Increasing hepatic arterial flow to hypovascular hepatic tumours using degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the intrahepatic distribution of a low molecular weight marker, 99Tcm-labelled methylene diphosphonate (MDP), was studied in rats with hypovascular HSN liver tumours. MDP was injected regionally, via the hepatic artery, alone or co-administered with DSM, with or without subsequent occlusion of either the hepatic artery or the portal vein. Tumour vascularity was measured with 57Co-labelled microspheres. Co-injection with DSM immediately significantly increased hepatic retention of marker in both tumour (T) (median 22.40 (range 16.82-39.58)% injected dose) and normal liver (N) (9.08 (4.85-12.59) %ID) the greater effect seen in T (P < 0.01). After DSM degradation, very little MDP remained in N (0.61 (0.28-1.40) %ID) but there was significant retention in T (10.01 (6.73-20.28) %ID, P < 0.01). Clamping the hepatic artery had minimal effect on the retention of MDP when administered alone. Regional injection of 16.5 microM 57Co microspheres resulted in a N:T ratio of 2.25:1. Concomitant injection of the 40 microM DSM was 57Co microspheres reversed this ratio to 1:2. The results indicate that DSM selectively enhances the retention of MDP to a hypovascular hepatic tumour, not by causing intra-tumour stasis, but by directing a greater arterial flow to hypovascular areas in the liver.

Use of radionuclide imaging to determine gastric emptying of carbohydrate solutions during exercise.

OBJECTIVE: To investigate the repeatability of continual assessment of the gastric emptying rates of carbohydrate solutions in exercising subjects using 99mtechnetium labelling. METHODS: Gastric emptying of a 5% glucose solution and an iso-osmotic maltodextrin solution was measured using 3 MBq of 99mtechnetium labelled diethylene triamine penta-acetic acid (DTPA) and continuous gamma camera imaging in five male subjects. The subjects performed four 1 h trials at 70% VO2 peak on a cycle ergometer. After 15 min, 200 ml of a radiolabelled solution of glucose or maltodextrin were ingested in a blind crossover protocol. The two solutions were each ingested on separate occasions (trial 1 and trial 2) to establish repeatability. RESULTS: Statistical analysis showed no differences between trial 1 and trial 2 for both solutions. There were no significant differences for the emptying rates between the two test solutions. CONCLUSIONS: Posterior imaging using a computer linked gamma camera following the ingestion of 99mtechnetium labelled DTPA mixed with carbohydrate solutions provides a repeatable method of assessing gastric emptying characteristics in exercising subjects. This technique showed no significant differences between the emptying rates of a single dose of iso-osmotic glucose or maltodextrin solution.

Abnormalities of gastric emptying in portal hypertension.

OBJECTIVES: To investigate: 1) the rate of gastric emptying of portal hypertensive patients and 2) whether alterations in gastric emptying play any role in the development of portal hypertensive gastropathy. METHODS: Fifty patients (37 with esophageal varices) with cirrhosis and seven with extrahepatic portal hypertension underwent upper GI endoscopy followed by radionuclide gastric emptying studies using a semi-solid meal. Twenty-six patients also under went corrected wedged hepatic venous pressure measurement. Sixteen normal subjects underwent gastric emptying studies only. RESULTS: Varices were completely obliterated by sclerotherapy in 17 patients and were patent in 27. Thirty-seven patients had portal hypertensive gastropathy, 25 of whom had mild changes and 12 severe. No significant difference in gastric emptying was observed between patients with mild and severe portal hypertensive gastropathy and between those with portal hypertensive gastropathy and a normal gastric mucosa. There was no significant difference in gastric emptying between normal subjects and portal hypertensive patients although the latter group showed a tendency for faster gastric emptying. No difference in the rate of gastric emptying was observed between portal hypertensive patients with intrahepatic and extrahepatic pathology. However, patients with esophageal varices (patent and obliterated) emptied their stomachs significantly faster than those without (p = 0.01). There was no correlation between the rate of gastric emptying and corrected wedged hepatic venous pressure. CONCLUSIONS: It would appear that, although alterations in gastric emptying are common in portal hypertension, gastric emptying does not appear to play a causative role in the mucosal changes characteristic of portal hypertensive gastropathy.

Changes in liver blood flow associated with the growth of hepatic LV10 and MC28 sarcomas in rats.

Abnormalities in liver blood flow are known to occur in patients and animals with overt hepatic tumour. This study investigated the changes in liver blood flow associated with the development of overt hepatic tumour in two different models. Hepatic tumour was induced by intraportal inoculation of either 300 LV10 sarcoma cells or 10(5) MC28 sarcoma cells in rats. Liver blood flow and hepatic haemodynamics were measured 3 weeks later when overt liver tumour was present. The hepatic perfusion index (HPI), the ratio of hepatic arterial to total liver blood flow, was raised and portal venous inflow reduced in rats with LV10 tumours, but not in those with MC28 lesions. Hepatic arterial flow was unchanged in LV10 tumours when the HPI was raised and neither model demonstrated arteriosystemic or portosystemic shunting. The changes in portal venous inflow were associated with a significant increase in portal and splanchnic vascular resistance. These studies suggest that liver blood flow changes in the presence of overt hepatic tumour are not related to portal venous obstruction but may be caused by a circulating splanchnic vasoconstrictor.

A new method to measure renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol).

1. A method has been developed to measure the renal tubular degradation of small filtered proteins in man using radiolabelled aprotinin (Trasylol), a 6500 Da cationic polypeptide. 2. Aprotinin (0.5 or 5.0 mg) was labelled with either 99mTc (40 MBq) or 131I (1 MBq) and injected intravenously in 19 renal patients (10 with normal renal function and nine on haemodialysis). Activity in plasma and urine was measured over 48 h, and chromatography with Sephadex-G-25-M was used to separate labelled aprotinin from free 99mTcO4- or 131I-. Renal uptake was measured for 99mTc-labelled aprotinin only. 3. The volumes of distribution were similar in all patients: 18.2 +/- 0.4 litres in those with normal renal function and 20.2 +/- 0.1 litres in the others. Chromatography showed all plasma activity as undegraded aprotinin and urine activity only as the free labels (99mTcO4- or 131I-). 4. In patients with normal renal function, activity in the kidneys rose rapidly to 24.2 +/- 2.8% of dose after 90 min and to 42.2 +/- 3.4% of dose after 24 h. In the dialysis patients, activity over the kidneys was only 2.7 +/- 0.8% of dose at 24 h. Extra-renal uptake was insignificant in all patients with normal kidney function. 5. Both 99mTcO4- and 131I- appeared in the urine promptly after injection, and the rates of excretion of the two isotopes were similar, varying little over 24 h (1.8 +/- 0.04% of dose/h and 1.7 +/- 0.04% of dose/h for 99mTc and 131I, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of portal venous flow on the washout of a regionally injected marker substance 99mTc-methylene diphosphonate after hepatic arterial blockade with degradable starch microspheres.

Patients with hepatic metastases derived from colorectal carcinoma have a poor prognosis. Regional chemotherapy, either alone, or combined with agents such as degradable starch microspheres (DSM) that reduce or abolish intrahepatic arterial flow and potentiate the delivery of cytotoxics to hepatic metastases, have not significantly improved survival. We have investigated one positive mechanism, namely the effect of portal venous washout of cytotoxics, for the poor efficacy of drugs administered either alone or in combination with DSM via the hepatic artery in the rat. Using a radiolabelled marker, 99mTc-methylene diphosphonate (MDP), to represent a cytotoxic drug, the initial studies indicated that with the hepatic artery and portal vein clamped, a volume of 0.05 ml of the marker administered via the hepatic artery resulted in the most uniform intrahepatic distribution with minimal washout into the systemic circulation (21 +/- 3.7%). When the hepatic artery was clamped, the washout of MDP was reduced from 100% (with clamps on the portal vein and hepatic artery) to 84.2 +/- 7.7%. DSM administered concomitantly with MDP, resulted in a greater reduction of the portal venous washout of the marker (63 +/- 2.4%). Administration of DSM and MDP via the hepatic artery and with the portal vein clamped further reduced the washout of the marker to (21 +/- 2.26), results similar to those observed with inflow vessel clamps. Following restoration of portal venous flow, there was a rapid washout of 53.7 +/- 7.6% of the marker into the systemic circulation. The results of this study suggest that portal venous washout of regionally delivered cytotoxics, either alone or in combination with DSM, offer an explanation for the poor efficacy of regional chemotherapy in improving the prognosis of patients with hepatic metastases.

Changes in hepatic haemodynamics in rats with overt liver tumour.

Overt liver tumour was induced in Fisher rats by intraportal administration of 1.6 x 10(7) Walker carcinosarcoma cells. Control groups of rats received similar volumes of dead cells or saline intraportally. All animals were studied at 3 weeks when overt tumour was present. The Hepatic Perfusion Index (HPI) was significantly raised in rats with overt tumour compared to both groups of control animals. Portal flow and portal venous inflow were significantly reduced in the presence of overt tumour but hepatic arterial flow did not alter. These observations suggest that the alteration in the HPI in the presence of overt tumour results from an alteration in portal venous flow and inflow even though the blood supply to the tumour is principally derived from the hepatic artery. The changes in hepatic haemodynamics in the presence of tumour were accompanied by a reduction in portal pressure, an increase in splanchnic vascular resistance and an increase in the degree of arteriovenous shunting through the liver. Portal vascular resistance was unchanged. These findings indicate that the presence of overt hepatic tumour results in gross derangements of hepatic blood flow. These changes must be taken into consideration when attempting to potentiate the delivery of cytotoxic drugs to hepatic tumour by manipulation of hepatic haemodynamics.

The effects of intra-arterial vasoconstrictors on the distribution of a radiolabelled low molecular weight marker in an experimental model of liver tumour.

Regional chemotherapy for colorectal liver metastases has not demonstrated a convincing survival benefit over systemic chemotherapy. This may be due to poor delivery of chemotherapeutic drugs to hypovascular liver tumour. Since vasoactive agents may influence hepatic blood flow this study investigated the effects of systemic and regional vasoconstrictors on the delivery of a regionally delivered marker in an experimental model of liver tumour. Systemic administration of angiotensin II caused a significant retention of marker in normal liver, but not in tumour compared to controls. Regional delivery of angiotensin II and phenylephrine caused significantly greater retention of marker in tumour than liver with an overall 4-fold increased retention of marker one minute after its injection. Ninety minutes after injection there was still significant retention of marker compared to control animals. Regional delivery of hepatic artery vasoconstrictors increase delivery of marker and may increase delivery of chemotherapeutic drug to liver tumour.

Changes in hepatic haemodynamics and hepatic perfusion index during the growth and development of hypovascular HSN sarcoma in rats.

Experimental liver tumours were induced in the Hooded Lister rat by the intraportal inoculation of 10(6) HSN sarcoma cells. The hepatic perfusion index was raised 10 days after the inoculation of cells (at the micrometastatic stage) and when overt tumour was present 20 days after inoculation. Overt tumours were hypovascular compared with normal liver. Portal venous flow and portal venous inflow fell significantly when the hepatic perfusion index was increased, but hepatic arterial flow did not alter. Portal vascular resistance and splanchnic vascular resistance were both increased in tumour-bearing animals but portal pressure, arteriosystemic shunting and portosystemic shunting did not increase significantly at any stage during the growth of hepatic tumour. These findings confirm that the hepatic perfusion index can be elevated in the presence of both micrometastic and overt hepatic tumour and that the changes are not due to either arteriosystemic shunting or mechanical portal venous obstruction.

Changes in the hepatic perfusion index during the development of experimental hepatic tumours.

A model of microscopic liver tumour has been developed in the Fisher rat by intraportal injection of 1.6 x 10(7) Walker 256 carcinosarcoma cells. Rats were studied at 2, 4 and 6 days after the inoculation of live Walker cells. A control group received dead Walker cells. No tumour was visible in control groups at 2, 4 and 6 days after inoculation. Similarly in rats injected with live cells no tumour was visible at 2 days after inoculation but at 4 and 6 days the percentage hepatic replacement was (mean +/- s.d.) 7.0 +/- 2.3 and 27.9 +/- 6.80 respectively. The hepatic perfusion index was significantly raised at 4 and 6 days after inoculation of live cells compared with control animals and those receiving viable cells after 2 days inoculation. Portal flow and portal venous inflow were significantly reduced when the hepatic perfusion index increased but hepatic arterial flow did not alter. Changes in the hepatic haemodynamics were accompanied by increases in the portal and splanchnic vascular resistance and an increase in the amount of arteriovenous shunting through the liver. These findings confirm studies that the hepatic perfusion index is useful in the detection of occult liver metastases but that the change is not a consequence of an increase in the hepatic arterial flow.

Mechanisms governing the biphasic pattern of gastric emptying after truncal vagotomy and pyloroplasty.

The pattern of gastric emptying after truncal vagotomy and drainage is usually biphasic. An early rapid phase is followed by a characteristically abrupt transition to slow emptying. The mechanisms responsible for this pattern were studied in six dogs with truncal vagotomy and pyloroplasty, fitted with a proximal duodenal cannula. Gastric emptying was measured using gamma camera imaging of a radiolabelled 15% dextrose test meal. Sixty one hour studies were done using five designs. (1) With the cannula closed gastric emptying was initially rapid, followed by stasis (emptying at 15 min - 32% (5.3), 60 min - 34% (4.8); mean (SE)). (2) With the cannula open emptying was very rapid (15 min - 76% (4.2) p less than 0.001, 60 min - 88% (2.6) p less than 0.001 ANOVA). (3) Distal duodenal instillation of isotonic saline, at a rate equivalent to gastric emptying with the cannula closed, did not retard this rapid emptying (15 min - 78% (10.6), 60 min - 90% (5.4)). (4) With duodenal instillation of 15% dextrose, gastric emptying remained faster than in studies without diversion (15 min - 50% (7.0) NS, 60 min - 65% (6.8) p less than 0.01), but was slower than during diversion alone (p less than 0.05). (5) Finally, duodenal instillation of 15% dextrose before administration of the test meal produced slower initial emptying without subsequent stasis (15 min - 24% (4.5), 60 min - 47% (10.6)), although the amounts emptied were not significantly different from those with the cannula closed. These results indicate that after truncal vagotomy and pyloroplasty small bowel resistances play a significant role in controlling gastric emptying. Osmoreceptor responses persist after truncal vagotomy, but sympathetic inhibitory responses to small bowel distension are not involved in the regulatory process.

Relationship between gastric emptying of liquid and postvagotomy diarrhoea.

Gastric emptying of liquid was studied in 10 normal volunteers and in 27 patients previously treated with truncal vagotomy and drainage. Thirteen of the twenty-seven patients complained of persistent postvagotomy diarrhoea. For each study 300 ml 15 per cent dextrose, labelled with 99mTc-diethylene triamine penta-acetic acid (DTPA), was ingested at a standard rate by subjects who sat facing a gamma camera. Imaging proceeded for 30 min. Gastric area activity curves were corrected for emptying of the test meal during ingestion, and for movement using a new image alignment technique. Gastric emptying at 15 min was 10 +/- 2.6 per cent (mean +/- s.e.m.) in healthy volunteers, 48 +/- 7.3 per cent in patients without diarrhoea, and 84 +/- 2.3 per cent in those with diarrhoea (P less than 0.001, ANOVA). Gastric emptying from 15 min onwards was slower than normal in both patient groups (P less than 0.001). These results show that initial gastric emptying is rapid following truncal vagotomy and drainage, and this change is greater in patients with postvagotomy diarrhoea. No patient with diarrhoea had normal initial gastric emptying.

Abnormal pattern of gastric emptying of liquid in chronic duodenal ulcer.

Gastric emptying was measured in 12 patients with chronic duodenal ulceration and compared with the results from 10 healthy volunteers. The test meal of 300 ml 15% dextrose, labelled with 99mTc-DTPA, was ingested in increments over 6 min. Gamma camera imaging proceeded over 30 min, with a 1-min frame time. A direct correction was applied for the fraction emptying into the small bowel during the ingestion period. Gastric emptying at 6 min was significantly greater in the group with duodenal ulcer (14.4 +/- 2.7% vs. 4.2 +/- 0.9%: mean +/- SEM, p less than 0.01). From this time onwards there were no significant differences in the rates of gastric emptying. These results suggest that chronic duodenal ulcer is associated with an abnormal pattern of gastric emptying of liquid, characterised by an initial rapid phase.