Yoogoo Kang

Epsilon-aminocaproic Acid for Treatment of Fibrinolysis during Liver Transplantation

In 97 adult patients receiving liver transplants, the coagulation system was monitored by thrombelastography and by coagulation profile including PT; aPTT; platelet count; level of factors I, II, V, VII, VIII, IX, X, XI, and XII; fibrin degradation products; ethanol gel test; protamine gel test; and euglobulin lysis time. Preoperatively, fibrinolysis defined as a whole blood clot lysis index of less than 80% was present in 29 patients (29.9%), and a euglobulin lysis time of less than 1 h was present in 13 patients. Fibrinolysis increased progressively during surgery in 80 patients (82.5%) and was most severe on reperfusion of the graft liver in 33 patients (34%). When whole blood clot lysis (F < 180 min) was observed during reperfusion of the graft liver, blood coagulability was tested by thrombelastography using both a blood sample treated in vitro with &epsis;-aminocaproic acid (0.09%) and an untreated sample. Blood treated with &epsis;-aminocaproic acid showed improved coagulation without fibrinolytic activity in all 74 tests. When whole blood clot lysis time was less than 120 min, generalized oozing occurred, and the effectiveness of &epsis;-aminocaproic acid was demonstrated in vitro during the pre-anhepatic and post-anhepatic stages, &epsis;-aminocaproic acid (1 g, single intravenous dose) was administered. In all 20 patients treated with &epsis;-aminocaproic acid, fibrinolytic activity disappeared; whole blood clot lysis was not seen on thrombelastography during a 5-h observation period, and whole blood clot lysis index improved from 28.5 ± 29.5% to 94.8 ± 7.4% (mean ± SD, P < 0.001). None of the treated patients had hemorrhagic or thrombotic complications. In patients undergoing liver transplantation, the judicious use of a small dose of &epsis;-aminocaproic acid, when its efficacy was confirmed in vitro, effectively treated the severe fibrinolysis without clinical thrombotic complications.

Postreperfusion syndrome: Hypotension after reperfusion of the transplanted liver

Sixty-nine patients undergoing liver transplantation were evaluated to elucidate the relationship between hypotension and physiological changes seen on reperfusion of the grafted liver. Measured variables included hemodynamic profiles, core temperature, serum potassium, ionized calcium levels, arterial blood-gas tensions, and acid-base state. Measurements were taken 60 minutes after skin incision (baseline), 5 minutes before reperfusion, and 30 seconds and 5 minutes after reperfusion. On the basis of changes in mean arterial pressure (MAP) patients were divided in two groups. Group 1 (n = 49) maintained MAP greater than 70% and group 2 (n = 20) had MAP less than 70% of the baseline value for at least 1 minute within 5 minutes after reperfusion. On reperfusion, changes common to both groups were 27% increase in cardiac filling pressures, 23% base deficit, and 30% serum potassium level and a decrease of 16% in cardiac output and 9% in temperature. Compared with group 1, group 2 had greater decrease in systemic vascular resistance (SVR) (1097 +/- 868 and 741 +/- 399 dyn.s-1. cm-5, respectively, P < .05) and higher potassium level (4.5 +/- 0.8 and 5.3 +/- 0.8 mmol/L, P < .05). Collectively in both groups, there was no correlation between MAP and physiological variables; however, there was a poor correlation with SVR (r = .32, P < .01). Reperfusion hypotension seen in group 2 patients correlated only with a decrease in systemic vascular resistance (r = .5, P < .05). Acute hyperkalemia, hypothermia, and acidosis do not appear to be major causes of reperfusion hypotension.

Noninvasive monitoring of cerebral perfusion pressure in patients with acute liver failure using transcranial doppler ultrasonography

Elevated intracranial pressure (ICP) leads to loss of cerebral perfusion, cerebral herniation, and irreversible brain damage in patients with acute liver failure (ALF). Conventional techniques for monitoring ICP can be complicated by hemorrhage and infection. Transcranial doppler ultrasonography (TCD) is a noninvasive device which can continuously measure cerebral blood flow velocity, producing a velocity‐time waveform that indirectly monitors changes in cerebral hemodynamics, including ICP. The primary goal of this study was to determine whether TCD waveform features could be used to differentiate ALF patients with respect to ICP or, equally important, cerebral perfusion pressure (CPP) levels. A retrospective study of 16 ALF subjects with simultaneous TCD, ICP, and CPP measurements yielded a total of 209 coupled ICP‐CPP‐TCD observations. The TCD waveforms were digitally scanned and seven points corresponding to a simplified linear waveform were identified. TCD waveform features including velocity, pulsatility index, resistive index, fraction of the cycle in systole, slopes, and angles associated with changes in the slope in each region, were calculated from the simplified waveform data. Paired ICP‐TCD observations were divided into three groups (ICP < 20 mmHg, n = 102; 20 ≤ ICP < 30 mmHg, n = 74; and ICP ≥ 30 mmHg, n = 33). Paired CPP‐TCD observations were also divided into three groups (CPP ≥ 80 mmHg, n = 42; 80 > CPP ≥ 60 mmHg, n = 111; and CPP < 60 mmHg, n = 56). Stepwise linear discriminant analysis was used to identify TCD waveform features that discriminate between ICP groups and CPP groups. Four primary features were found to discriminate between ICP groups: the blood velocity at the start of the Windkessel effect, the slope of the Windkessel upstroke, the angle between the end systolic downstroke and start diastolic upstroke, and the fraction of time spent in systole. Likewise, 4 features were found to discriminate between the CPP groups: the slope of the Windkessel upstroke, the slope of the Windkessel downstroke, the slope of the diastolic downstroke, and the angle between the end systolic downstroke and start diastolic upstroke. The TCD waveform captures the cerebral hemodynamic state and can be used to predict dynamic changes in ICP or CPP in patients with ALF. The mean TCD waveforms for corresponding, correctly classified ICP and CPP groups are remarkably similar. However, this approach to predicting intracranial hypertension and CPP needs to be further refined and developed before clinical application is feasible. Liver Transpl 14:1048–1057, 2008.

Right ventricular function during orthotopic liver transplantation.

Right ventricular (RV) function was assessed in 20 patients undergoing orthotopic liver transplantation to determine its role in the hemodynamic instability frequently seen during this procedure. A modified pulmonary artery catheter equipped with a fast response thermistor was used to determine RV ejection fraction (EFrv) allowing for calculation of RV end-diastolic volume index (EDVIrv as the ratio of stroke index [SI] to EFrv) and RV end-systolic volume index (ESVIrv as the difference between EDVIrv and SI). The above hemodynamic measures were taken during dissection for hepatectomy (stage I), during the anhepatic stage (stage II), and after reperfusion of the grafted liver, the neohepatic stage (stage III). No patient had pulmonary hypertension during the study interval. No correlation was observed between right atrial pressure (Pra and EDVIrv indicating that Prv, is a less reliable clinical in dicator of RV preload. RV function appeared to be well preserved throughout the procedure, as indicated by a relatively constant and supranormal EFrv although a small and probably clinically unimportant decrease in EFrv, was observed during the anhepatic stage (0.52, 0.50, and 0.55 during stages I, II, and III, respectively). There was a strong correlation between SI and EDVIrv, for pooled data over a wide range of EDVIrv, (60--185 mL·m−2). Although unstable central blood temperature precluded the determination of EFrv, within the first 5 min after reperfusion, RV function was unaltered otherwise during uncomplicated orthotopic liver transplantation using venovenous bypass, indicating that orthotopic liver transplantation per se is not associated with significant RV dysfunction.

Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: Relationship to outcome

The purpose of this retrospective study was to examine the potential role of cerebral hemodynamic and metabolic factors in the outcome of patients with fulminant hepatic failure (FHF). Based on the literature, a hypothetical model was proposed in which physiologic changes progress sequentially in five phases, as defined by intracranial pressure (ICP) and cerebral blood flow (CBF) measurements. Seventy‐six cerebral physiologic profiles were obtained in 26 patients (2 to 5 studies each) within 6 days of FHF diagnosis. ICP was continuously measured by an extradural fiber optic monitor. Global CBF estimates were obtained by xenon clearance techniques. Jugular venous and peripheral artery catheters permitted calculation of cerebral arteriovenous oxygen differences (AVDO2), from which cerebral metabolic rate for oxygen (CMRO2) was derived. A depressed CMRO2 was found in all patients. There was no evidence of cerebral ischemia as indicated by elevated AVDO2s. Instead, over 65% of the patients revealed cerebral hyperemia. Eight of the 26 patients underwent orthotopic liver transplantation—all recovered neurologically, including 6 with elevated ICPs. Of the 18 patients receiving medical treatment only, all 7 with increased ICP died in contrast to 9 survivors whose ICP remained normal (P < 0.004). Hyperemia, per se, was not related to outcome, although it occurred more frequently at the time of ICP elevations. Six patients were studied during brain death. All 6 revealed malignant intracranial hypertension, preceded by hyperemia. In conclusion, the above findings are consistent with the hypothetical model proposed. Prospective longitudinal studies are recommended to determine the precise evolution of the pathophysiologic changes. (Liver Transpl 2005;11:1353–1360.)

Massive pulmonary thromboembolism during liver transplantation.

Pulmonary embolism occurs rarely during surgery, including liver transplantation, although posttransplantation pulmonary embolism has been reported (1-7). Usually, pulmonary embolism occurs in patients without liver disease. It would seem unlikely to occur in patients undergoing liver transplantation, who have deficient levels of coagulation factors and low platelet counts. We present a case of fatal massive pulmonary embolus in a patient undergoing liver transplantation. No previous cases have been reported in the literature.

Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal failure.

&NA; We determined the pharmacokinetics and duration of action of a bolus dose of doxacurium (15 μg/kg) in 27 patients anesthetized with isoflurane and nitrous oxide. Nine patients had normal renal and liver functions and were undergoing a variety of surgical procedures, nine were undergoing cadaveric kidney transplantation because of end‐stage renal disease, and nine were undergoing cadaveric liver transplantation because of end‐stage hepatocellular disease. Plasma concentrations of doxacurium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by a noncompartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train‐of‐four stimulation of the ulnar nerve. The degree of neuromuscular blockade after doxacurium administration was described as the percent of control of the first train‐of‐four response. The pharmacokinetic variables were (normal vs hepatic failure vs renal failure, respectively): volume of distribution at steady state (220 ± 110 vs 290 ± 60 vs 270 ± 130 mL/kg [mean ± SD]), plasma clearance (2.7 ± 1.6 vs 2.3 ± 0.4 vs 1.2 ± 0.7 mL·kg−1·min−1), mean residence time (95.2 ± 57 vs 129.4 ± 30 vs 270 ± 210 min), and elimination half‐life (99 ± 54 vs 115 ± 31 vs 221 ± 156 min). Plasma clearance and mean residence time differed significantly between patients with renal failure and control patients. There was no significant difference in the onset times or in clinical effective duration, although the clinical duration tended to be longer and more variable in the patients with renal failure. This unpredictable response and the possibility of prolonged blockade should be borne in mind if doxacurium is to be used in patients with renal failure.

Ionization and Hemodynamic Effects of Calcium Chloride and Calcium Gluconate in the Absence of Hepatic Function

Serial serum ionized calcium concentrations were measured before and after administration of either calcium chloride or calcium gluconate during the anhepatic stage of liver transplantation in 15 patients to determine the release of ionized calcium in the absence of hepatic function. When hypocalcemia (Ca++ less than 0.8 mM) occurred during the anhepatic stage, patients were randomly assigned to treatment with chemically equivalent doses of either calcium chloride (10 mg/kg, n = 8) or calcium gluconate (30 mg/kg, n = 7). Serum concentrations of ionized calcium and citrate, hematocrit, arterial blood gas tensions, acid-base state, and hemodynamic profiles were determined before and up to 10 min after calcium therapy. In both groups of patients initial similar and rapid increases in Ca++ (0.98 +/- 0.14 mM in the calcium chloride group and 1.05 +/- 0.10 mM in the calcium gluconate group) were followed by gradual decreases over the next 10 min. Measured hemodynamic values were similar in the two groups, and neither group showed improvement in cardiovascular function after calcium therapy, possibly because of the decrease in preload that occurred during the anhepatic stage. Equally rapid increases in Ca++ after administration of calcium chloride and gluconate in the anhepatic state suggest that calcium gluconate does not require hepatic metabolism for the release of Ca++ and is as effective as calcium chloride in treating ionic hypocalcemia in the absence of hepatic function.

THE HEPATOPULMONARY SYNDROME

The hepatopulmonary syndrome is a disease entity seen in association with liver failure and other disease entities. It is a devastating consequence of liver failure that results in a significant morbidity for affected patients. Currently, there are no identified medications that ameliorate the symptoms of hypoxemia in this disease state. Recent research, however, has begun to unravel the pathobiology of the vascular dilations that arise in the lungs of patients with liver failure. In this article, a compendium of current knowledge is presented, as well as the contemporary methods for identifying and treating patients.

Intraoperative Coagulation Changes in Children Undergoing Liver Transplantation

Intraoperative changes in blood coagulation were observed in eight children undergoing liver transplantation using a simplified coagulation profile (prothrombin time [PT], activated partial thromboplastin time [aPTT], and platelet count) and thrombelastography. Preoperatively, PT and aPTT were moderately prolonged (1.5 times control), and platelet count was greater than 100,000/mm3 in all patients but one (91,000/mm3). During the preanhepatic and anhepatic stages, PT, aPTT, reaction time, and coagulation time improved toward normal values, but platelet count and maximum amplitude did not change. Significant changes in coagulation occurred on reperfusion of the grafted liver: PT, aPTT, reaction time, and coagulation time were prolonged, and platelet count, maximum amplitude, and clot formation rate decreased. A heparin effect, which did not require treatment, was seen on reperfusion in four patients. Fibrinolysis occurred during the operation in five patients and was treated with Epsilon-aminocaproic acid (EACA) in one. Blood coagulation improved slowly, and values were close to baseline 90 min after reperfusion. In general, the coagulation changes seen in these children are similar to those in adults but less severe, possibly because of the preponderance of cholestatic disease in children compared with the more common hepatocellular disease in adults.