Control of Bleeding Varices by Vasopressin: A Prospective Randomized Study WILLARD C. JOHNSON, M.D., WARREN C. WIDRICH, M.D., JACK E. ANSELL, M.D., ALAN H. ROBBINS, M.D., DONALD C. NABSETH, M.D.

From July 1975 to November 1976 25 patients with bleeding esophagogastric varices documented by endoscopy who failed to respond to conservative medical treatment were transferred to the Surgical Service. These patients, who were mainly Child's Class "C" alcoholic cirrhotic patients, were treated with vasopressin infused continuously using a standardized dose into either a peripheral vein or the superior mesenteric artery (SMA) according to a predetermined randomization. No significant difference in efficacy for control of bleeding (average rate = 56%) related to route of administration was found. Because catheter-related complications in the SMA group were significantly greater, we concluded that the method of choice in vasopressin treatment of esophagogastric variceal bleeding is a continuous infusion by way of a peripheral vein. C ONTROL OF ACUTE GASTRO-ESOPHAGEAL

variceal

hemorrhage in patients with portal hypertension is a difficult problem for which there is no definitive solution. Current recommendations include emergency porto-caval shunt surgery,22 Sengstaken-Blakemore (S-B) tube insertion,3 blood and coagulation factor replacement, and vasopressin administration.19 The vasopressor effect of pituitary extracts was noted by Oliver21 in 1895 and the effect of decreased portal pressure was observed by Clark in 1928.5 Successful control of variceal bleeding in two patients with a bolus intravenous injection of 20 u of vasopressin was reported by Kehne et al.16 in 1956. Bolus intravenous vasopressin subsequently received widespread clinical application.7'24'25 The problems of severe systemic effects and, frequently, a tendency to rebleed after initial control was achieved prompted Nusbaum et al.19 in 1968 to recommend the technique of continuous infusion of vasopressin into the superior mesenteric artery. More recently Thomford et al.30 and Barr et al.2 have noted that continuous

From the Departments of Surgery, Radiology and Medicine, Boston Veterans Administration Hospital and Tufts University School of Medicine, Boston, Massachusetts

peripheral intravenous infusion of vasopressin appears to affect portal pressure to the same extent as infusion through the superior mesenteric artery. Their findings were also consistent with observations of other investigators9 15 that the systemic effect of vasopressin on coronary artery flow and cardiac output was similar regardless of site of administration. In 1975 Sirinek et al.27 suggested that, since selective infusion of vasopressin into the SMA requires special equipment and personnel, delays administration of the drug, introduces the hazards of arterial catheterization, and may not avoid potentially undesirable side effects, the continuous administration of vasopressin through a peripheral vein may be preferable. The purpose of this prospective randomized study was to evaluate the two routes of vasopressin administration in patients with severe liver disease and life-threatening hemorrhage with regard to efficacy of bleeding control and occurrence of undesirable side effects.

Presented at the Annual Meeting of the American Surgical Association. Boca Raton, Florida, March 23-25, 1977. Reprint requests: Willard C. Johnson, M.D., Department of Surgery, Boston V.A. Hospital, 150 South Huntington Avenue, Boston, Massachusetts 02130.

369

Patient Selection and Methods From July 1975 to November 1976 patients with bleeding gastric and/or esophageal varices documented by endoscopy who failed to respond to lavage, antacid therapy, and blood and coagulation factor replacement were transferred from the Medical Service to the Surgical Intensive Care Unit. Each patient was treated with continuous vasopressin and the route of administration was determined by a random number table.6 No patient with bleeding varices was excluded as being too sick or because of coagulopathy or concurrent gastritis.

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FIG. 1. Schematic representation of the treatment of variceal hemorrhage by continuous vasopressin infusion: Group 1, by peripheral vein; Group 2, by SMA catheter.

Vasopressin was administered with an IVAC 500 infusion pump (IVAC Corp., San Diego, Ca.) (Fig. 1). The dose of vasopressin was standardized and given at a continuous rate of 0.4 u/min until bleeding stopped or for 24 hours. After control, vasopressin was reduced to a rate of 0.2 u/min for 24 hours, then 0.1 u/min for the next 24 hours. Saline was infused for a further 24 hours before discontinuation of treatment. If re-bleeding occurred while the catheter was in place, the initial dose was reinstituted and the weaning process was begun again. It was noted that a reduction of the initial dosage to 0.2 u/min was required before bleeding was controlled because of cardiac defects. Catheterization for direct arterial infusion was accomplished in the following manner. Arteriography of the celiac and superior mesenteric arteries was performed. A steam-shaped Becton-Dickenson RPX catheter (I.D., 0.054 inch tapered over a 0.045 inch guide-wire) was inserted through a femoral artery and positioned into the superior mesenteric artery under fluoroscopic control. To enhance visualization of the mesenteric venous system, portal vein and gastroesophageal varices, papaverine hydrochloride, 45 mg, was given intra-arterially immediately prior to methylglucamine iothalamate, 80 ml, for arteriography. Fourteen films were exposed during a 24-second period and a fifteenth film was exposed 30 seconds later.

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If there was no extravasation of contrast medium and if gastro-esophageal varices alone were demonstrated, the catheter was left in position. If the right hepatic artery originated from the SMA, the catheter was repositioned to a more peripheral location to avoid vasopressin perfusion of the liver. The arterial puncture site was treated by "defatting" with alcohol, application of betadine ointment to the catheter and an occlusive dressing. The dressing was changed every 24 hours and catheter care was repeated. During vasopressin therapy, patients were followed with continuous cardiac monitoring and serial EKGs. Liver function tests and coagulation studies were also performed. Blood was collected in 3.8% sodium citrate (1:10 dilution) for coagulation studies and in EDTA for platelet counts. Platelet-poor plasma was separated by centrifugation at 2000 g x 15 minutes at 40 and the samples were tested immediately. The following hematological studies were done; prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen concentration, fibrinogen degradation products, platelet counts and bleeding time. A clinically important coagulation deficit was defined as a prothrombin time greater than five seconds above control, a partial thromboplastin time greater than 15 seconds above control or a platelet count or less than 50,000. Vitamin K, fresh-frozen plasma and platelet transfusions were given as indicated. All patients were treated with antacids, via nasogastric tube while actively bleeding, and then with oral administration of 30cc Mylanta IT® (Stuart Pharmaceuticals, Wilmington, De.) Control of bleeding was defined as not requiring more than 1000cc of blood replacement during vasopression infusion and for 15 days thereafter. Temporary control of bleeding was defined as not requiring more than 1000cc of blood replacement during vasopressin infusion, but blood replacement totalling more than 1000cc was required due to rebleeding in the 15 days following discontinuation of vasopressin. Combined control of bleeding was defined as control of bleeding accomplished, after initial failure of vasopressin alone, with the addition of a Sengstaken-Blakemore tube; transfusion requirements for 15 days thereafter were less than 1000cc. Results

Because of the development of two major catheter complications in the SMA group, results were tabulated when 25 patients had been studied. The groups were comparable in severity of illness. All patients had a history of heavy alcoholic intake and more than 85% of patients in each group had Class "C" liver disease by Child's Classification. The average blood loss before

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CONTROL OF BLEEDING VARICES BY VASOPRESSIN

TABLE 2. Control of Bleeding

introduction into the study was seven to eight units for each group. About 40o of patients in each group had evidence of a clinically important coagulopathy. A few patients in each group had both bleeding varices and gastritis (Table 1). Control of Bleeding Bleeding was controlled during infusion and for 15 days after vasopressin administration in 50% (7/14) of the SMA group and in 64% (7/11) of the peripheral vein group (Table 2). This difference is not statistically significant. Eight patients (four in each group) failed to respond to v1asopressin therapy. Sengstaken-Blakemore tubes were inserted into these patients and this combined therapy was successful in two patients in each group. Four patients, each of whom had severe coagulopathy, exsanguinated; two of these patients were in the SMA group and two were in the peripheral vein group. Three patients in the SMA group rebled during the 15-day period following discontinuation of infusion. Bleeding was subsequently controlled in these patients by either peripheral vein vasopressin or an S-B tube. TABLE 1. Patient Data Profile

Vasopressin Infusion via

No. patients entered History and Physical Examination Heavy alcohol consumption Average no. units blood before randomization in current hospitalization

Diagnosis: Bleeding varices Bleeding varices and gastritis Child's "C" classification Encephalopathy (moderate) (mild) (absent) Ascites (tense) (present) (absent)

SMA

Peripheral

Catheter

Vein

14

11

14

11

8.0 u

7.3 u

12 2 12

9 2 10

2 5 7

1 4

5 5 4

5 4 2

6

Vasopressin Infusion Via SMA Catheter

Peripheral

7

7

3

0

Exsanguination

2 2

2 2

Total no. patients

14

11

Control-during and after vasopressin Temporary control-during vasopressin only Combined control-vasopressin and S-B tube

Vein

Catheter Related Complications Two patients in the SMA group sustained significant catheter-related complications (Table 3). Subintimal dissection leading to occlusion of the SMA orifice occurred in one patient. Bleeding was controlled for 11 days with a combination of Sengstaken-Blakemore tube insertion for 24 hours, followed by intravenous vasopressin and left gastric vein occlusion, but this patient died with multiple organ failure. At autopsy there was no evidence of ischemic bowel disease. The second patient developed a septic femoral pseudoaneurysm which ruptured and required proximal ligation of the external iliac artery and distal ligation of the superficial femoral artery. This patient survived and now has claudication at 100 yards after brisk walking. Five patients had minor catheter-related complications. In the SMA group, two patients developed small hematomas at the insertion site, one patient had groin bleeding of a degree to require catheterization of the other groin, and one patient had a superficial sepsis at the groin puncture site. In the peripheral vein group, one patient developed forearm phlebitis. With regard to catheter-related complications, the groups are significantly different (p = 0.065). Cardiac Effects No patient in either group sustained myocardial infarction as evidenced by serial EKGs. Arrythmias TABLE 3. Complications of Vasopressin Infusion

Vasopressin Infusion Via Laboratory Data Average total bilirubin (mgo) Average serum albumin (g%) Average no. sec PT above control Average no. sec PTT above control Average platelet count Presence of clinically important coagulation deficits

3.5 2.68 4.2 10 115,000 6 pts

5.0 2.60 4.8 12 107,000 5 pts

No. patients entered Major catheter complications Minor catheter complications

Cardiac arrhythmias 30-day mortality

SMA Catheter

Peripheral

14 2 4 6 4

11 0 1 1 5

Vein

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were noted in 6 patients in the SMA group (three bradycardias, two PVCs and one Wenckebach phenomenon). One patient in the peripheral vein group developed Wenckebach phenomenon. Arrhythmias responded to reduction of the vasopressin dose from 0.4 u/min to 0.2 u/min in all but one patient who required the addition of a slow drip lidocaine infusion to control persistent PVCs. Isuprel (isoprotorenol hydrochloride) was not administered. Patient Survival

The 30-day survival rate for the entire series was 64% (16/25), and currently 48% (12/25) of the patients are alive 6 to 21 months following entry into the study. Of the patients with clinically important coagulopathy, 45% survived for 30 days, whereas 79o of the patients without coagulation deficits survived. This difference is not statistically significant. In surviving patients, the average maximum serum bilirubin increase during vasopressin infusion was 2.7 mg% in the peripheral vein group and 2.5 mgo in the SMA group. Thirty days later the average serum bilirubin level was 2.1 mg%o in the SMA group and 2.2 mgo in the peripheral vein group. In general, we were unable to statistically correlate survival with serum bilirubin. The best prognostic factor of long-term survival was the initial response to vasopressin therapy. Of the 14 patients whose bleeding was controlled during and after vasopressin therapy (Table 2), 11 patients survived. Of the 11 patients who were classified as Temporary Control, Combined Control or Exsanguination, only one patient is alive in the 6 to 21 month follow-up period. This observation is highly significant (p < 0.01).

Statistical Analysis By Student's "t" test for unpaired data, we found no difference in the efficacy of vasopressin in control of acute gastro-esophageal variceal bleeding related to route of administration.6 When the groups were compared with regard to catheter-related and cardiac complications as well as ability to control bleeding, it was noted that a difference was significant (p < 0.04) by Fischer's Exact Test6 and that the peripheral vein group appeared to fare better. It, therefore, was evident that the only clinical justification for continuation of the study would be with the hypothesis that SMA infusion of vasopressin was more effective in the control of hemorrhage than peripheral vein infusion. It was calculated that with an assigned betaerror of 20%o and alpha error 5%, a sample size of 336 patients would be required to statistically validate

a 15% therapeutic benefit.6 Since the results of our study of 25 patients showed a control rate of 64% for peripheral vein vasopressin and a control rate of 50% for SMA vasopressin, it seemed very unlikely that the SMA route could be 15% more effective than the peripheral vein. By lowering our expectations to demonstrate a 10% difference in therapeutic efficacy, it would be necessary to evaluate a sample size of nearly 600 patients. Weighing our experience with catheter complications as well as other reports in the literature,4 14'19'23 it can be expected that 15 major and 45 minor complications would be likely to occur during a study of this scope.

Discussion

Nusbaum et al.19 reported a 98% success rate in bleeding control with superior mesenteric arterial infusion of vasopressin. In 1975 we reviewed our experience with 49 patients and those of other investigators.14 While variceal hemorrhage was initially controlled by SMA vasopressin infusion in 80o of the reported 181 cases, complete control was obtained in 50%. Since patients with upper gastrointestinal bleeding are frequently treated conservatively before vasopressin infusion is instituted, a "selection process" may explain the difference in success rate that we and others have found with SMA vasopressin therapy. Our success rate with intravenous vasopressin in uncontrollable bleeders in the present study is comparable to the experience we reported in 1975 with SMA infusion in a similar patient population. Vasopressin is known to exert an intense vasoconstrictor action on the prehepatic splanchnic viscera and this effect is generally believed to be the cause of the reduced portal pressure which usually follows. Texter and co-workers29 have concluded that the increase in resistance occurs largely in the small vessel segment from small artery to small vein. Eiseman et al.8 and Johnson et al.'3 have suggested that the increased resistance in response to vasopressin occurs in submucosal arteriovenous shunts. The observation by Erwald et al.10 that prehepatic splanchnic oxygen uptake is unchanged during vasopressin administration would tend to support the latter theory. Shepherd et al.26 have reported a close relationship between 86Rb extraction and oxygen uptake in perfused gut loops and have suggested that oxygen uptake may be a reliable means of measuring the degree of capillary perfusion. The observation by Erwald et al.10 that mesenteric oxygen uptake is unchanged during vasopressin infusion is more consistent with a direct effect of vasopressin upon submucosal arteriovenous com-

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munications than with a major effect of vasopressin the small vessel segment, since a reduction in capillary perfusion would presumably be reflected in decreased mesenteric oxygen uptake. The suppression of portal venous Po2 in response to vasopressin noted by Millette et al.18 is also consistent with an effect of vasopressin to close off submucosal arteriovenous communications. Regardless of the major site of action, it is clear that the effect of vasopressin on the prehepatic splanchnic vasculature results in a diminution of blood flowing through the portal vein. That a decrease in portal blood flow is not always accompanied by a proportional decrease in portal pressure has been noted by Millette et al.18 Our findings (unpublished) and those of Nusbaum et al.20 and Barr et al.2 also suggest that many cirrhotic patients do not respond to vasopressin infusion with notable reductions of portal venous pressure. This observation is not surprising in the cirrhotic patient where direct transmission of hepatic arterial pressure to the portal venous system may occur as a result of severe distortion of the hepatic architecture and of an increased number of presinusoidal hepatic artery to portal vein communications.28 The intense and sustained vasoconstrictive effects of vasopressin on the prehepatic vasculature are confined to the splanchnic vessels. The effect of vasopressin on hepatic arterial vessels is transient, lasting less than five minutes, and is frequently followed by increased arterial flow.11 Erwald has demonstrated that in conscious alcoholic patients there is a compensatory increase in hepatic arterial flow when portal blood flow is reduced during vasopressin administration. Hepatic oxygen uptake remains the same.10 Vasopressin has been effective in controlling bleeding from gastro-esophageal varices despite minimal reductions in portal pressure. The mechanism for this is unclear. It may be that with reduced blood flow in the portal vein, the kinetic energy of portal blood is dissipated in the hepatofugal flow toward the varices and that the pressure within the varix is not necessarily that within the portal vein. In an angiographic study in the dog, Aronsen and Nylander1 have observed the radiographic disappearance of submucosal esophageal varices during vasopressin infusion. Our impression that a direct response of vasopressin to shut off submucosal arteriovenous communications may be related to this observation is, of course, conjectural. The theory proposed by Aronsen and Nylander1 and others20 that the submucosal varices are compressed by vasopressin-induced contracture of the muscle layer of the esophageal wall is difficult to reconcile with the experimental evidence that suggests that stimuon

373

latory effects of vasopressin on the gastrointestinal tract are limited to propulsive waves and that intestinal tone in man and dog is depressed by vasopressin.12 The mechanism by which variceal bleeding control is sustained after vasopressin is discontinued is also not clearly understood. Possible reduction in intra-variceal pressure would not be sustained after discontinuation of the drug, however, vasopressin may induce thrombosis in the vessel. Healing of an area traumatized by heavy alcohol intake or reflux esophagitis may also occur during the period of vasopressin control as a result of antacid therapy. During this time correction of coagulation deficits may contribute to bleeding control when vasopressin is discontinued. We have found the continuous infusion of vasopressin to be useful in the treatment of massive gastroesophageal variceal bleeding. It is our impression that the intravenous route is as effective as the direct intra-arterial route and we now employ it almost exclusively. Cardiac arrythmias appear to be dose-related and problems rarely occur with vasopressin doses of 0.2 u/min or less. Sirinek and Thomford27 have suggested that Isuprel may be useful in counteracting vasopressin-induced bradycardia and cardiac output reduction. Although none of the patients in our study sustained evidence of myocardial infarction, the known constrictive effect of vasopressin on coronary arteries has made us reluctant to use a drug which increases oxygen demand of the heart. Our current method of treatment of the cirrhotic patient presenting with massive variceal bleeding is, briefly, as follows: 1) The patient is treated with continuous intravenous vasopressin in a standardized dosage described in this study, and receives overall support, antacid therapy and correction of coagulation deficits. 2) If bleeding is not controlled by vasopressin infusion, the Sengstaken-Blakemore tube is inserted to manage the acute bleeding episode, followed by transhepatic obliteration of the left gastric vein for more permanent control.17'31 3) If control of bleeding is still not attained, an emergency shunt procedure is performed. In our experience, failure to control bleeding is rare in patients without severe coagulopathy. 4) When bleeding is controlled, four to six weeks of hospitalization is recommended to provide nutritional support, to improve liver function, and to institute diuretic therapy for ascites. Percutaneous transhepatic portography is performed to determine the specific flow characteristics of the portal and splanchnic venous systems.31 5) Finally, selective spleno-renal shunting procedures are performed, when possible, in an effort to obviate recurrent bleeding episodes and the high incidence of

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JOHNSON AND OTHERS

encephalopathy observed after standard porto-caval shunt procedures.

16.

Acknowledgment The authors wish to thank Dr. Shigeru Ochi, biostatistician, V. A. Hines Cooperative Studies Program Coordinating Center, for assistance with the statistical analysis.

17.

References

18.

1. Aronsen, K. F. and Nylander G.: The Mechanism of Vasopressin Hemostasis in Bleeding Esophageal Varices. An Angiographic Study in the Dog. Acta. Chir. Scand., 131: 443, 1966. 2. Barr, J. W., Larkin, R. C. and Rosch, J.: Similarity of Arterial and Intravenous Vasopressin on Portal and Systemic Hemodynamics. Gastroenterology, 69:13, 1975. 3. Bauer, J. J., Kreel, I. and Kark, A. E.: The Use of the Sengstaken-Blakemore Tube for Immediate Control of Bleeding Esophageal Varices. Ann. Surg., 179:273, 1974. 4. Berardi, R. S.: Vascular Complications of Superior Mesenteric Artery Infusion with Pitressin in Treatment of Bleeding Esophageal Varices. Am. J. Surg., 127:757, 1974. 5. Clark, G. A.: Comparison of the Effects of Adrenalin and Pituitrin on the Portal Circulation. J. Physiol. 66:274, 1928. 6. Colton, T.: Statistics in Medicine. Boston, Little Brown and Co., 1974. 7. Conn, H. 0. and Dalessio, D. H.: Multiple Infusions of Posterior Pituitary Extract in the Treatment of Bleeding Esophageal Varices. Ann. Intern. Med., 57:804, 1962. 8. Eiseman, B., Silen, W., Tyler, P. and Earley T.: The Portal Hypotensive Action of Pituitrin. Surg. Forum, 10:286, 1959. 9. Ericsson, B. F.: Hemodynamic Effects of Vasopressin. An Experimental Study in Normovolaemic and Hypovolaemic Anaesthetized Dogs. Acta Chir. Scand., Suppl. 414, 1971. 10. Erwald, R., Wiechel, K. L. and Strandell, T.: Effect of Vasopressin on Regional Splanchnic Blood Flows in Conscious Man. Acta Chir. Scand., 142:36, 1976. 11. Hanson, K. M.: Vascular Response of Intestine and Liver to Intravenous Infusion of Vasopressin. Am. J. Physiol., 219:779, 1970. 12. Ingelfinger, F. J.: The Modification of Intestinal Motility by Drugs. N. Engl. J. Med., 229:114, 1943. 13. Johnson, L. L., Nelson, H. M. Jr., Hardesty, W. H. and Peskin, G. W.: Enteric Arteriovenous Anastomoses and Their Contribution to Portal Hemodynamics. Surg. Forum, 11: 272, 1960. 14. Johnson, W. C. and Widrich, W. C.: Efficacy of Selective Splanchnic Arteriography and Vasopressin Perfusion in Diagnosis and Treatment of Gastrointestinal Hemorrhage. Am. J. Surg., 131:481, 1976. 15. Kaufman, S. L., Maddrey, W. C., Harrington, D. P. and White, R. I. Jr.: Hemodynamic Effects of Intra-Arterial

DISCUSSION

DR. WILLIAM S. BLAKEMORE (Toledo, Ohio): First of all, there is a growing weight of evidence from small series that intravenous Pituitrin is effective, and maybe just as effective, as intraarterial. However, there are several aspects of these arguments which remain less than fully convincing. First, the complication rate in this series is 20 to 100 times greater than those in the hands of experienced angiographers. There has been a continued emphasis since introducing the technique that those people who know how to do it should do it, and that those people who are learning should do it only under close supervision. Secondly, the cardiac arrhythmias are on twice the recommended dose, and it was recommended, and has always been, that the dosage

19.

20. 21.

22.

23.

24.

25. 26.

27.

28. 29.

30.

31.

Ann. Surg. * September 1977

and Intra-Venous Vasopressin Infusions in Patients with Portal Hypertension. Invest. Radiol., 11:368, 1976. Kehne, J. H., Hughes, F. A., Gompertz, M. L.: The Use of Surgical Pituitrin in the Control of Esophageal Varix Bleeding. Surgery, 39:917, 1956. Lunderquist, A., Simert, G., Tylen, U. and Vang, J.: Follow-up of Patients with Portal Hypertension and Esophageal Varices Treated with Percutaneous Obliteration of Gastric Coronary Vein. Radiology, 122:59, 1977. Millette, B., Huet, P. M., Lavoie, P., Viallet, A.: Portal and Systemic Effects of Selective Infusion of Vasopressin into the Superior Mesenteric Artery in Cirrhotic Patients. Gastroenterology, 69:6, 1975. Nusbaum, M., Younis, M. T., Baum, S. and Blakemore, W. S.: Control of Portal Hypertension. Arch. Surg., 109:342, 1974. Nusbaum, M. and Conn, H. O.: Arterial Vasopressin Infusions: Science or Seance? Gastroenterology, 69:263, 1975. Oliver, G. and Schafer, E. A.: On the Physiological Action of the Extracts of Pituitary Body and Certain Other Grandular Organs. J. Physiol., 18:277, 1895. Orloff, M. J., Chandler, J. G., Charters, A. C. III, et al.: Emergency Portacaval Shunt Treatment for Bleeding Esophageal Varices. Arch. Surg., 108:293, 1974. Roberts, C. and Maddison, F. E.: Partial Mesenteric Arterial Occlusion with Subsequent Ischemic Bowel Damage Due to Pitressin Infusion. Am. J. Roentgenol. Radium Ther. Nucl. Med. 126:829, 1976. Schwartz, S. I., Bales, H. W., Emerson, G. L., et al.: The Use of Intravenous Pituitrin in Treatment of Bleeding Esophageal Varices. Surgery, 45:72, 1959. Shaldon, S. and Sherlock, S.: The Use of Vasopressin (Pitressin) in the Control of Bleeding from Esophageal Varices. Lancet, 2:222, 1%0. Shepherd, A. P., Mailman, D., Burks, T. F. and Granger, H. J.: Effects of Norepinephrine and Sympathetic Stimulation on Extraction of Oxygen and 86Rb in Perfused Canine Small Bowel. Circulation Res., 33:166, 1973. Sirinek, K. R., Martin, E. W. and Thomford, N. R.: Simultaneous Isoproterenol Affords Cardiodynamic Advantages During Vasopressin Administration. J. Surg. Res., 20:299, 1976. Takeuchi, J., Kubo, T., Yoshida, I. I., et al.: Hemodynamics in the Dog Liver After Carbon Tetrachloride Injury. J. Appl. Physiol., 32:320, 1972. Texter, E. C., Jr., Chou, C. C., Merrill, S. L., et al.: Direct Effects of Vasoactive Agents on Segmental Resistance of the Mesenteric and Portal Circulation. J. Lab. Clin. Med., 64:624, 1964. Thomford, N. R. and Sirinek, K. R.: Intravenous Vasopressin in Patients with Portal Hypertension: Advantages of Continuous Infusion. J. Surg. Res., 18:113, 1975. Widrich, W. C., Robbins, A. H., Nabseth, D. C., et al.: Portal Hypertension Changes Following Selective Splenorenal Shunt Surgery. Radiology, 121:295, 1976.

intra-arterially be monitored by repeat angiography after a short interval of initiating treatment. Thirdly, the arguments related to the use of this in portal hypertension should not be confused with the rationale for use of this for other modalities, such as drug infusion, superselective catheterization, of varices, for arterial bleeding, and selective embolectomy, all of which are still under trial, and may also come under such critical review. We're thankful to Stephen Wangensteen and a student from Charlottesville, as a matter of fact, for pointing out the side effects of equal dosage of intraarterial and intravenous Pituitrin in patients with cardiac lesions. Therefore, I think that the answers are not here; that you could equally take from the data that we have in the abstract that, be-