Hepatic Arterial Perfusion Research Articles

Ursodeoxycholate–Induced Hypercholeresis in Cirrhotic Rats: Further Evidence for Cholehepatic Shunting

The aim of the investigation was to explore whether ursodeoxycholate, a tertiary bile acid with potential for treatment of chronic cholestasis in cirrhotic liver disease, has the same physiological effects in cirrhotic as in normal rats. Furthermore, we wanted to investigate whether ductular proliferation, as it occurred in this situation, increases the bicarbonate stimulatory effect of ursodeoxycholate. Rats (n = 16) were rendered cirrhotic by continuous exposure to phenobarbital-carbon tetrachloride; untreated animals (n = 13) served as controls. In cirrhotic rats in vivo, ursodeoxycholate (20 mumoles/min/kg) stimulated bile salt secretion and bile flow less than in controls. Nevertheless, the increment in ursodeoxycholate-induced biliary bicarbonate--the bicarbonate stimulatory potency--was increased by 29% in cirrhotic animals (0.55 +/- 0.08 mmol vs. 0.71 +/- 0.11 mmol; p < 0.05). This finding could be related to ductular proliferation because the volume fraction of bile ductules, determined stereologically, increased from 0.3% +/- 0.1% to 2.7% +/- 0.6% in cirrhotic rats (p < 0.005). To explore further the behavior of ductules during ursodeoxycholate stimulation, we carried out experiments in the in situ perfused rat liver. In the portally perfused organ, replacement of bicarbonate by tricine-acetate abolished ursodeoxycholate-induced hypercholeresis. In the dually perfused organ (perfusion of both portal vein and hepatic artery) perfusion of the hepatic artery with bicarbonate-containing buffer, ursodeoxycholate had a similar stimulatory effect as in vivo in both control and cirrhotic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlative imaging of the liver and hepatobiliary system

Many imaging techniques can be used to assess the liver and hepatobiliary system. Each modality has individual strengths and limitations, which usually vary depending on the specific clinical situation. This review discusses several specific common clinical situations where imaging of the liver and biliary system is necessary and describes the various imaging options. Space-occupying liver lesions are discussed, and particular attention is paid to the assessment of liver metastasis, hepatoma, and incidentally discovered liver lesions such as hemangioma, adenoma, and focal nodular hyperplasia. The value of ultrasound, computed tomography, magnetic resonance imaging, and scintigraphic techniques in this patient population is described. Isolated sulfur colloid hepatic scintigraphy is not of great value in the evaluation of these patients. Therefore, this review describes in some detail the value of physiological liver scintigraphy, including gallium and iminodiacetic acid (IDA) scanning as well as dynamic flow imaging of the liver such as hepatic artery perfusion scintigraphy and tagged red cell scintigraphy. Imaging of the biliary tree also is described. The roles of ultrasound and scintigraphy are compared and contrasted as related to the diagnosis of acute cholecystitis, common duct obstruction, and postoperative complications.

Technical considerations and complications associated with the placement of 180 implantable hepatic arterial infusion devices.

Treatment regimens with hepatic arterial chemotherapy infusion are being investigated in an attempt to improve survival and quality of life for patients with primary and metastatic liver malignancies. The successful delivery of chemotherapeutic drugs through an implantable hepatic arterial infusion device depends on the surgeon's understanding of hepatic arterial anatomy, the proper cannulation technique, and the operative measures necessary to prevent misperfusion of drug. Between January 1, 1987, and December 31, 1991, we placed implantable hepatic arterial infusion devices in 180 patients. The records of these patients were review to determine (1) the incidence and surgical management of variant hepatic arterial anatomy and (2) the complications associated with surgical placement of these devices. Variant hepatic arterial anatomy requiring ligation of the variant vessel or nonstandard cannulation was seen in 66 patients (36.7%). Treatment response rates and duration of treatment were no different for these 66 patients than for the 114 patients with standard hepatic arterial anatomy (p = 0.94). There were no operative deaths in this series. Operative or early postoperative (within 30 days) complications occurred in 10 patients (5.5%). However, late complications or device-related malfunctions developed in 52 patients (28.8%). An understanding of regional arterial anatomy is required to surgically place a catheter to achieve bilobar hepatic arterial perfusion and avoid gastroduodenal misperfusion of drug. Placement of hepatic arterial infusion devices has a low rate of early morbidity, but surgeons should be aware of late complications that may develop in patients undergoing hepatic arterial chemotherapy infusion through an implantable device.

Experimental Studies of Portal Venous Embolization with Iodized Oil in Rats with Experimentally Induced Liver Cancer

To assess the feasibility of portal venous embolization (PVE) with iodized oil in the treatment of human hepatocellular carcinoma (HCC), the distribution of iodized oil after PVE and tumor vascularity after hepatic arterial embolization (HAE) with iodized oil was determined in 25 rats with n-nitrosodiethylamine-induced liver cancer. Under microscopic guidance, HAE with 1 mL of iodized oil was performed in 10 rats. After HAE, low-kilovoltage radiography in four rats and Microfil perfusion techniques in six were used to investigate the distribution of iodized oil and the portal blood supply, respectively. Low-kilovoltage radiography and histologic examination were performed to observe the distribution of iodized oil in 15 rats after PVE with doses of 0.6 mL/kg in each rat. After HAE with iodized oil, it was common that tumor nodules smaller than 5 mm in diameter were filled with Microfil perfused through the portal vein. After PVE, tumor nodules (< 5 mm) were completely filled with iodized oil, while filling defects were observed in larger tumor nodules (> 5 mm), which could have been filled through hepatic arterial perfusion. PVE with iodized oil may have a role in the treatment of hepatic malignant tumors, and it may play an important role in early detection and treatment of small tumor nodules (< 5 mm) supplied mainly by the portal vein.

Continuous interoperative monitoring of hepatic arterial blood perfusion using a noninvasive surface electrode

Continuous interoperative monitoring of hepatic arterial blood perfusion using a noninvasive surface electrode

Regional indices of relative hepatic arterial perfusion from dynamic liver scintigraphy

Regional indices of relative arterial hepatic perfusion have been studied in 21 control subjects following dynamic radiocolloid scintigraphy of the liver (DLS). Three different indices have been calculated: the hepatic perfusion index (HPI); the hepatic arterial ratio (HAR) and the mesenteric fraction (MF). Three regions were defined in the upper, mid and lower right hepatic lobes and the three indices were calculated for each region. There was reasonable agreement between regional values of the same index with inter-regional correlation coefficients above 0.7 and standard errors in straight line fits of less than 0.093. There were significant regional differences for (1-MF) and HPI indices, but not for HAR. The index (1-MF) was calculated for each pixel and presented as a parametric image in 16 control subjects. The parametric images indicated the raised regional arterial indices due to overlying lung, right kidney and aorta. Parametric images may be of value to show the hepatic area free of significant overlying tissue and therefore available for analysis by DLS. However, the results suggest that the observed variability of single pixel indices limit the potential of parametric imaging for the localization of small focal lesions.

Unsatisfactory hepatic perfusion after placement of an implanted pump and catheter system: angiographic correlation.

Thirty-five patients with scintigrams showing unsatisfactory hepatic artery perfusion after surgical placement of an implanted pump and catheter system were examined with selective angiography (33 cases) or digital subtraction angiography (DSA) during which the contrast material was injected through the side port of the pump (six cases). In 34 of 35 cases, the cause of the unsatisfactory (either extrahepatic or incomplete) hepatic perfusion was defined. DSA was definitive in only two cases, in which extrahepatic flow through collateral vessels was demonstrated. The cause of the perfusion defect was hepatic artery thrombosis in 14 cases, extrahepatic flow through collateral vessels in 14 cases, a misplaced catheter in four cases, and a short proper hepatic artery without adequate length for mixing in two cases. Although hepatic artery perfusion scintigraphy is the primary tool for evaluation of hepatic perfusion after catheter placement, angiography plays an important role in treating the subset of patients with unsatisfactory hepatic perfusion.

Modulation of liver tumor blood flow with hepatic arterial epinephrine: a SPECT study.

Changes in the relative arterial flow to hepatic tumors and adjacent normal liver, in response to varied doses of hepatic arterial epinephrine, were studied with single photon emission computed tomography. In 18 patients with known hepatic tumors, hepatic artery perfusion scans were obtained with the concurrent infusion of technetium-99m-labeled macroaggregated albumin and escalating doses of epinephrine (0-10 micrograms/min). Regions of interest were drawn around tumor and adjacent normal liver in three planes, and the average tumor-to-liver ratio (T:L) was calculated. In all 18 patients, there was a measurable baseline T:L perfusion advantage (range, 1.7-18.7; mean, 4.8). In 12 of 18 patients, this ratio increased with epinephrine (range, 1.1-53.6 times the baseline value; mean, 7.1). In six patients, no improvement in T:L could be demonstrated. In 14 patients the lung shunt index, a measurement of arteriovenous shunting, increased with escalating doses of epinephrine. This pilot study suggests that the infusion of epinephrine may improve the therapeutic index of certain regional therapies such as bolus drug infusions, hepatic arterial embolization, and radioactive microsphere therapy.

Hepatic Perfusion during Hepatic Artery Infusion Chemotherapy

The standard method for the evaluation of hepatic perfusion during hepatic artery infusion (HAI) chemotherapy is planar hepatic artery perfusion scintigraphy (HAPS). Planar HAPS was performed with 2 mCi of [99mTc] macroaggregated albumin infused at 1 ml/min and compared with single photon emission CT (SPECT) HAPS and with a new study, CT performed during the slow injection of contrast material through the HAI catheter (HAI-CT). Thirteen patients underwent 16 HAI-CT studies, 14 planar HAPS studies, and 9 SPECT HAPS studies. In 13 of 14 studies (93%) HAI-CT and planar HAPS were in complete agreement as to the perfusion pattern of intrahepatic metastases and normal liver. In nine studies where all modalities were performed, the findings identified by HAI-CT and planar HAPS agreed in all cases, whereas the results of two SPECT scans disagreed with the other studies. With respect to perfusion of individual metastases, 14 of 14 HAI-CT studies, 12 of 13 planar HAPS studies, and 9 of 9 SPECT HAPS studies correctly demonstrated the perfusion status of individual lesions as indicated by the pattern of changes in tumor size determined on CT obtained before and after the perfusion studies. Hepatic artery infusion CT was superior for delineation of individual metastases, particularly small lesions, and for the evaluation of nonperfused portions of the liver. Planar HAPS detected extrahepatic perfusion in four patients, and this was not detected by HAI-CT. We conclude that HAI-CT and scintigraphy are complementary techniques. Hepatic artery infusion CT has advantages for the evaluation of intrahepatic perfusion, and planar HAPS is superior to HAI-CT for the detection of extrahepatic perfusion.

Arterial perfusion abnormalities of the liver after hepatic arterial infusion chemotherapy and their correlation with changes in the metastases: evaluation with CT and angiography.

We studied the progress of hepatic arterial perfusion abnormalities in 50 patients receiving long-term arterial infusion chemotherapy for palliative treatment of liver metastases from colorectal cancers and correlated the findings with changes in the metastases. Intraarterially and IV enhanced CT scans and digital subtraction angiograms of the liver were made in all patients before chemotherapy and at 3-month intervals during chemotherapy for 1 year. Before the chemotherapy, all patients had normal hepatic arterial perfusion. Arterial perfusion abnormalities were detected in 30 patients (60%) after 6 months of chemotherapy and in 41 patients (82%) after chemotherapy for 1 year. After 6 months of chemotherapy, 36% of the regressive and 39% of the progressive metastases were located in areas with arterial perfusion abnormalities. After 1 year of chemotherapy, 54% of the regressive and 60% of the progressive metastases were situated in portions of the liver with perfusion abnormalities. Hepatic arterial perfusion abnormalities were found to be progressive during intraarterial infusion chemotherapy. No relationship between arterial perfusion abnormalities and tumor response to chemotherapy could be detected.

A method for hepatic arterial perfusion studies in the rat

The current model for selective hepatic arterial infusion therapy was evaluated for its suitability for short-term pharmacokinetic experiments. This preparation consists of selective cannulation of the common hepatic artery via the gastroduodenal artery of the rat. Radioactive microspheres were injected to determine hepatic or extrahepatic sites of perfusion. Radioactive microsphere determination of hepatic arterial flow and cardiac output were also performed. Our data indicate that at high flow rates (2 ml/min), significant loss of drug would occur due to retrograde flow. Modification of the model to include temporary proximal hepatic artery occlusion ensures hepatic delivery of greater than 95% of drug. Furthermore, temporary hepatic artery occlusion does not alter cardiac output or hepatic artery occlusion does not alter cardiac output or hepatic arterial blood flow. Selective hepatic arterial infusion in rats with synchronous temporary hepatic artery occlusion is an adequate model for short-term pharmacokinetic studies.

Colorectal cancer. Are adjuvant therapies beneficial?

The American Cancer Society's recommendations for screening the population at normal risk for colorectal cancer have been promoted since 1983. Additional study of the effectiveness of these recommendations is in progress, but the medical community has generally endorsed them and urges their implementation in office practice. To date, chemotherapy is not clearly indicated as adjuvant therapy, but enrollment of patients in cooperative group protocols is recommended. Use of second-look surgery to resect selected recurrent tumors has increased in recent years, in part because of the contribution of the computed tomographic scan and carcinoembryonic antigen assay to follow-up of postoperative patients. For advanced disease, technologic advances have improved the technique of hepatic artery perfusion with chemotherapeutic agents, but evidence of a survival advantage afforded by this method is still lacking. Single-agent chemotherapy with fluorouracil remains the best choice for palliating advanced disease, but hepatic artery perfusion with floxuridine also may relieve liver-dominant disease.

Role of the hepatic artery in canalicular bile formation by the perfused rat liver. A multiple indicator dilution study.

The role of the hepatic artery in tracer water exchange and regulation of permeation of small solutes during canalicular bile formation was studied in the rat using a system that permitted perfusion of both hepatic artery and portal vein. Hepatic vein and biliary multiple indicator dilution curves were obtained after injection of indicators into either vessel. The main difference in hepatic venous dilution curves was a 3.1-fold longer t0 (time spent in nonexchanging vessels) and a 5% larger equivalent water space after injection into the hepatic artery. Biliary tracer recovery of water was markedly higher after arterial injection than after portal vein injection. Both taurocholate and taurodehydrocholate stimulated bile flow and increased biliary tracer recovery after injection into either vessel. The biliary recovery of sucrose relative to that of water, which is a measure of biliary sucrose permeation, was much lower when given into the hepatic artery than when given into the portal vein. During taurocholate infusion, it decreased by 33% in the hepatic artery but increased 36% in the portal vein. Taurodehydrocholate, by contrast, did not affect permeation of sucrose given into the portal vein. Our studies demonstrate marked exchange of tracer water in the biliary epithelium. Taurocholate, but not taurodehydrocholate, increases permeation of sucrose into bile in the portal vein bed while both bile salts decrease it in the arterial bed.

Single photon emission computed tomographic studies (SPECT) of hepatic arterial perfusion scintigraphy (HAPS) in patients with colorectal liver metastases: improved tumour targetting by microspheres with angiotensin II.

As intra-arterial chemotherapy for liver metastases of colorectal origin becomes accepted, methods of further improving drug delivery to the tumour have been devised. Degradable microspheres have been shown to reduce regional blood flow by transient arteriolar capillary block, thereby improving uptake of a co-administered drug, when injected into the hepatic artery. In our study of five patients, we combined hepatic arterial perfusion scintigraphy (HAPS) and SPECT to assess the localization of approximately 1 X 10(5) labelled microspheres of human serum albumin (99Tcm MSA) in tumour. In addition, in three patients, we assessed the effect of an intra-arterial infusion of the vasoactive agent angiotension II during HAPS. Results were interpreted by comparing transaxial slices with corresponding slices of a tin colloid liver-spleen scan. Two of five patients showed good localization of 99Tcm MSA in tumour without an angiotensin II infusion. Of the three patients receiving angiotensin II, all showed good tumour targetting with the vasoconstrictor compared with only one of these three before its use. Thus, hepatic arterial infusion of angiotensin II greatly improves microsphere localization in tumour in some patients with colorectal liver metastases. This technique may be useful in the assessment of tumour targetting before and during locoregional therapy.

Arteriovenous shunting of microspheres in patients with colorectal liver metastases

In patients receiving locoregional therapy for liver metastases degradable microspheres are being increasingly used in an attempt to improve cytotoxic delivery to the tumour. However, counterproductive arteriovenous shunting through the liver following intrahepatic arterial injection can occur, leading to deposition in the lung. Measurement of the degree of shunting is important in the monitoring of this kind of therapy. In this study we describe the use of technetium-labelled microspheres of serum albumin (99Tcm MSA) to measure baseline shunting during hepatic arterial perfusion scintigraphy in five patients with liver metastases of colorectal origin, and assess the significance of the values obtained for relative lung uptake (RLU) which we define as: RLU = Activity in lung field/Activity in liver + lung fields X 100%. We found that shunting was less than 5% in all cases, zero shunting occurring in 14 of the 16 patients studied. The sources of error in this technique have been assessed, the most important being the presence of free pertechnetate in the injectate. The use of Boots 10 ml vials and glass syringes respectively to dispense and administer this radiopharmaceutical reduces this error to a small predictable level. In our small group of patients, we found no evidence to suggest that use of the vasoactive agent angiotensin II significantly increases baseline shunting in patients with colorectal liver tumour.

Local thrombolytic therapy for hepatic artery thrombosis following chemotherapy infusion catheter placement.

Nine patients with hepatic artery thrombosis subsequent to catheter placement (four surgical and five percutaneous) for hepatic arterial infusion chemotherapy were treated with local thrombolytic therapy. The thromboses were located in the common hepatic, proper hepatic and hepatic arteries. Thrombolytic therapy was instituted within seven days of catheter placement, at a rate of 5,000 to 20,000 units/hour (streptokinase) or 5,000 to 15,000 units/hour (urokinase) for 15 to 64 hours. All patients had repeat angiography and 99mTc-MAA hepatic artery perfusion scintigraphy after the infusion. In eight of the patients, thrombolytic therapy resulted in dissolution of the thrombus and recanalization of the hepatic artery. In three of these patients, rethrombosis occurred within a few days, and was attributed to underlying arterial abnormalities. The other five had documented continued hepatic arterial patency allowing completion of the chemotherapy course. The patient who did not respond to the lytic therapy had developed extensive collateral flow through the gastroduodenal artery to the liver.

DSA--control of implanted devices for arterial hepatic perfusion.

In contrast to conventional film angiography, the perfusion pattern of hepatic arterial chemotherapy was consistently visualized by DSA in 40 patients with implanted Infusaid pump or Port-A devices. Incomplete perfusion of a liver region by the cytotoxic agent was recognized by DSA as accurately as by nuclide scintigraphy. Furthermore, DSA appeared to be more sensitive in determining aberrantly perfused extrahepatic regions; this was especially true when there was a nonligated right hepatic artery. Specific details of vascular lesions and associated complicating events also could be satisfactorily analyzed by DSA only.

A dog model using an implanted system for protracted hepatic arterial chemotherapy

A model for hepatic arterial chemotherapy studies using large dogs and an implantable infusion pump has been developed. Using this technique near complete perfusion (>90%) of the liver can be achieved in vivo as determined by hepatic arterial perfusion scintigraphy with technitium 99m macroaggregated albumin. The system is reliable and has been in use for a total of 1353 days (mean of 104 days, range 52–239) in 13 dogs. Pump implantation causes no apparent acute liver damage based on pre- and post-operative alkaline phosphatase and serum glutamic-pyruvic transaminase determinations and does not affect the general mobility or behavior of the animals. Careful placement of the catheter and attention to the physicochemical properties of the solutions loaded are factors contributing to the success of the model. The model permits comprehensive preclinical pharmacokinetic and toxicologic studies of new or preexistent chemotherapeutic agents in the same device that will be used for later administration in human subjects. By providing the means to examine and develop new treatment modalities, it enables the design of even more potent cytotoxic therapy directed into the tumor vascular bed.

Saphenous vein graft as a conduit for hepatic artery catheters in anomalies of the hepatic arterial system.

Access to the hepatic arterial system for perfusion chemotherapy is complicated by a high rate (45%) of anomalies including replaced and/or accessory arteries, as well as atrophic, absent, or thrombosed vessels. The use of a short segment of saphenous vein graft provides access for hepatic arterial perfusion in each of these situations and is safe, easily performed, and enduring.

Immunoscintigraphy and Radioimmunotherapy in Patients with Pancreatic Carcinoma

A new monoclonal antibody (BW 494/32) labeled with 131I or 111In was used for planar and tomographic immunoscintigraphy (IS) in patients with pancreatic carcinoma. It appears that IS for pancreatic carcinoma and its metastases remains a hopeful but still difficult procedure and labeling with 111In is of advantage and results in more convincing images in the case of tumor lesions distant from liver and spleen. Attempts at radioimmunotherapy with 131I-anti-CA 19-9 and with 131I-494/32 in a patient with local recurrence of a pancreatic cancer and with large liver metastases were without success because of extremely poor blood supply to the metastatic tumor masses. Intraarterial infusion of the tracer without or with blockade and perfusion of the common hepatic artery with saline solution could not enhance the tracer uptake compared to that after intravenous infusion. High intratumoral concentrations, however, as achieved e.g. by intratumoral instillation in animal studies, represent a necessary precondition for effective beta-irradiation of tumor lesions.