Tyramine kinetics and metabolism in cirrhosis.

Hypertyraminemia is common in hepatic cirrhosis and correlates in severity with encephalopathy. The mechanism of cirrhotic hypertyraminemia has not been established. The alternative possibilities are increased production from tyrosine and impaired degradation by monoamine oxidase. This investigation determined the pharmacokinetics of tyramine after an intravenous bolus injections of [3H]-tyramine (180--200 muCi 12 Ci/mmol sp act) in 13 cirrhotics and 9 controls. In normals, [3H]tyramine levels initially declined rapidly (alpha-phase) followed by a slower decline (beta-phase) with an average t 1/2 of 20.8 min. Average normal metabolic clearance rate and production rate were 13.2 liters/min and 15.4 microgram/min, respectively. In cirrhotic patients, the plasma disappearance curve for [3H]tyramine was qualitatively similar to that of the control subjects with no apparent different in beta-t 1/2 (17.2 min). The hypertyraminemia of cirrhosis resulted primarily from overproduction of tyramine, as the production rate (32.0 microgram/min) in these patients was significantly greater (P less than 0.05) than in controls, whereas the metabolic clearance rate remained normal (average 12.2 liters/min). A difference in ratio of tyramine metabolic products was noted as well. Cirrhotics had a high ratio of plasma 4-hydroxyphenylethanol:4-hydroxyphenylacetic acid (60:40 vs. 30:70) as compared with normals. Although the tyramine clearance rates are similar in normals and cirrhotics, different mechanisms may be responsible for catabolism.

Carcinoma of the thyroid with a mixed medullary, papillary, follicular, and undifferentiated pattern.

While papillary and follicular thyroid carcinomas are frequently mixed, this is a case of a medullary, papillary, follicular, and undifferentiated carcinoma of the same gland. In addition, all four tumor types were metastatic to regional lymph nodes. The patient described herein did not demonstrate features of the multiple endocrine neoplasia type 2 syndrome. Immunoperoxidase staining for calcitonin and thyroglobulin was positive in the follicular and medullary areas of tumor. Because the embryologic origin of the thyroidal follicular cells is from the endoderm and the origin of the parafollicular cells of the medullary carcinoma is from the ectodermal neural crest, this case seems noteworthy for demonstrating mixed metastatic tumor of composite embryologic origin. Alternatively, this case may represent an extension of what has recently been termed differentiated thyroid carcinoma, intermediate type by Ljungberg and co-workers.

Neutrophil-specific 99mTc-labeled anti-CD15 monoclonal antibody imaging for diagnosis of equivocal appendicitis.

UNLABELLED: We evaluated 99mTc-labeled anti-CD15 immunoglobulin M monoclonal antibody (LeuTech) for diagnosing acute appendicitis in patients with an equivocal clinical presentation. LeuTech avidly binds to circulating and sequestered human polymorphonuclear neutrophils in vivo, eliminating in vitro cell labeling and blood handling. METHODS: We studied 49 patients to evaluate the safety and efficacy of LeuTech imaging. 99mTc-labeled LeuTech was prepared on site using a lyophilized kit, 99mTc-labeled pertechnetate, and 2 different incubation techniques, 1 at room temperature and the other at 37 degrees C. The abdomen was serially imaged for up to 3 h after the intravenous administration of 370-740 MBq 99mTc-labeled LeuTech. Scans were read as positive or negative for acute appendicitis or other intraabdominal infection. The institutional diagnosis was established by surgery, other diagnostic studies, or 1-mo clinical follow-up. RESULTS: Scans were positive for appendicitis in all 26 patients with appendicitis, for a sensitivity of 100%, and negative for appendicitis in 19 of 23 patients without appendicitis, for a specificity of 83%. Accuracy, positive predictive value, and negative predictive value were 92%, 87%, and 100%, respectively. Results were not different between the LeuTech preparations. The rate of laparotomies with negative findings in patients who underwent surgery was 10%. The average time from injection to LeuTech visualization in the appendix for cases positive for appendicitis was 9 min. No serious adverse reactions occurred. CONCLUSION: LeuTech imaging is safe, rapid, and sensitive for diagnosis of appendicitis in equivocal cases. The potential advantages of LeuTech over currently available radiopharmaceuticals for infection imaging are ease of preparation, absence of blood handling, excellent image quality, no requirement for SPECT, and rapid diagnostic uptake.

Pulmonary capillary wedge pressure estimates of left ventricular preload are inaccurate in endotoxin shock: contribution of Starling resistor forces to septic pulmonary hypertension.

We tested the hypothesis that Starling resistor forces play a significant role in the increase in pulmonary vascular resistance during endotoxin shock. Anesthetized pigs (n = 9) were given Escherichia coli endotoxin (ETX; .5 mg/kg intravenously over 30 min). Mean pulmonary arterial pressure (MPAP) and pulmonary capillary wedge pressure (PCWP) were recorded through a Swan-Ganz catheter. Pulmonary capillary pressure (Pc) was obtained from the analysis of the transient pulmonary artery pressure decay curve upon balloon inflation. Both proximal (Ra) and distal (Rv) pulmonary vascular resistance were calculated from cardiac output (CO), MPAP, Pc, and PCWP. Left atrial pressure (LAP) was measured directly via a left atrial catheter. Left ventricular end-diastolic wall thickness (LV-EDWT) was monitored by sonomicrometry, and used as an index of left ventricular preload. The results at baseline (t = 0) and t = 60 (30 min after the cessation of endotoxin infusion) were compared with saline control animals (n = 6). Data were analyzed with a two-way ANOVA followed by contrast of residuals (p < or = .05). After endotoxin, arterial blood pressure and CO fell significantly, an effect not seen in control pigs. In the control group neither LAP nor PCWP changed significantly over time, and remained equivalent to each other. In the septic shock group there was no difference between LAP and PCWP at t = 0. However, by t = 60 LAP dropped and PCWP rose significantly. This fall in LAP and increase in PCWP were significantly different from the time-matched control values, and from each other.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of diaspirin cross-linked hemoglobin in sepsis.

We tested the hypothesis that diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp.) would improve blood pressure, organ perfusion, and mortality during sepsis. Rats were catheterized to assess general hemodynamics (protocol 1) or regional blood flow (protocol 2). Sepsis was induced by intraperitoneal introduction of a cecal slurry (100 mg/kg). In protocol 1, rats received either 100 or 250 mg/kg DCLHb, or albumin at 1, 2, or 4 h after sepsis induction. Hemodynamics were recorded at these times and daily for 72 h. DCLHb increased blood pressure, prevented 72 h leukocytosis, and reduced mortality, but the timing of DCLHb administration was crucial. In protocol 2 only moribund septic animals received 100 mg/kg DCLHb or iso-oncotic albumin i.v. Hemodynamics and regional organ blood flows were measured at baseline, immediately before and after treatment, and at 24 h. DCLHb immediately increased blood pressure with no changes in cardiac output, heart rate, or regional perfusion. DCLHb increased regional perfusion to vital areas at 24 h (compared to albumin group). Distribution of cardiac output in albumin-treated rats was significantly skewed toward skeletal muscle at a time when cardiac output was significantly lower as compared with DCLHb treated animals. In conclusion, DCLHb safely elicited a pressor response, and improved regional perfusion to selected tissues. However, DCLHb benefits were best obtained when given within a specific time frame.

Modeling splanchnic hemodynamics after distal splenorenal shunt: a computer simulation and sensitivity analysis.

The distal splenorenal shunt operation was specifically designed to preserve portal flow and maintain elevated portal pressure. However, although this goal is met in the immediate postoperative period, flow decreases over time, and in as many as 75% of alcoholic patients, portal flow is lost in the first year. Various explanations have been offered for this observation, and modifications of the original operation have been proposed (splenopancreatic disconnection). Although other portacaval shunts have been successfully modeled as electrical circuits, this approach has never been described for the distal splenorenal shunt. In this study we developed a computer program that modeled the distal splenorenal shunt as an electrical circuit. We performed an analysis to determine the sensitivity of portal flow to changes in each resistance element and then performed a series of simulation experiments to critically examine the various explanations offered for the gradual changes in hepatic hemodynamics. We found that portal flow was most sensitive to resistance in the renal vein followed by resistance in the anastomosis. The simulation experiments suggested a new alternative to splenopancreatic disconnection--restricting the ability of the splenic vein, anastomosis, or renal vein to dilate. Additional clinical studies will be needed to test these predictions.

Quantitation and fractionation of nutrient hepatic blood flow in normal persons, in persons with portal hypertensive cirrhosis, and after small-diameter portacaval H grafts.

Patients maintaining portal perfusion following small-diameter portacaval H grafts have better survival and lower portasystemic encephalopathy rates than those with reversed flow. To determine why this is so, we measured nutrient hepatic blood flow with the use of 99m-Tc-diisopropyl-IDA (DISIDA) clearance pharmacokinetics fractionated into its hepatic arterial and portal venous components. Patients with cirrhosis and portal hypertension had significantly lower nutrient hepatic blood flow than normal persons; this was due almost entirely to reduced portal flow. In patients with prograde portal flow after small-diameter H grafts nutrient hepatic blood flows were nominally reduced from levels seen in patients with portal hypertensive cirrhosis. Postoperative patients with reversed portal flow had significantly less nutrient hepatic blood than those with prograde flow. There was no evidence of significant hepatic arterial compensation for lost portal flow. Of four hemodynamic variables--portal flow direction, portal flow, arterial flow, and nutrient hepatic blood flow--only nutrient hepatic blood flow showed an independent correlation with clinical outcome. Portal perfusion is a critical factor in maintenance of adequate nutrient hepatic blood flow, primarily because hepatic arterial flow does not compensate chronically for lost portal perfusion.

Serial measurement of portal hemodynamics after partial portal decompression.

In a serial analysis of splanchnic hemodynamics, we compared partial with total portal decompression in 16 alcoholic cirrhotic patients who underwent portacaval shunts for variceal hemorrhage. Partial decompression was achieved with 8 or 10 mm polytetrafluorethylene portacaval H grafts and aggressive collateral ligation. Total decompression was achieved with larger diameter H grafts (12 or 14 mm). Early and follow-up (mean interval, 18 months) postoperative studies of portal hemodynamics included: direct measurement of shunt gradients, scintigraphic quantitation of portal and mesenteric flow distribution to the liver, and a portal and splenic collateral scoring system developed from standardized splenic venography. Partial portal decompression reduced portal pressure by 43% +/- 8% compared with 81% +/- 5% after total decompression (p less than 0.01). Scintigraphy demonstrated that partial decompression provided a greater fraction of portal flow to the liver than did total decompression (57% +/- 9% versus 2% +/- 1% intrahepatic radioactivity) and mesenteric flow distribution (14.5% +/- 5.4% versus 1.2% +/- 0.7%). Only one patient with partial decompression had a significant loss of portal perfusion during the interval studies. Significantly more residual collaterals were visualized in patients with partial decompression than in those with total decompression, and interval studies showed no significant changes from early studies. We conclude that partial decompression maintains higher portal pressures, more residual collaterals, and a greater fraction of portal and mesenteric flow to the liver than does total decompression. A modest but uniform reduction of portal pressure minimizes stimulus for new collateral formation and further shunting of portal flow.

Esophagocardiomyotomy--floppy Nissen fundoplication effectively treats achalasia without causing esophageal obstruction.

BACKGROUND: Effective surgical treatments for achalasia of the esophagus facilitate swallowing by division of muscles that fail to relax normally during swallowing. If esophagocardiomyotomy is performed, a complementary antireflux procedure is mandatory to prevent postoperative gastroesophageal reflux. We evaluated patients who had undergone a circumferential antireflux procedure after esophagocardiomyotomy to determine the effects of this procedure in patients with an aperistaltic esophagus. METHODS: During the past 15 years we treated 94 patients with achalasia by use of pneumatic dilation (66), esophageal myotomy (19), or esophagocardiomyotomy with floppy Nissen fundoplication (24). Achalasia was defined by radiographic and manometric criteria until 1986 when computerized axial manometry of the esophagus was initiated, providing information about the three-dimensional contour and "volume" of the lower esophageal sphincter in addition to the usual manometric data. RESULTS: Dysphagia was effectively relieved in all, and neither postoperative reflux nor esophageal obstruction was observed after esophagocardiomyotomy followed by floppy Nissen fundoplication. The measured lower esophageal sphincter pressures and sphincter volume were markedly reduced. CONCLUSIONS: Esophagocardiomyotomy with floppy Nissen fundoplication is an effective treatment for achalasia; clinical evidence of obstruction of the esophagus was not seen, and manometric data were typical of a weakened sphincter.

Selective impairment of nutrient absorption from intestines with chronic venous hypertension.

Malnutrition is frequently associated with advanced cirrhosis. To investigate the role of portal hypertension in nutritional impairment, we developed an animal model to isolate and characterize the effects of chronic intestinal venous hypertension on intestinal nutrient absorption. We performed mesenteric arteriovenous anastomosis combined with portal vein banding in rats. Hepatic architecture and excretory function (bile flow and bile salt output) were unaltered, while severe and persistent intestinal venous hypertension was produced. We then measured in vivo absorption rates of three test nutrients (vitamin D3, valine, and tryptophan) and water. Vitamin D3 absorption was significantly impaired by intestinal congestion, while amino acid absorption was unaffected. Splanchnic hypertensive rats absorbed less water than controls. We conclude that chronic intestinal venous hypertension alone selectively impairs nutrient absorption.

Clinical implications of portal hemodynamics after small-diameter portacaval H graft.

To assess the role of portal hemodynamics in the development of postshunt encephalopathy, we studied 19 patients after small-diameter portacaval H grafting (SD-PCHG). We used contrast studies as well as technetium-labeled macroaggregated albumin injected into the portal vein to assess direction of portal flow. We then quantitated the mesenteric fraction of flow perfusing the liver by injecting macroaggregated albumin into a peripheral mesenteric vein tributary. We found that none of seven patients with prograde flow by both scintigraphy and angiography developed postoperative encephalopathy, but the incidence was 58% in the remaining patients (p = 0.02). The fraction of mesenteric flow perfusing the liver after SD-PCHG was 12% +/- 4%, but this did not significantly correlate with encephalopathy rates. We conclude that after SD-PCHG, prograde portal flow minimizes encephalopathy rates. Although encephalopathy occurs in patients with predominantly reversed flow, a subgroup of patients with reversed flow remain without symptoms. The absolute fraction of mesenteric flow perfusing the liver has less influence on encephalopathy rates than has direction of portal flow. This study identifies a complex relationship between portal hemodynamics and encephalopathy.

Single-lumen vs double-lumen catheters for total parenteral nutrition. A randomized, prospective trial.

Multilumen catheters have been condemned for hyperalimentation based on reports of infection rates between 10% and 25% in uncontrolled studies. Because of the potential usefulness of multilumen catheters, we studied infection rates in a prospective, randomized trial. All patients requiring total parenteral nutrition were randomized to either single- or double-lumen catheters. Single-lumen catheters were used for dextrose-amino acids only. Medications or fat emulsions were given either by another central line or peripherally. Double-lumen catheters were used for dextrose-amino acid solutions, compatible medications, and fat emulsions. Catheters were cultured (48 single lumen and 53 double lumen) from 112 patients who successfully completed the study. No patients in either group developed catheter sepsis. We concluded that parenteral nutrition can be given as safely via double-lumen catheters as single-lumen catheters when strict protocols are established and followed.

Partial portacaval shunt for variceal hemorrhage: longitudinal analysis of effectiveness.

OBJECTIVE: To determine rates of survival, long-term patency, and recurrent variceal hemorrhage among patients with alcoholic cirrhosis treated by partial portacaval shunt. DESIGN: Single-institution cohort follow-up study of 72 consecutive patients who underwent small-diameter portacaval H-graft shunt with collateral ablation during a 10-year period (1981 through 1990). Subjects were enrolled and followed up for up to 15 years. Shunt patency was assessed by portography and/or ultrasonography. We performed 7-year Kaplan-Meier analyses of survival (in 65 patients in Child classes A and B), shunt patency, and absence of variceal bleeding. SETTING: Tertiary academic referral center of the US Department of Veterans Affairs. PATIENTS: Patients with alcoholic cirrhosis were considered for operation after at least 1 proven episode of variceal hemorrhage. Patients with portal vein thrombosis were excluded; patients in Child class C underwent operation only for compelling indications. Of the 72 who underwent partial shunting, 38 were in Child class A, 27 were in class B, and 7 were in class C. INTERVENTIONS: Partial portacaval shunt (6-, 8- or 10-mm polytetrafluoroethylene H-graft with collateral ablation) and serial follow-up. MAIN OUTCOME MEASURES: Study end points were death, recurrent variceal hemorrhage, and unavailability for follow-up. Other measures included graft patency and nonvariceal rebleeding. RESULTS: Cumulative probability of 7-year patency for grafts at risk was 95%. The 7-year probability for absence of variceal bleeding in patients at risk was 92%. In 65 patients in Child classes A and B, operative mortality was 7.7% and the cumulative probability of 7-year survival was 54%. CONCLUSION: For variceal bleeding associated with alcoholic cirrhosis, the small-diameter polytetrafluoroethylene portacaval H-graft with collateral ablation affords durable patency and protection against variceal rebleeding.

Computer-derived equations for predicting survival postoperatively. Their usefulness and limitations.

We used multivariate analysis to determine whether survival following perforations of the gastrointestinal tract could be accurately predicted from preoperative data. Of 12 variables tested, four were found to have predictive value. These were age, pulmonary disease, preoperative shock, and the attending surgeon. When these four variables were employed in a logistic regression equation on 42 patients, it correctly predicted which 21 patients died before leaving the hospital. To produce an equation useful for other hospitals, we recalculated it without the attending surgeon variable. Again, the equation was used to predict survival. The correlation of predicted vs observed outcome remained high, and, using a 2 x 2 chi 2 test, the correlation was significant. We then cross validated the three-variable model on data from a second hospital. The model accurately predicted the new data equally well. We believe that predictive models can identify risk factors in a variety of patient populations and can determine who is likely to benefit from specific treatment modalities.

Influence of portal hemodynamics on long-term survival of alcoholic cirrhotic patients after small-diameter portacaval H grafts.

Estimating postoperative survival rates after portasystemic shunt procedures has concerned surgeons during the last 40 years. The relationship between survival and Child's classification has clearly demonstrated the importance of preoperative hepatic functional reserve. Maintaining hepatic portal perfusion has been proposed as an additional protective factor but has never been proved clinically. Our analysis of survival after partial shunting with small-diameter portacaval H grafts has shown that both hepatic functional reserve and postoperative portal perfusion correlate with postoperative survival in alcoholic patients, but the latter was a stronger correlate of long-term survival. A predictive model based on both factors has been described for estimating the overall survival rate of alcoholics after partial shunting with small-diameter portacaval H grafts.

The emergency portacaval H graft in alcoholic cirrhotic patients: influence of shunt diameter on clinical outcome.

Emergency partial portal decompression was achieved with 8 or 10 mm portacaval H graft shunts combined with aggressive collateral ligation in 18 patients in whom bleeding esophageal varices could not be controlled medically. They were compared with 11 similar risk patients undergoing larger diameter portacaval H graft shunts (12 to 14 mm) for the same indications. Variables studied included 90 day operative mortality, hepatic encephalopathy rates, corrected portal pressure, and variceal re-bleeding. Operative mortality was similar in both groups and correlated strongly with Child's class. However, the incidence of portasystemic encephalopathy in survivors was significantly lower after partial decompression than after total decompression. No patient in either group rebled from varices. We conclude from our series of high risk alcoholic cirrhotic patients, that although mortality after partial and total portal decompression is similar, the lower incidence of encephalopathy in survivors suggests that partial decompression has advantages over total decompression when emergency control of variceal bleeding is necessary.

Analysis of nutrient hepatic blood flow after 8-mm versus 16-mm portacaval H-grafts in a prospective randomized trial.

BACKGROUND: In previous unrandomized studies, we demonstrated that patients undergoing 8-mm diameter portacaval H-grafts with collateral ablation (partial shunts) have lower rates of portasystemic encephalopathy (PSE) postoperatively than patients undergoing total portacaval shunts. We postulated that nutrient hepatic blood flow was greater after partial shunts because 8-mm grafts preserved some portal flow. METHODS: To test this hypothesis, we analyzed hepatic hemodynamics in 18 of 30 randomized patients who consented to be studied after complete operative recovery, grouped according to shunt size. We measured nutrient hepatic blood flow using 99m-Tc-Mebrofenin tracer elimination kinetics, and fractionated it into its portal venous and hepatic arterial components. PSE was assessed by blinded observers. Stepwise logistic regression was used to select the variable that best predicted encephalopathy. From 1989 to 1993, we conducted a randomized, prospective trial of partial (8 mm) versus total (16 mm) portacaval H-grafts. Group differences were compared using one-way analysis of variance (ANOVA). RESULTS: Hepatic encephalopathy occurred in 2 of 10 patients with partial shunts versus 5 of 8 patients with total shunts. Nutrient hepatic blood flow was significantly higher for partial shunts compared with total shunts (403 +/- 601 versus 243 +/- 17mL/min). Three variables--nutrient hepatic blood flow, portal blood flow, and hepatic arterial flow--were analyzed by stepwise logistic regression. Nutrient hepatic blood flow was selected as the best predictor of hepatic encephalopathy. In this series, PSE did not occur in any patient with more than 325 mL/min of nutrient hepatic blood flow. CONCLUSION: These findings provide a physiologic basis for clinical observations demonstrating a lower incidence of PSE with partial shunts and indicates the superiority of partial over total shunts. Partial shunts, by preserving portal flow, maintain higher nutrient hepatic blood flow than total shunts and thus minimize PSE rates.

A prospective, randomized clinical investigation of cholecystoenterostomy and choledochoenterostomy.

A prospective, randomized clinical trial was conducted to assess the efficacy of bilioenteric bypass in noncalculous distal biliary obstruction. Thirty-one patients required bypass for either malignant obstruction or chronic pancreatitis and were randomized into two groups: cholecystoenterostomy or choledochoenterostomy with cholecystectomy. Nine bypasses failed after cholecystoenterostomy and two after choledochoenterostomy (p less than 0.04). Eight of the 9 failures occurred in the subgroup of 22 patients with malignant biliary obstruction. In this subgroup, five bypasses failed within 90 days of operation, all after cholecystoenterostomy (p = 0.03 compared with choledochoenterostomy). The results indicate that choledochoenterostomy is the superior operation for malignant distal biliary obstruction. Additional studies will be necessary to identify the procedure of choice for benign noncalculous obstructions.

Three-phase study of phlebitis in patients receiving peripheral intravenous hyperalimentation.

We found clinical phlebitis in 57 of 88 patients with peripheral hyperalimentation (65%). To determine if this was a problem common to all intravenous fluid therapy at our hospital, we performed a point-prevalence study. The prevalence of phlebitis in nonhyperalimentation intravenous patients was 18% (84 of 456 patients). We then performed a randomized, prospective, double-blind trial of sham versus standard in-line filters to determine if bacteria or filterable particulate matter was responsible for phlebitis in the peripheral hyperalimentation group. The standard-filter group had a phlebitis rate of 74% compared with 64% in the sham-filter group. We then eliminated in-line filters and replaced the standard glucose-based solution with a glycerol-based peripheral hyperalimentation solution. The phlebitis rate decreased from 68% to 27% (p less than 0.001). In conclusion, phlebitis in peripheral hyperalimentation patients was probably due to chemical properties of the peripheral hyperalimentation solution rather than bacteria or particulates.

Radionuclide angiography of the liver and spleen. Noninvasive method for assessing the ratio of portal venous to total hepatic blood flow and portasystemic shunt patency.

Radioactivity verus time curves were generated for the first pass of technetium-99m pertechnetate through the left ventricle, kidneys, spleen and liver, after a 20 mCi peripheral intravenous bolus injection. The rate of change of radioactivity in these organs before recirculation is proportional to blood flow through the organ. The hepatic perfusion index, defined as the ratio of portal flow to total hepatic blood flow, was correlated with the angiographic grade of portal perfusion. The hepatic perfusion index in seven normal subjects was 66.0 +/- 3.4 percent (mean +/- standard error of the mean), and in 22 cirrhotic patients with decreasing angiographic perfusion of grades 1 to 4 the index was 54 +/- 4.6, 37 +/- 2.6, 17 +/- 4.7 and 3 +/- 1.1 percent, respectively. The correlation between the calculated perfusion index and the angiographic grade of portal flow was highly significant (p less than 0.001). The passage of radionuclide through the spleen differed before and after shunt surgery in patients with portal hypertension. The slope to height ratio, based on the downslope of the splenic curve, was significantly greater (p less than 0.01) in the shunted patients and provided a simple index for assessing shunt patency.