy and elevated inspired oxygen concentrations in mice.

Our study showed a statistically significant incidence of pulmonary edema in mice receiving amiodarone and 100% oxygen. This finding, together with a variety of clinical reports, indicates that in patients receiving amiodarone therapy, FiO2 should be maintained at the lowest possible level, consistent with adequate oxygenation.

Implications for clinical monitoring of intra-arterial blood pressure based on the frequency content of worst-case pressure waveforms.

There is no consensus regarding the minimum acceptable frequency response for a system intended for routine monitoring of invasive blood pressure in the operating rooms or intensive care units. Part of the problem stems from the diverse criteria used to validate faithful reproduction of the pressure waveform and waveform parameters. Another part of the problem is related to the site of pressure measurement: some anatomic sites have waveforms that are more difficult to reproduce than others. The most often quoted criteria, around which many clinical blood pressure monitoring systems have been constructed, are based on reproduction of all details of the pressure waveform from the most demanding anatomic sites. However, the routine clinical setting is primarily concerned with obtaining accurate values for systolic and diastolic blood pressures as recorded from peripheral arterial sites. This study was designed to obtain worst-case, in the sense of most difficult to measure, blood pressure waveforms from the femoral artery and the left ventricle using a canine model. The purpose of worst-case analysis was to create pressure waveforms that were at both extremes of frequency content, i.e., a rapidly beating heart with extraordinary contractility and a more slowly beating heart with little contractility. The premise of this type of analysis is that all naturally occurring pressure waveforms within a very broad physiologic range would fall within these extremes; therefore, the ability to measure the extreme waveforms would imply the ability to measure all those in between. Worst-case waveforms chosen from among 360 pressure waveforms were analyzed to determine the minimum frequency content of each waveform that would be required for faithful reproduction of systolic and diastolic pressures and the dP/dt. The criterion for faithful reproduction was chosen to be +/- 5% or 1 mmHg, whichever is greater. Data from the worst-case canine study, with supporting data collected intraoperatively from three patients, demonstrate that systolic and diastolic pressures can be obtained from a peripheral measurement site within 5%, requiring only two harmonics in conjunction with an appropriately low-pass-filtered catheter manometer system. Left ventricular pressure waveforms require five harmonics to reproduce the systolic and diastolic pressures within 5% or 1.0 mmHg, whichever is greater. Determination of the maximum dP/dt within +/- 5% from the worst-case peripheral and left ventricular waveforms required 20 and 22 harmonics, respectively.

Direct measurement of hepatic blood flow in native and transplanted organs, with accompanying systemic hemodynamics.

The purpose of this study was to investigate intraoperatively a population of patients with end-stage liver disease before and after liver transplantation with respect to (a) the range of hepatic and systemic hemodynamics and their changes associated with transplantation and (b) the ability to identify native hemodynamic correlates with specific diagnostic groups. Hepatic artery and portal vein blood flows were determined with square-wave electromagnetic flowmetry. Significant differences related to the type of preservation solution used--Euro-Collins or University of Wisconsin--were identified in some hepatic and systemic hemodynamic measurements from the graft livers. Specifically, cardiac output, total liver blood flow and liver weight were significantly increased in the Euro-Collins group compared with the native and University of Wisconsin groups. Hepatic artery flow was significantly greater and portal vein pressure was significantly lower in the University of Wisconsin group than in the native or Euro-Collins group. In general, comparing the graft and native livers, hepatic artery and portal vein blood flow increased significantly after transplantation, as did hepatic oxygen consumption. Portal vein pressures were dramatically reduced, but systemic arterial pressure remained remarkably constant. The percentage of cardiac output going to the liver increased, as did the portal vein percentage of the total liver blood flow. Diagnostic groups could not clearly be associated with characteristic native liver or systemic hemodynamics. Hemodynamics may be associated more with the stage of the disease process than the disease itself.

Continuous thermodilution cardiac output measurement in intensive care unit patients.

A new continuous thermodilution cardiac output measurement technique and companion flow-directed pulmonary artery catheter were evaluated in intensive care unit (ICU) patients. Continuous cardiac output was monitored for 6 hours in each patient, and, at selected intervals, a series of bolus thermodilution cardiac output determinations was made and averaged for comparison. A total of 222 data pairs was obtained in 54 patients. The cardiac outputs ranged from 2.8 to 10.8 L/min. The linear regression is represented by the following equation: continuous thermodilution = 0.99 bolus thermodilution + 0.02. The correlation coefficient r was 0.94, the Syx was 0.54. The mean relative error was 0.3%, and the standard deviation of the relative error was 11.5%. The absolute measurement bias was 0.02 L, and the 95% confidence limits were 1.07 and -1.03 L. The results demonstrated that the new continuous thermodilution cardiac output measurement technique provided acceptable accuracy and was considerably easier to use in the clinical situations studied in the ICU.

Blood transfusion in orthotopic liver transplantation: six-year experience.

Patients undergoing orthotopic liver transplantation (OLT) are susceptible to massive blood loss and require transfusion. Possible reasons for increased transfusion demands include platelet abnormalities, thrombocytopenia secondary to hypersplenism, clotting factor deficiencies, fibrinolysis, increased surgical blood loss associated with portal hypertension and previous surgical procedures, and hypothermia. The purpose of this study was to review trends in blood product usage during our first 6 years of experience performing OLT.

Perioperative hemodynamic heterogeneity of brain dead organ donors.

Brain death is accompanied by a loss of homeostatic mechanisms leading to physiologic changes which have been shown to be detrimental to donor organs prior to procurement. The management of the brain dead organ donor (BDOD) is frequently left to transplant coordinators, often registered nurses, who follow standardized protocols for that management. The use of a standardized protocol assumes that these donors display homogeneity. To investigate this assumption, the anesthesiology fellows and faculty involved in multiorgan transplantation at the Baylor University Medical Center/UTSWMC conducted a study into the perioperative hemodynamics of the BDOD.

Effect of intraoperative low-dose dopamine on renal function in liver transplant recipients.

Patients undergoing orthotopic liver transplantation frequently receive dopamine infusions to preserve renal function. To test the benefit of such infusions on renal function, 48 nonanuric patients presenting for OLT were entered into a randomized double-blind protocol. After exclusion of 1 patient for intraoperative nephrectomy, 22 patients received dopamine at a rate of 3 micrograms.kg-1.min-1 during surgery and the first postoperative 48 h, and a control group of 25 patients received saline. Venovenous bypass was used in 45 of 47 patients. During the hepatic vascular anastomoses, the donor liver was flushed with cold saline. In 7 patients, the flush contained mannitol (50 g) as part of a surgical protocol to investigate its role as a potential free radical scavenger. Initially, it appeared that there was an increase in urine output during the neohepatic phase in those patients receiving dopamine versus controls (4.20 +/- 3.3 vs 2.10 +/- 1.3 ml.kg-1.h-1, respectively). Upon further statistical analysis, this increase was associated with inclusion of mannitol in the liver flush of 5 patients in the dopamine group. After excluding all patients receiving flush containing mannitol, there was no significant difference in urine output during the neohepatic phase between the dopamine group and controls (2.94 +/- 0.45 and 2.10 +/- 0.28 ml.kg-1.h-1, respectively). The glomerular filtration rates at 1 month after surgery were similar and decreased approximately 40% in each group. Although a beneficial effect of dopamine in all situations cannot be ruled out the authors conclude that routine perioperative use of dopamine is of little value in nonanuric patients presenting for orthotopic liver transplantation.

Perioperative renal function in patients undergoing orthotopic liver transplantation. A randomized trial of the effects of verapamil.

Patients who undergo orthotopic liver transplantation often experience a significant drop in GFR postoperatively. Postulated mechanisms include intraoperative hemodynamic changes, suboptimal renal perfusion during the anhepatic stage, and cyclosporine administration. We undertook a prospective double-blind study to investigate these factors, as well as to determine the protective effects of verapamil on perioperative renal function. Twenty-five patients with normal renal function undergoing OLT received either placebo (n = 13) or verapamil (n = 12) intraoperatively and for six weeks post-OLT. No CsA was administered until after reperfusion of the graft liver, and venovenous bypass (VVB) was utilized in all cases. Patients completing six weeks of the study experienced 61% and 48% decreases in GFR within the placebo and verapamil groups respectively. A significant decrease in GFR occurred in the placebo group between one and six weeks post-OLT, and a significant drop in GFR occurred in the verapamil group by one week post-OLT. Differences between the groups were not significant, however. Systemic, renal, and hepatic hemodynamics were similar at all times between groups, and renal hemodynamics and urine output were unchanged during VVB. We conclude that (1) perioperative factors do not contribute to renal dysfunction post-OLT when VVB is used; (2) VVB preserves renal hemodynamics during the anhepatic phase; (3) CsA is the most likely causative agent for post-OLT renal dysfunction; and (4) intraoperative verapamil serves no protective role, as administered in this study.

Intraoperative evaluation of EuroCollins and University of Wisconsin preservation solutions in patients undergoing hepatic transplantation.

The effects of cold liver preservation with two solutions, EuroCollins and University of Wisconsin, were compared in terms of hepatic function and hemodynamic parameters obtained intraoperatively during orthotopic liver transplantation. Data from 101 consecutive liver transplants were analyzed retrospectively, comparing 50 grafts preserved with EC with 51 preserved with UW solution. Hepatic hemodynamics parameters included portal venous and hepatic arterial flows, determined with an electromagnetic flowmeter. Vascular pressures, blood gases and pH measurements were obtained directly from the portal vein, hepatic vein, and peripheral artery. Serial measurements of serum glucose, SGOT, and SGPT were performed following reperfusion. Preservation related graft failure occurred in 4 of 50 patients in the EC group, but not in any of 51 patients in the UW group. Cold Ischemia time (hours +/- SEM) was significantly prolonged in UW group (7.23 +/- 1.4 vs. 5.21 +/- 0.9). Rate of temperature change (degrees C/hour +/- SEM) after reperfusion was similar in both groups (EC = 0.62 +/- 0.35, UW = 0.71 +/- 0.4). Peak serum SGOT, SGPT, and glucose levels following reperfusion were significantly higher in the EC group, as was PRBC and FFP administration. Systemic hemodynamics in both groups of patients were similar. However, UW-preserved grafts demonstrated a significantly higher hepatic artery resistance, with no other differences in hepatic hemodynamics seen. UW solution appears to extend cold ischemia time without adversely affecting liver function. However, the etiology and clinical significance of the increased hepatic artery resistance seen in UW-stored liver grafts are unknown.

A technique for automatic tubing occlusion in response to air bubble detection when using a centrifugal pump.

A double acting pneumatically powered cylinder, energized by an electrically activated solenoid valve, is used to occlude the outflow line from a Bio-Medicus (a) constrained vortex pump. The cylinder is mounted on a tubing guide that is fastened to a pole clamp. A Sarns (b) air bubble detector, placed on the pump inflow line is used to provide the signal to activate the solenoid valve. The outflow occluder is capable of 100% occlusion of 3/8 x 3/32 inch Tygon tubing up to pressures of 2586 mmHg. The occluder system is able to work with many types of bubble detectors and is applicable to any form of non-occlusive pump.

Efficacy of oral cyclosporine given prior to liver transplantation.

The bioavailability of oral cyclosporine (CYS) dissolved in a large quantity of milk given just before liver transplantation (LTX) was evaluated in 30 patients, given randomly timed oral CYS before LTX, by measurements of CYS blood levels at induction, 2 h later, and at the time of graft reperfusion. Adequate blood CYS levels, defined as greater than or equal to 500 ng/mL (FPIA), could reliably be achieved only when the drug was administered 4 to 7 h preoperatively. Patients receiving the drug less than 4 h preoperatively generally had low levels thereafter (two of seven patients had greater than or equal to 500 ng/mL in any sample, compared with 13 of 14 patients in the 4-7-h group, P less than 0.011); an interval of greater than 7 h yielded unpredictable results. Fluids and blood products transfused, and preoperative ascites or ICU care, were not related to blood CYS levels. Oral CYS should be given 4 to 7 h before LTX to achieve adequate levels.

A pressure and volume-limited inflation syringe.

Excessive pressures generated in balloon-tipped pulmonary artery (PA) catheters, which have migrated distally, contribute to the morbidity and mortality associated with their use. A simple syringe modification is described by which additional dead space is added to the inflation syringe. The volume of injected gas is also increased to compensate for the dead space, thus ensuring correct balloon inflation. The added dead space acts as a compression chamber should normal balloon inflation be restricted (Safety Syringe). An additional modification is described in which the syringe nozzle is reduced to a pinhole, thus decreasing the rate of gas escape and lessening the possibility of rapid lateral impact of the balloon on the PA wall (Super Safety Syringe). The syringes were compared with a standard volume-limited syringe. Pressures were recorded at the intraluminal site of balloon contact in rigid tubes, live porcine PA, and human cadaver PA. The Safety Syringe consistently generated pressures of less than 975 mmHg, the lowest pressure at which human PA rupture has been demonstrated, under the most adverse simulated clinical conditions. The currently used volume-limited syringe generated a pressure of approximately 1500 mmHg when balloon inflation was restricted, and in one human cadaver PA, produced rupture. The pinhole modification of the Super Safety Syringe increased the time to generate maximum pressure from less than 0.25 s to about 1.5 s.