Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices: A DoubleBlind, Randomized, Placebo-Controlled Trial C. Söderlund, I. Magnusson, S. Törngren & L. Lundell To cite this article: C. Söderlund, I. Magnusson, S. Törngren & L. Lundell (1990) Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices: A Double-Blind, Randomized, Placebo-Controlled Trial, Scandinavian Journal of Gastroenterology, 25:6, 622-630 To link to this article: http://dx.doi.org/10.3109/00365529009095539
Published online: 08 Jul 2009.
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Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices A Double-Blind, Randomized, Placebo-Controlled Trial C. SODERLUND, I. MAGNUSSON, S. TORNGREN & L. LUNDELL Dept. of Surgery, Sodersjukhuset, Stockholm, and Dept. of Surgery, Sahlgren’s Hospital, Gothenburg, Sweden
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Soderlund C, Magnusson I, Torngren S, Lundell L. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices. A double-blind, randomized, placebo-controlled trial. Scand J Gastroenterol 1990, 25, 622-630 The haemostatic effect of terlipressin (triglycyl-lysine vasopressin; Glypressinm) on bleeding from oesophageal varices was evaluated in a placebo-controlled, doubleblind, randomized clinical trial. Patients with clinically suspected liver cirrhosis were included in the study if they had been admitted to hospital with an extensive haemorrhage within the last 24 h before diagnostic endoscopy. The patients randomized after stratification for seventy of liver disease. Terlipressin or placebo was administered as intravenous bolus injections every 4th h during a period of 24 to 36 h or until the clinical course necessitated active intervention (failure or withdrawal). Sixty patients entered the study; 31 patients were allocated to receive terlipressin, and 29 patients to receive placebo. Bleeding from varices was arrested in 28 of the 31 receiving terlipressin, as compared with 17 of the 29 receiving placebo (p < 0.01). Patients receiving active drug required significantly fewer blood transfusions (p < 0.05). Most of the side effects were classified as mild and were registered in the terlipressin group.
Key words: Gastrointestinal bleeding; haemostasis; liver cirrhosis; oesophageal varices; terlipressin (GlypressinB); vasopressin Claes Soderlund, M.D . , Ph. D . , Dept. of Surgery, Sodersjukhuset, S-100 64 Stockholm, Sweden
Balloon tamponade, vasopressin infusion, and endoscopic sclerotherapy, either as monotherapy or in combination, are widely used for the acute treatment of bleeding oesophageal varices. All these modalities have disadvantages: the use of tamponade is complicated for the physician and unpleasant and potentially dangerous for the patient (1). Vasopressin has few serious side effects if given as a low-dose, continuous intravenous infusion (2), but a haemostatic effect has not been established in placebo-controlled randomized trials (3,4). Emergency sclerotherapy is preferred by many (5,6). This endoscopic technique, however, requires time for resuscitation of the patient and is more difficult to perform during ongoing bleeding. A highly trained
endoscopist must consequently be at hand ( 5 ) , and sclerotherapy is therefore primarily a daytime procedure. In patients with hepatic cirrhosis bleeding should be stopped without delay, to prevent the protein load to the liver from the absorbed blood. Continued bleeding may precipitate hepatic encephalopathy and multiorgan failure (‘hepatorenal syndrome’) and aggravate an already disturbed coagulation profile. The aim of this study was to investigate whether the long-acting vasopressin analogue triglycyllysine vasopressin (terlipressin; GlypressinB) could control acute variceal haemorrhage for at least 24 h, thus serving to buy time before more definite therapy. Terlipressin was selected instead
Terlipressin for Bleeding Varices
of traditional vasopressin because of recent favourable reports regarding haemostatic efficacy, patient tolerance, and simplicity of administration (7,s).
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PATIENTS A N D METHODS Inclusion and exclusion criteria Eligible patients were those who fulfilled the following inclusion criteria: extensive upper gastrointestinal tract bleeding within the last 24 h before diagnostic endoscopy in a patient with demonstrated or clinically suspected liver cirrhosis and, at endoscopy, currently bleeding varices or varices of at least size 3 (10) and fresh blood in the upper gastric tract, and no other lesion with bleeding stigmata. Diagnostic endoscopy had to be performed within 12 h of admission. We defined extensive bleeding as a bleeding likely to require the transfusion of at least two units of whole blood (900 ml) or an equal amount of packed erythrocytes within 24 h. Pregnant patients and patients with a body weight below 55 kg were excluded. Randomization Inclusion, randomization, and start of test medication administration were carried out by one of the investigators in the endoscopy unit immediately after the diagnostic endoscopy had been performed (Fig. 1). The hepatic function was determined in accordance with Pugh's modification (Child A , 5-7 marks; B , 8-10; C, 1115) of the Child-Turcotte classification (11).The patients were included consecutively and ran-
0 I
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domized in blocks of four with stratification for Pugh grade C severity of liver disease. Coded boxes containing indistinguishable vials of placebo (mannitol) or 2 mg of terlipressin were provided by the manufacturer, Ferring AB, Malmo, Sweden. Treatment period The flow chart is shown in Fig. 1. The drugs were administered as intravenous bolus injections starting immediately after randomization and then every 4th h until a control endoscopy with sclerotherapy was performed after 24 to 36 h or until the end point failure or withdrawal had been reached. Failure was defined as a need for active intervention (for example, with tamponade and/or emergency sclerotherapy) to stop variceal bleeding during the treatment period. The assessment of failure was made by one of the investigators in full cooperation and agreement with the house staff, and the decision was explained in the protocol. This judgement was based on close monitoring (below) of the patient, mostly in the intensive care unit. Withdrawal was defined as discontinuing the study before control endoscopy because of adverse reactions, new priorities, or any other reason apart from those included under failure. Monitoring Determination of blood pressure, pulse rate (continuous ECG monitoring), serum haemoglobin, and nasogastric tube content were performed at least every 4th h. Haematemesis and/
4
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36
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Endoscopy Inclusion Randomization Test drug 10 cc/4 h i.v. (Placebo or 2 mg Glypressin) for 24-36 hours = to control endoscopy or until 'failure' or 'withdrawal'
Time(h)
Control endoscopy --I
Fig. I . The flow chart for the placebo and terlipressin (Glypressin@)groups. All the steps at time zero (left) were taken at diagnostic endoscopy.
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C. Soderlund et al.
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or melaena and transfusion requirements were noted. Possible side effects were listed in the protocol and actively looked for and refuted or confirmed at least every 4th h. A second-look control endoscopy (including sclerotherapy) for possible diagnostic errors and presence or absence of active variceal bleeding or fresh blood was carried out 24 to 36 h after inclusion (end point). The reason for the variation in time was to adhere to the usual clinical situation, in which urgent sclerotherapy is not routinely performed outside office hours.
Comparison between proportions was made with Fisher’s exact test. Mann-Whitney’s test was applied for comparison of blood transfusions. The difference between repeated measurements of blood pressure, pulse rate, and serum haemoglobin of the two groups was studied with analysis of variance (ANOVA). RESULTS
Between November 1985 and August 1988, 60 consecutive patients entered the study. The two study groups were comparable with regard to sex ratio, age, weight, aetiology and severity of liver EfJicacy The outcome of the therapy was determined disease, and biochemistry at the time of entry into both as an overall assessment of success or failure the study (Tables 1-111). Eighty per cent of the patients in each group (above) and as the efficacy and safety of the test had an alcoholic aetiology of their hepatic cirmedication. Success was defined as no need for active inter- rhosis (Table I). One-third of the patients had vention for any reason during the treatment poor hepatic function-modified Child class C category. period. Nine placebo group patients and 19 terlipressin Efficacy was defined as no or just a slight blood mix in two consecutive gastric rinses 4 h apart in a patients had a previous history of variceal bleedhaemodynamically stable patient and no ongoing ing (p = 0.02, Fisher’s exact test). bleeding or fresh blood at control endoscopy. Diagnostic endoscopy Follow-~pstudy The median delay between admission and Transfusion requirements were recorded also inclusion for endoscopy was 2.3h (range, 0during the 24 h subsequent to control endoscopy. 34.3 h) in the placebo group and 3.5 h (0-47.3 h) Moderate haemorrhage during the treatment in the terlipressin group (NS). Three and two period could be reflected in a delayed need for blood. Outcome was assessed in terms of mortality and causes of death for the entire hospiTable I. Patient data at inclusion talization period. Placebo Terlipressin Ethics und statistics Informed consent was obtained from all htale/fernaie (no. of patients) 20: 11 21:8 patients, and the study protocol was approved Age (years 2 SD) 57 rt 11 60 2 13 74 2 14 73 ? 15 by the Swedish National Board of Health and Weight (kg 2 SD) Cirrhosis aetiology Welfare and by the local ethical committees. (no. patients) In designing this study we calculated with a Alcoholic 25 24 3 3 Primary biliary haemostatic effect for terlipressin of 70% and a 1 3 Cryptogenic spontaneous cessation of bleeding (placebo ef1 Posthepatitic fect) of 40% (12,13). With a level of significance Pugh class (no. of patients) A+B 20 20 at 0.05 and a power of 0.8, a minimum of 41 11 C 9 patients had to be included. To compensate for 9.4 ? 1.8 9.2 2 2.3 Pugh score (+SD) uncertainties in these assumptions, we decided to All differences NS. include 60 patients.
Terlipressin for Bleeding Varices
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Table 11. Biochemistry values at inclusion Placebo
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Bilirubin (pmol/l) (normal < 22) ASAT* (pkat/l) (normal < 0.7) Albumin (g/l) (normal > 36) Haemoglobin (g/l) (normal > 140) Prothrombin (70 of normal) Platelet count ( x 1OY/1) (normal > 150)
34.3
?
23.7
2.8 t 8.4
Terlipressin 51.4 2 58.7 1 . 4 5 2 1.18
28.4 2 5.7
28.9 t 5.2
96.5 2 23.7
99.7
46.6 ? 14.0 138.7 2 54.1
?
17.4
55.8 ? 26.1 110.4 t 64.7
All differences NS. * ASAT = aspartate aminotransferase
patients, respectively, were (wrongly) included with a delay of more than 12 h. Fifteen and 13 patients in the placebo and terlipressin groups (NS), respectively, had actively bleeding varices at the time of initial endoscopy. Fresh blood and moderate or large varices without other lesions with bleeding stigmata were seen in the rest of the patients. Four patients had concomitant gastric (two patients in the placebo group, one terlipressin patient) or duodenal (placebo group) ulcers without signs of bleeding. The size of the varices (10) were found to be a median of size 3 (mean, 3.8 5 0.5) and size 4 (mean, 3.5 +- 0.7) in the placebo and terlipressin groups, respectively (NS). Efficacy Control of haemorrhage was successful in 17
placebo group patients (59%) versus 29 terlipressin group patients (90%, p = 0.0067) (Table IV). The mean length of therapy for successfully treated patients in the two study groups was 28 and 27 h (NS). The corresponding times for treatment failures were 14 and 24 h (NS) (Fig. 2). The mean blood pressure for the placebo group was 118/65 mm Hg (*4/2 mm Hg) and about 10 mmHg higher (131/75 3/2) for those given terlipressin (p < 0.05). The pulse rate decreased from 99 ( 2 4 ) in placebo patients to 85 ( r 3 ) in terlipressin patients (p < 0.005). The mean serum haemoglobin did not differ between the groups. Ten patients given placebo and 15 patients in the terlipressin group had melaena (NS), whereas 10 and 3 patients, respectively, experienced haematemesis (p < 0.05).
*
Table 111. Hepatic function at inclusion: stratification for randomization
Encephalopathy (no. of patients) None Minimal Coma/precoma Ascites (no. of patients) None Moderate Severe Classification score (mean + SD) Stratum I: grade A + B* Stratum 11: grade C* All differences NS. * These two strata were separately randomized.
Placebo
Terlipressin
22 7 0
26 4 1
14 10 5
16 10 5
8.35 + 0.82 11.89
+ 0.60
7.75 i1.29 11.82 0.87
+
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her high age, despite clinical and endoscopic signs to warrant intervention. Placebo Terlipressin Control endoscopy was performed a median of 1.2 h (range, 0-8.0 h) subsequent to the last test Success 17 (59%) = o,W7* 28 (90%) Failure 12 3 injection (NS). The size of varices was the same as that found at diagnostic endoscopy, a median = 0.024* 26 (84%) Efficacy 16 (55%) of size 3 (mean, 3.7 0.2). Non-efficacy 13t 5t One patient with minor bleeding detected at * Fisher's exact test. control endoscopy was classified as showing nonIncluding one (placebo) and two (terlipressin) successfully treated patients who bled at control endos- efficacy of treatment. COPY. One patient died of hepatic failure after 27 h, before control endoscopy. However, this patient was classified as a success because there were no Placebo group. Active intervention because of signs of bleeding during the treatment period. variceal bleeding was judged necessary in 12 Thus control endoscopy, confirming the clinical patients, 1 of whom belonged to modified Child diagnosis of treatment failure, was carried out in class A, 8 to class B, and 3 to class C. Seven all but two patients (one operated on, one died), patients had received emergency sclerotherapy; and sclerotherapy was carried out in all but three in four patients the balloon tamponade was patients (the elderly woman was control-examinserted, followed by sclerotherapy in three ined but not sclerosed). Terlipressin group. Three Child class C patients patients and by oesophageal transection in one patient. One 87-year-old patient classified as a failed after 8, 26, and 38h, respectively (Fig. failure did not receive active therapy because of 3). In fact all three patients received emergency Table IV. Outcome
*
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+
"/o of pats.
in each group
Each 'step' indicates the failure of one patient
Placebo
p=0.0067
20 -
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J
Time (h) Fig. 2. Cumulative failure rates in the placebo and terlipressin (Glypressin@)groups.
Terlipressin for Bleeding Varices Units O
r
Mran+S E M
0 Placebo Ciypressin
T
T
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FoIIow-UP
Fig. 3. Blood transfusion requirements at admission, during a median of 25 h (both groups) of treatment, and during a 24-h follow-up period.
sclerotherapy ; thus all patients in the terlipressin group were submitted to control endoscopy and sclerotherapy. Two more patients with minor haemorrhage at control endoscopy were classified showing nonefficacy of treatment. Control endoscopy was carried out a median of 1.3 h (range, G 6 . 3 h) after the last test injection (NS). The variceal size (10) was found to be a median of 3 (mean, 3.4 t 0.7)-that is, identical to that found at diagnostic endoscopy.
Blood transfusions Thirteen patients in the placebo group versus 16 in the terlipressin group (NS) received a median of three units of blood before inclusion. During the treatment period 25 and 20 patients (NS) had transfusions with a median of 2.5 (range, 1-13) versus 1.0 (range, 1-5) units of blood (p < 0.05) in the placebo and terlipressin groups, respectively (Fig. 3). Posttreatment (24 h) requirements did not differ between the two groups. For the whole period from inclusion until 24 h after treatment the total need for transfusions was a median of three (range, 0-15) versus two (range, G6) units in the two groups (p < 0.05). The 12 patients in the placebo group classified as failures needed a median of 6 (range, 0-18) units of blood during the same period; the cor-
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responding amount for the three terlipressin patients was 6,8, and 8 units (NS). Two placebo and 9 terlipressin patients (p < 0.05) had no transfusion at all during this same period.
Adverse reactions Four patients in the placebo group versus 15 terlipressin patients (p < 0.05) experienced adverse events (Table V). Abdominal cramps were noted in eight terlipressin recipients. Events related to haemodynamic changes, including facial pallor, were reported for 11 patients. Adverse reactions were mild in all but three GVP patients. Two GVP patients received medication for bradycardia, and one patient in the placebo group received nitroglycerin for chest pain. One patient allocated to terlipressin had to be withdrawn at 30 h because of severe bradycardia.
Follow-up Study There was no significant difference between the groups in the amount of blood transfused during the first 24 h after conclusion of the drug administration (Fig. 3). Eleven (38%) placebo patients and three (10%) terlipressin patients died before discharge (p = 0.0141). All deaths were related to bleeding or to hepatic failure secondary to bleeding varices. Nine and one of the dead patients, respectively, were classified as treatment failures. All three patients assessed as showing non-efficacy were discharged. DISCUSSION This is the first placebo-controlled trial to show a significant beneficial effect of vasoconstrictive therapy on bleeding oesophageal varices in comparison with placebo. In the first placebo-controlled study (12) performed almost 30 years ago no patients ceased to bleed in the placebo group, versus 55% in the vasopressin group. However, that study was not blinded. In two similar but blinded trials (3,4) no trend was noted in favour of vasopressin. In contrast to the many studies performed with
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Table V. Adverse reactions during the study period (no. patients) Placebo
Terlipressin (n = 15)'
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( n = 4)*
Events Gastrointestinal Cramps Nausea Diarrhoea Haemodynamic Facial pallor Increase in blood pressure Bradycardia ECG change Other (chest pain, tiredness) Severity Mild Moderate Severe Drug therapy to control side effects
3
9
2 1 2 1
8 3 2 11 7 7 6 2
1
2
0
4 0 0
12 2 1t 2
1
* p < 0.05.
t Withdrawn after 30 h because of bradycardia.
vasopressin there are few clinical trials of terlipressin and bleeding varices (8,13-15). Recently, Freeman et al. (7) noted a trend in favour of terlipressin over placebo in a doubleblind randomized trial similar to the present one. There were, however, several main differences: the Freeman trial only included 29, compared with our 60 patients; repeated lavage through a nasogastric tube to disclose bleeding was not performed, nor was control endoscopy, nor stratification for Child class C liver function, the known main determinant of outcome (16). Vasopressin exerts a splanchnic vasoconstrictive effect, and a subsequent fall in portal pressure is observed (13). Significant systemic vasoconstriction also follows, which might account for important dose-dependent complications in up to one-fourth of the patients (17-19). Different vasopressin derivatives have different mesenteric selectivity of action (20). A claim for fewer vascular complications with terlipressin as compared with vasopressin (13-15) has not been confirmed by all investigators (20,21). In the present study, half of the GVP patients had some adverse reactions, which were mild in all but three patients with bradycardia (Table V). No
terlipressin patient experienced chest pain despite the relatively high dosage (2 mg) used. There would be problems in the blinding in a placebo-controlled study in which half of the patients in the group receiving the active drug experienced well-known and easily recognized vasoconstrictive effects. This issue has been discussed in conjunction with vasopressin/placebo trials (3,22). Three-fourths of our terlipressin patients, however, did not experience. gastrointestinal discomfort (two placebo patients did). Three-fourths of the terlipressin patients did not show facial pallor (one placebo gioup patient did)-the best known and commonest vasoconstrictor adverse reaction (Table V). Furthermore, only one patient received nitroglycerin for chest pain, supposed to be caused by terlipressin. This patient turned out to belong to the placebo group. The assessment of failure was a joint decision between the investigators and the staff. In every case it turned out to be obvious from the monitored variables (see Patients and Methods section) when a patient was bleeding to such an extent that intervention was clinically necessary. Furthermore, since emergency endoscopic sclero-
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Terlipressin for Bleeding Varices
therapy was given to the treatment failures, a further confirmation of the variceal haemorrhage could be obtained. Traditional vasopressin has been found to provide short-term haemostasis in half to two-thirds of patients with bleeding varices. Regardless, the survival rate has consistently failed to improve (13, 19). In the present study the efficient short-term haemostasis with terlipressin therapy was 84% in unselected cirrhotic patients with major bleeding from oesophageal varices. The haemostasis in the placebo group was significantly lower, 55% (Table JV). Although it must be stressed that this trial was primarily designed to investigate shortterm effects, a significant decrease in hospital mortality (10% versus 38%) was found for the terlipressin patients. Since all dead patients died of bleeding or hepatic failure secondary to bleeding, a connection between efficient early haemostasis and lower mortality in the terlipressin group can be postulated. Is it possible that these results have been influenced by unrealized differences between the two study groups? They nearly were identical in the most important data at inclusion-that is, hepatic function (Pugh score) and the number of patients with an alcoholic aetiology of cirrhosis (Table I). No significant difference or consistent trend was identified at inclusion with regard to laboratory data, degree of encephalopathy, or ascites (Tables I1 and 111). More terlipressin patients had a history of previous variceal haemorrhage. This might be a sort of selection, since patients in better general condition should survive the initial haemorrhage more often, being able to present with further bleeding. This theory has, however, not been proved in current studies (9,23-25). It also may be irrelevant for the short period (2436 h) primarily studied in this trial, especially since patients with prior bleeding could rebleed again more easily (26). We conclude that terlipressin is safe, well-tolerated, and significantly more efficacious than placebo in the early control of variceal bleeding, as verified by control endoscopy. This conclusion is supported by a significant reduction in the amount of blood transfusion and frequency of
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haematemesis during the studied time period, and a lower mortality during the hospitalization. ACKNOWLEDGEMENTS We thank Pontus Lindblom and Anders Zachrisson (Ferring AB) for supplying Glypressin and for assistance with trial design, monitoring, and fruitful discussions, and Silvana Cappi (University of Lund) for statistical advice and calculations. REFERENCES 1. Conn HO, Simpson JA. Excessive mortality associated with ballon tamponade of bleeding varices: a critical appraisal. JAMA 1967, 202, 135-139 2. Chojkier M, Groszman RJ,Atterbury CE, et al. A controlled comparison of continuous intraarterial and intravenous infusion of vasopressin in hemorrhage from esophageal varices. Gastroenterology 1979, 77, 540-546 3. Fogel MR, Knauer CM, Andred LL, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding. Ann Intern Med 1982, 96, 546-569 4. Dahl CR, Mallory A, Hansen R, Schaefer JW. Continuous intravenous (iv) vasopressin (vp) for upper gastrointestinal hemorrhage-a controlled trial. Gastroenterology 1983, 84, 1132 5. Soderlund C. Endoscopic sclerotherapy of oesophageal varices. Acta Chir Scand 1985, 15l(suppl 524) 6. Fleig W, Stange E, Ruettenhauer K, Ditschuneit H. Emergency endoscopic sclerotherapy for bleeding esophageal varices: a prospective study in patients not responding to balloon tamponade. Gastrointest Endoscopy 1983, 29, 8-14 7. Freeman JG, Cobden I, Record CO. Placebo-controlled trial of terlipressin (Glypressin) in the management of acute variceal bleeding. J Clin Gastroenterol 1989, 11, 58-64 8. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleeding esophageal varices: a placebo-controlled, double-blind study. Hepatology 1986, 6, 112-115 9. Soderlund C. Variceal haemorrhage. A study of unselected patients with massive bleeding from oesophageal varices. Acta Chir Scand 1982, 148, 275-280 10. Dagradi A, Stempien S, Owens K. Bleeding esophagastric varices. Arch Surg 1966, 92, 944-947 11. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R . Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973, 60, 646-649 12. Merigan TC, Plotkin G, Davidson C. Effect of intravenously administered posterior pituitary extract on hemorrhage from bleeding esophageal varices. N Engl J Med 1962, 266, 134-135 13. Soderlund C. Vasopressin and glypressin in upper
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gastrointestinal bleeding. Scand J Gastroenterol 1987, 22(suppl 137), 50-55 14. Vosmik J, Jedlicka K, Mulder JL, Cort JH. Action of the triglycyl hormonogen of vasopressin (Glypressin) in patients with liver cirrhosis and bleeding esophageal varices. Gastroenterology 1977, 72, 605-609 15. Freeman JG, Cobden I, Lishman AH. Controlled trial of terlipressin (Glypressin) versus vasopressin in the early treatment of oesophageal varices. Lancet 1982, 1, 66-68 16. Hussey KP. Vasopressin therapy for upper gastrointestinal tract hemorrhage. Has its efficacy been proven? Arch Intern Med 1985, 145, 1263-1267 17. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rodes J. Comparison of intravenous somatostatin and vasopressin infusion in treatment of acute variceal varices. Hepatology 1984, 4, 442-446 18. Blei AT, Vasopressin analogs in portal hypertension. Different molecules but similar questions. Hepatology 1986, 6, 146-147 19. Conn HO. Vasopressin and nitroglycerin in the treatment of bleeding varices: the bottom Line. Hepatology 1986, 6, 523-525 Received 1 November 1989 Accepted 12 December 1989
20. Merkel C, Gatta A, Bolognesi M, et al. Hemodynamic changes of systemic, hepatic, and splenic circulation following triglycyl-lysin-vasopressin administration in alcoholic cirrhosis. Dig Dis Sci 1988, 33, 1103-1109 21. Blei AT, Groszmann RJ, Gusberg R, Conn HO. Comparison of vasopressin and triglycyl-lysin-vasopressin on splanchnic and systemic hemodynamics in dogs. Dig Dis 1980, 25, 688-691 22. Groszmann RJ. Drug therapy of portal hypertension. Am J Gastroenterol 1987, 82, 107-113 23. Graham DY, Smith JL. The course of patients after variceal haemorrhage. Gastroenterology 1981, 80, 8CO-809 24. Soderlund C. Variceal hemorrhage. Gastroenterology 1981, 81, 635. 25. Garden OJ, Motyl H, Gilmour WH, Utley RJ, Carter DC. Prediction of outcome following acute variceal haemorrhage. Br J Surg 1985, 72, 91-95 26. Westaby D, Macdougall BRD, Saunders JB, Williams R. A study of risk factors in patients with cirrhosis and variceal bleeding. In:Westaby B, Macdougall BRD, Williams R, eds. Variceal bleeding. Pitman, London, 1982, 21-33
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices: A DoubleBlind, Randomized, Placebo-Controlled Trial C. Söderlund, I. Magnusson, S. Törngren & L. Lundell To cite this article: C. Söderlund, I. Magnusson, S. Törngren & L. Lundell (1990) Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices: A Double-Blind, Randomized, Placebo-Controlled Trial, Scandinavian Journal of Gastroenterology, 25:6, 622-630 To link to this article: http://dx.doi.org/10.3109/00365529009095539
Published online: 08 Jul 2009.
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Citing articles: 7 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [University of Tasmania]
Date: 29 September 2015, At: 12:15
Terlipressin (Triglycyl-Lysine Vasopressin) Controls Acute Bleeding Oesophageal Varices A Double-Blind, Randomized, Placebo-Controlled Trial C. SODERLUND, I. MAGNUSSON, S. TORNGREN & L. LUNDELL Dept. of Surgery, Sodersjukhuset, Stockholm, and Dept. of Surgery, Sahlgren’s Hospital, Gothenburg, Sweden
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Soderlund C, Magnusson I, Torngren S, Lundell L. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices. A double-blind, randomized, placebo-controlled trial. Scand J Gastroenterol 1990, 25, 622-630 The haemostatic effect of terlipressin (triglycyl-lysine vasopressin; Glypressinm) on bleeding from oesophageal varices was evaluated in a placebo-controlled, doubleblind, randomized clinical trial. Patients with clinically suspected liver cirrhosis were included in the study if they had been admitted to hospital with an extensive haemorrhage within the last 24 h before diagnostic endoscopy. The patients randomized after stratification for seventy of liver disease. Terlipressin or placebo was administered as intravenous bolus injections every 4th h during a period of 24 to 36 h or until the clinical course necessitated active intervention (failure or withdrawal). Sixty patients entered the study; 31 patients were allocated to receive terlipressin, and 29 patients to receive placebo. Bleeding from varices was arrested in 28 of the 31 receiving terlipressin, as compared with 17 of the 29 receiving placebo (p < 0.01). Patients receiving active drug required significantly fewer blood transfusions (p < 0.05). Most of the side effects were classified as mild and were registered in the terlipressin group.
Key words: Gastrointestinal bleeding; haemostasis; liver cirrhosis; oesophageal varices; terlipressin (GlypressinB); vasopressin Claes Soderlund, M.D . , Ph. D . , Dept. of Surgery, Sodersjukhuset, S-100 64 Stockholm, Sweden
Balloon tamponade, vasopressin infusion, and endoscopic sclerotherapy, either as monotherapy or in combination, are widely used for the acute treatment of bleeding oesophageal varices. All these modalities have disadvantages: the use of tamponade is complicated for the physician and unpleasant and potentially dangerous for the patient (1). Vasopressin has few serious side effects if given as a low-dose, continuous intravenous infusion (2), but a haemostatic effect has not been established in placebo-controlled randomized trials (3,4). Emergency sclerotherapy is preferred by many (5,6). This endoscopic technique, however, requires time for resuscitation of the patient and is more difficult to perform during ongoing bleeding. A highly trained
endoscopist must consequently be at hand ( 5 ) , and sclerotherapy is therefore primarily a daytime procedure. In patients with hepatic cirrhosis bleeding should be stopped without delay, to prevent the protein load to the liver from the absorbed blood. Continued bleeding may precipitate hepatic encephalopathy and multiorgan failure (‘hepatorenal syndrome’) and aggravate an already disturbed coagulation profile. The aim of this study was to investigate whether the long-acting vasopressin analogue triglycyllysine vasopressin (terlipressin; GlypressinB) could control acute variceal haemorrhage for at least 24 h, thus serving to buy time before more definite therapy. Terlipressin was selected instead
Terlipressin for Bleeding Varices
of traditional vasopressin because of recent favourable reports regarding haemostatic efficacy, patient tolerance, and simplicity of administration (7,s).
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PATIENTS A N D METHODS Inclusion and exclusion criteria Eligible patients were those who fulfilled the following inclusion criteria: extensive upper gastrointestinal tract bleeding within the last 24 h before diagnostic endoscopy in a patient with demonstrated or clinically suspected liver cirrhosis and, at endoscopy, currently bleeding varices or varices of at least size 3 (10) and fresh blood in the upper gastric tract, and no other lesion with bleeding stigmata. Diagnostic endoscopy had to be performed within 12 h of admission. We defined extensive bleeding as a bleeding likely to require the transfusion of at least two units of whole blood (900 ml) or an equal amount of packed erythrocytes within 24 h. Pregnant patients and patients with a body weight below 55 kg were excluded. Randomization Inclusion, randomization, and start of test medication administration were carried out by one of the investigators in the endoscopy unit immediately after the diagnostic endoscopy had been performed (Fig. 1). The hepatic function was determined in accordance with Pugh's modification (Child A , 5-7 marks; B , 8-10; C, 1115) of the Child-Turcotte classification (11).The patients were included consecutively and ran-
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domized in blocks of four with stratification for Pugh grade C severity of liver disease. Coded boxes containing indistinguishable vials of placebo (mannitol) or 2 mg of terlipressin were provided by the manufacturer, Ferring AB, Malmo, Sweden. Treatment period The flow chart is shown in Fig. 1. The drugs were administered as intravenous bolus injections starting immediately after randomization and then every 4th h until a control endoscopy with sclerotherapy was performed after 24 to 36 h or until the end point failure or withdrawal had been reached. Failure was defined as a need for active intervention (for example, with tamponade and/or emergency sclerotherapy) to stop variceal bleeding during the treatment period. The assessment of failure was made by one of the investigators in full cooperation and agreement with the house staff, and the decision was explained in the protocol. This judgement was based on close monitoring (below) of the patient, mostly in the intensive care unit. Withdrawal was defined as discontinuing the study before control endoscopy because of adverse reactions, new priorities, or any other reason apart from those included under failure. Monitoring Determination of blood pressure, pulse rate (continuous ECG monitoring), serum haemoglobin, and nasogastric tube content were performed at least every 4th h. Haematemesis and/
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Endoscopy Inclusion Randomization Test drug 10 cc/4 h i.v. (Placebo or 2 mg Glypressin) for 24-36 hours = to control endoscopy or until 'failure' or 'withdrawal'
Time(h)
Control endoscopy --I
Fig. I . The flow chart for the placebo and terlipressin (Glypressin@)groups. All the steps at time zero (left) were taken at diagnostic endoscopy.
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or melaena and transfusion requirements were noted. Possible side effects were listed in the protocol and actively looked for and refuted or confirmed at least every 4th h. A second-look control endoscopy (including sclerotherapy) for possible diagnostic errors and presence or absence of active variceal bleeding or fresh blood was carried out 24 to 36 h after inclusion (end point). The reason for the variation in time was to adhere to the usual clinical situation, in which urgent sclerotherapy is not routinely performed outside office hours.
Comparison between proportions was made with Fisher’s exact test. Mann-Whitney’s test was applied for comparison of blood transfusions. The difference between repeated measurements of blood pressure, pulse rate, and serum haemoglobin of the two groups was studied with analysis of variance (ANOVA). RESULTS
Between November 1985 and August 1988, 60 consecutive patients entered the study. The two study groups were comparable with regard to sex ratio, age, weight, aetiology and severity of liver EfJicacy The outcome of the therapy was determined disease, and biochemistry at the time of entry into both as an overall assessment of success or failure the study (Tables 1-111). Eighty per cent of the patients in each group (above) and as the efficacy and safety of the test had an alcoholic aetiology of their hepatic cirmedication. Success was defined as no need for active inter- rhosis (Table I). One-third of the patients had vention for any reason during the treatment poor hepatic function-modified Child class C category. period. Nine placebo group patients and 19 terlipressin Efficacy was defined as no or just a slight blood mix in two consecutive gastric rinses 4 h apart in a patients had a previous history of variceal bleedhaemodynamically stable patient and no ongoing ing (p = 0.02, Fisher’s exact test). bleeding or fresh blood at control endoscopy. Diagnostic endoscopy Follow-~pstudy The median delay between admission and Transfusion requirements were recorded also inclusion for endoscopy was 2.3h (range, 0during the 24 h subsequent to control endoscopy. 34.3 h) in the placebo group and 3.5 h (0-47.3 h) Moderate haemorrhage during the treatment in the terlipressin group (NS). Three and two period could be reflected in a delayed need for blood. Outcome was assessed in terms of mortality and causes of death for the entire hospiTable I. Patient data at inclusion talization period. Placebo Terlipressin Ethics und statistics Informed consent was obtained from all htale/fernaie (no. of patients) 20: 11 21:8 patients, and the study protocol was approved Age (years 2 SD) 57 rt 11 60 2 13 74 2 14 73 ? 15 by the Swedish National Board of Health and Weight (kg 2 SD) Cirrhosis aetiology Welfare and by the local ethical committees. (no. patients) In designing this study we calculated with a Alcoholic 25 24 3 3 Primary biliary haemostatic effect for terlipressin of 70% and a 1 3 Cryptogenic spontaneous cessation of bleeding (placebo ef1 Posthepatitic fect) of 40% (12,13). With a level of significance Pugh class (no. of patients) A+B 20 20 at 0.05 and a power of 0.8, a minimum of 41 11 C 9 patients had to be included. To compensate for 9.4 ? 1.8 9.2 2 2.3 Pugh score (+SD) uncertainties in these assumptions, we decided to All differences NS. include 60 patients.
Terlipressin for Bleeding Varices
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Table 11. Biochemistry values at inclusion Placebo
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Bilirubin (pmol/l) (normal < 22) ASAT* (pkat/l) (normal < 0.7) Albumin (g/l) (normal > 36) Haemoglobin (g/l) (normal > 140) Prothrombin (70 of normal) Platelet count ( x 1OY/1) (normal > 150)
34.3
?
23.7
2.8 t 8.4
Terlipressin 51.4 2 58.7 1 . 4 5 2 1.18
28.4 2 5.7
28.9 t 5.2
96.5 2 23.7
99.7
46.6 ? 14.0 138.7 2 54.1
?
17.4
55.8 ? 26.1 110.4 t 64.7
All differences NS. * ASAT = aspartate aminotransferase
patients, respectively, were (wrongly) included with a delay of more than 12 h. Fifteen and 13 patients in the placebo and terlipressin groups (NS), respectively, had actively bleeding varices at the time of initial endoscopy. Fresh blood and moderate or large varices without other lesions with bleeding stigmata were seen in the rest of the patients. Four patients had concomitant gastric (two patients in the placebo group, one terlipressin patient) or duodenal (placebo group) ulcers without signs of bleeding. The size of the varices (10) were found to be a median of size 3 (mean, 3.8 5 0.5) and size 4 (mean, 3.5 +- 0.7) in the placebo and terlipressin groups, respectively (NS). Efficacy Control of haemorrhage was successful in 17
placebo group patients (59%) versus 29 terlipressin group patients (90%, p = 0.0067) (Table IV). The mean length of therapy for successfully treated patients in the two study groups was 28 and 27 h (NS). The corresponding times for treatment failures were 14 and 24 h (NS) (Fig. 2). The mean blood pressure for the placebo group was 118/65 mm Hg (*4/2 mm Hg) and about 10 mmHg higher (131/75 3/2) for those given terlipressin (p < 0.05). The pulse rate decreased from 99 ( 2 4 ) in placebo patients to 85 ( r 3 ) in terlipressin patients (p < 0.005). The mean serum haemoglobin did not differ between the groups. Ten patients given placebo and 15 patients in the terlipressin group had melaena (NS), whereas 10 and 3 patients, respectively, experienced haematemesis (p < 0.05).
*
Table 111. Hepatic function at inclusion: stratification for randomization
Encephalopathy (no. of patients) None Minimal Coma/precoma Ascites (no. of patients) None Moderate Severe Classification score (mean + SD) Stratum I: grade A + B* Stratum 11: grade C* All differences NS. * These two strata were separately randomized.
Placebo
Terlipressin
22 7 0
26 4 1
14 10 5
16 10 5
8.35 + 0.82 11.89
+ 0.60
7.75 i1.29 11.82 0.87
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her high age, despite clinical and endoscopic signs to warrant intervention. Placebo Terlipressin Control endoscopy was performed a median of 1.2 h (range, 0-8.0 h) subsequent to the last test Success 17 (59%) = o,W7* 28 (90%) Failure 12 3 injection (NS). The size of varices was the same as that found at diagnostic endoscopy, a median = 0.024* 26 (84%) Efficacy 16 (55%) of size 3 (mean, 3.7 0.2). Non-efficacy 13t 5t One patient with minor bleeding detected at * Fisher's exact test. control endoscopy was classified as showing nonIncluding one (placebo) and two (terlipressin) successfully treated patients who bled at control endos- efficacy of treatment. COPY. One patient died of hepatic failure after 27 h, before control endoscopy. However, this patient was classified as a success because there were no Placebo group. Active intervention because of signs of bleeding during the treatment period. variceal bleeding was judged necessary in 12 Thus control endoscopy, confirming the clinical patients, 1 of whom belonged to modified Child diagnosis of treatment failure, was carried out in class A, 8 to class B, and 3 to class C. Seven all but two patients (one operated on, one died), patients had received emergency sclerotherapy; and sclerotherapy was carried out in all but three in four patients the balloon tamponade was patients (the elderly woman was control-examinserted, followed by sclerotherapy in three ined but not sclerosed). Terlipressin group. Three Child class C patients patients and by oesophageal transection in one patient. One 87-year-old patient classified as a failed after 8, 26, and 38h, respectively (Fig. failure did not receive active therapy because of 3). In fact all three patients received emergency Table IV. Outcome
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+
"/o of pats.
in each group
Each 'step' indicates the failure of one patient
Placebo
p=0.0067
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Time (h) Fig. 2. Cumulative failure rates in the placebo and terlipressin (Glypressin@)groups.
Terlipressin for Bleeding Varices Units O
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Mran+S E M
0 Placebo Ciypressin
T
T
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FoIIow-UP
Fig. 3. Blood transfusion requirements at admission, during a median of 25 h (both groups) of treatment, and during a 24-h follow-up period.
sclerotherapy ; thus all patients in the terlipressin group were submitted to control endoscopy and sclerotherapy. Two more patients with minor haemorrhage at control endoscopy were classified showing nonefficacy of treatment. Control endoscopy was carried out a median of 1.3 h (range, G 6 . 3 h) after the last test injection (NS). The variceal size (10) was found to be a median of 3 (mean, 3.4 t 0.7)-that is, identical to that found at diagnostic endoscopy.
Blood transfusions Thirteen patients in the placebo group versus 16 in the terlipressin group (NS) received a median of three units of blood before inclusion. During the treatment period 25 and 20 patients (NS) had transfusions with a median of 2.5 (range, 1-13) versus 1.0 (range, 1-5) units of blood (p < 0.05) in the placebo and terlipressin groups, respectively (Fig. 3). Posttreatment (24 h) requirements did not differ between the two groups. For the whole period from inclusion until 24 h after treatment the total need for transfusions was a median of three (range, 0-15) versus two (range, G6) units in the two groups (p < 0.05). The 12 patients in the placebo group classified as failures needed a median of 6 (range, 0-18) units of blood during the same period; the cor-
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responding amount for the three terlipressin patients was 6,8, and 8 units (NS). Two placebo and 9 terlipressin patients (p < 0.05) had no transfusion at all during this same period.
Adverse reactions Four patients in the placebo group versus 15 terlipressin patients (p < 0.05) experienced adverse events (Table V). Abdominal cramps were noted in eight terlipressin recipients. Events related to haemodynamic changes, including facial pallor, were reported for 11 patients. Adverse reactions were mild in all but three GVP patients. Two GVP patients received medication for bradycardia, and one patient in the placebo group received nitroglycerin for chest pain. One patient allocated to terlipressin had to be withdrawn at 30 h because of severe bradycardia.
Follow-up Study There was no significant difference between the groups in the amount of blood transfused during the first 24 h after conclusion of the drug administration (Fig. 3). Eleven (38%) placebo patients and three (10%) terlipressin patients died before discharge (p = 0.0141). All deaths were related to bleeding or to hepatic failure secondary to bleeding varices. Nine and one of the dead patients, respectively, were classified as treatment failures. All three patients assessed as showing non-efficacy were discharged. DISCUSSION This is the first placebo-controlled trial to show a significant beneficial effect of vasoconstrictive therapy on bleeding oesophageal varices in comparison with placebo. In the first placebo-controlled study (12) performed almost 30 years ago no patients ceased to bleed in the placebo group, versus 55% in the vasopressin group. However, that study was not blinded. In two similar but blinded trials (3,4) no trend was noted in favour of vasopressin. In contrast to the many studies performed with
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Table V. Adverse reactions during the study period (no. patients) Placebo
Terlipressin (n = 15)'
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( n = 4)*
Events Gastrointestinal Cramps Nausea Diarrhoea Haemodynamic Facial pallor Increase in blood pressure Bradycardia ECG change Other (chest pain, tiredness) Severity Mild Moderate Severe Drug therapy to control side effects
3
9
2 1 2 1
8 3 2 11 7 7 6 2
1
2
0
4 0 0
12 2 1t 2
1
* p < 0.05.
t Withdrawn after 30 h because of bradycardia.
vasopressin there are few clinical trials of terlipressin and bleeding varices (8,13-15). Recently, Freeman et al. (7) noted a trend in favour of terlipressin over placebo in a doubleblind randomized trial similar to the present one. There were, however, several main differences: the Freeman trial only included 29, compared with our 60 patients; repeated lavage through a nasogastric tube to disclose bleeding was not performed, nor was control endoscopy, nor stratification for Child class C liver function, the known main determinant of outcome (16). Vasopressin exerts a splanchnic vasoconstrictive effect, and a subsequent fall in portal pressure is observed (13). Significant systemic vasoconstriction also follows, which might account for important dose-dependent complications in up to one-fourth of the patients (17-19). Different vasopressin derivatives have different mesenteric selectivity of action (20). A claim for fewer vascular complications with terlipressin as compared with vasopressin (13-15) has not been confirmed by all investigators (20,21). In the present study, half of the GVP patients had some adverse reactions, which were mild in all but three patients with bradycardia (Table V). No
terlipressin patient experienced chest pain despite the relatively high dosage (2 mg) used. There would be problems in the blinding in a placebo-controlled study in which half of the patients in the group receiving the active drug experienced well-known and easily recognized vasoconstrictive effects. This issue has been discussed in conjunction with vasopressin/placebo trials (3,22). Three-fourths of our terlipressin patients, however, did not experience. gastrointestinal discomfort (two placebo patients did). Three-fourths of the terlipressin patients did not show facial pallor (one placebo gioup patient did)-the best known and commonest vasoconstrictor adverse reaction (Table V). Furthermore, only one patient received nitroglycerin for chest pain, supposed to be caused by terlipressin. This patient turned out to belong to the placebo group. The assessment of failure was a joint decision between the investigators and the staff. In every case it turned out to be obvious from the monitored variables (see Patients and Methods section) when a patient was bleeding to such an extent that intervention was clinically necessary. Furthermore, since emergency endoscopic sclero-
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Terlipressin for Bleeding Varices
therapy was given to the treatment failures, a further confirmation of the variceal haemorrhage could be obtained. Traditional vasopressin has been found to provide short-term haemostasis in half to two-thirds of patients with bleeding varices. Regardless, the survival rate has consistently failed to improve (13, 19). In the present study the efficient short-term haemostasis with terlipressin therapy was 84% in unselected cirrhotic patients with major bleeding from oesophageal varices. The haemostasis in the placebo group was significantly lower, 55% (Table JV). Although it must be stressed that this trial was primarily designed to investigate shortterm effects, a significant decrease in hospital mortality (10% versus 38%) was found for the terlipressin patients. Since all dead patients died of bleeding or hepatic failure secondary to bleeding, a connection between efficient early haemostasis and lower mortality in the terlipressin group can be postulated. Is it possible that these results have been influenced by unrealized differences between the two study groups? They nearly were identical in the most important data at inclusion-that is, hepatic function (Pugh score) and the number of patients with an alcoholic aetiology of cirrhosis (Table I). No significant difference or consistent trend was identified at inclusion with regard to laboratory data, degree of encephalopathy, or ascites (Tables I1 and 111). More terlipressin patients had a history of previous variceal haemorrhage. This might be a sort of selection, since patients in better general condition should survive the initial haemorrhage more often, being able to present with further bleeding. This theory has, however, not been proved in current studies (9,23-25). It also may be irrelevant for the short period (2436 h) primarily studied in this trial, especially since patients with prior bleeding could rebleed again more easily (26). We conclude that terlipressin is safe, well-tolerated, and significantly more efficacious than placebo in the early control of variceal bleeding, as verified by control endoscopy. This conclusion is supported by a significant reduction in the amount of blood transfusion and frequency of
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haematemesis during the studied time period, and a lower mortality during the hospitalization. ACKNOWLEDGEMENTS We thank Pontus Lindblom and Anders Zachrisson (Ferring AB) for supplying Glypressin and for assistance with trial design, monitoring, and fruitful discussions, and Silvana Cappi (University of Lund) for statistical advice and calculations. REFERENCES 1. Conn HO, Simpson JA. Excessive mortality associated with ballon tamponade of bleeding varices: a critical appraisal. JAMA 1967, 202, 135-139 2. Chojkier M, Groszman RJ,Atterbury CE, et al. A controlled comparison of continuous intraarterial and intravenous infusion of vasopressin in hemorrhage from esophageal varices. Gastroenterology 1979, 77, 540-546 3. Fogel MR, Knauer CM, Andred LL, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding. Ann Intern Med 1982, 96, 546-569 4. Dahl CR, Mallory A, Hansen R, Schaefer JW. Continuous intravenous (iv) vasopressin (vp) for upper gastrointestinal hemorrhage-a controlled trial. Gastroenterology 1983, 84, 1132 5. Soderlund C. Endoscopic sclerotherapy of oesophageal varices. Acta Chir Scand 1985, 15l(suppl 524) 6. Fleig W, Stange E, Ruettenhauer K, Ditschuneit H. Emergency endoscopic sclerotherapy for bleeding esophageal varices: a prospective study in patients not responding to balloon tamponade. Gastrointest Endoscopy 1983, 29, 8-14 7. Freeman JG, Cobden I, Record CO. Placebo-controlled trial of terlipressin (Glypressin) in the management of acute variceal bleeding. J Clin Gastroenterol 1989, 11, 58-64 8. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleeding esophageal varices: a placebo-controlled, double-blind study. Hepatology 1986, 6, 112-115 9. Soderlund C. Variceal haemorrhage. A study of unselected patients with massive bleeding from oesophageal varices. Acta Chir Scand 1982, 148, 275-280 10. Dagradi A, Stempien S, Owens K. Bleeding esophagastric varices. Arch Surg 1966, 92, 944-947 11. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R . Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973, 60, 646-649 12. Merigan TC, Plotkin G, Davidson C. Effect of intravenously administered posterior pituitary extract on hemorrhage from bleeding esophageal varices. N Engl J Med 1962, 266, 134-135 13. Soderlund C. Vasopressin and glypressin in upper
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gastrointestinal bleeding. Scand J Gastroenterol 1987, 22(suppl 137), 50-55 14. Vosmik J, Jedlicka K, Mulder JL, Cort JH. Action of the triglycyl hormonogen of vasopressin (Glypressin) in patients with liver cirrhosis and bleeding esophageal varices. Gastroenterology 1977, 72, 605-609 15. Freeman JG, Cobden I, Lishman AH. Controlled trial of terlipressin (Glypressin) versus vasopressin in the early treatment of oesophageal varices. Lancet 1982, 1, 66-68 16. Hussey KP. Vasopressin therapy for upper gastrointestinal tract hemorrhage. Has its efficacy been proven? Arch Intern Med 1985, 145, 1263-1267 17. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rodes J. Comparison of intravenous somatostatin and vasopressin infusion in treatment of acute variceal varices. Hepatology 1984, 4, 442-446 18. Blei AT, Vasopressin analogs in portal hypertension. Different molecules but similar questions. Hepatology 1986, 6, 146-147 19. Conn HO. Vasopressin and nitroglycerin in the treatment of bleeding varices: the bottom Line. Hepatology 1986, 6, 523-525 Received 1 November 1989 Accepted 12 December 1989
20. Merkel C, Gatta A, Bolognesi M, et al. Hemodynamic changes of systemic, hepatic, and splenic circulation following triglycyl-lysin-vasopressin administration in alcoholic cirrhosis. Dig Dis Sci 1988, 33, 1103-1109 21. Blei AT, Groszmann RJ, Gusberg R, Conn HO. Comparison of vasopressin and triglycyl-lysin-vasopressin on splanchnic and systemic hemodynamics in dogs. Dig Dis 1980, 25, 688-691 22. Groszmann RJ. Drug therapy of portal hypertension. Am J Gastroenterol 1987, 82, 107-113 23. Graham DY, Smith JL. The course of patients after variceal haemorrhage. Gastroenterology 1981, 80, 8CO-809 24. Soderlund C. Variceal hemorrhage. Gastroenterology 1981, 81, 635. 25. Garden OJ, Motyl H, Gilmour WH, Utley RJ, Carter DC. Prediction of outcome following acute variceal haemorrhage. Br J Surg 1985, 72, 91-95 26. Westaby D, Macdougall BRD, Saunders JB, Williams R. A study of risk factors in patients with cirrhosis and variceal bleeding. In:Westaby B, Macdougall BRD, Williams R, eds. Variceal bleeding. Pitman, London, 1982, 21-33
