128

Journal of Hepatology, 1992; 16:128-137 ©1992 Elsevier ScientificPublishers Ireland Ltd. All rights reserved. 0168-8278/92/$05.00

HEPAT 01131

A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices 1 R. Shields a, S.A. Jenkins a, J.N. Baxter a, A.N. Kingsnorth", S. Ellenbogen a, C.A. M a k i n ~, I. G i l m o r e b, A.I. Morris b, D. Ashby c a n d C.R. West c Departments ofaSurgery and bGastroenterology, Royal Liverpool Hospital and "University Departments of Public Health and Occupational Mathematics. Liverpool University, Liverpool, United Kingdom

(Received 17 May 1991)

Since previous reports have suggested that somatostatin may be of value in the control of acute variceal haemorrhage, we compared its efficacy with that of injection sclerotherapy in a randomised controlled clinical trial. Eighty consecutive patients with endoscopically-proven severe variceal bleeding were randomised to injection sclerotherapy (n=41) or somatostatin (n-- 39) given as a continuous infusion of 250 #g/h for 5 days plus daily bolus administration of 250 #g. The efficacy of injection sclerotherapy and somatostatin infusion in controlling haemorrhage and preventing rebleeding (censored at 5 days), mortality (censored at 28 days) and complications was compared. The aetiology of the portal hypertension and transfusion requirements was similar between the two groups, but there were more patients with severe liver disease (Child's C) in the somatostatin group. There was no significant difference between the two treatments in the initial (p-- 1.0) or overall control of bleeding (p--0.58). Furthermore, somatostatin was as effective as injection sclerotherapy in controlling bleeding in patients with severe liver.disease or in those actively bleeding at the time of their endoscopy. The relative risk of rebleeding whilst receiving somatostatin compared to injection sclerotherapy was 1.39 [95% Confidence Interval (CI) 3.73; 0.52-1, but this was reduced to 0.98 (95% CI 0.37; 2.67) when readjusted for Child's grading, the only prognostic factor shown to be of significance. Mortality was not significantly different between the two groups of patients (p=0.31).The relative risk of dying whilst receiving somatostatin compared to injection sclerotherapy was 1.6 (95% CI 3.93; 0.66) but was reduced to 1.03 (95% CI 0.47; 2.47) when adjusted for Child's grading, the only significant prognostic factor. Complications in the somatostatin group were minor and less frequent than after injection sclerotherapy. The results of this study indicate that somatostatin is a safe treatment, which is as effective as endoscopic injection sclerotherapy for acute variceal bleeding. K e y words." Acute variceal haemorrhage; Injection sclerotherapy; Somatostatin

In the past 14 years endoscopic injection sclerotherapy has been accepted as a safe and effective treatment of acute variceai haemorrhage. In about 85-95% of patients bleeding is controlled. However, the facilities for sclerotherapy are not always available in an emergency nor is the expertise to inject a copiously bleeding varix.

Consequently, there is a need for a more universally available treatment to staunch variceal bleeding until definitive therapy can be undertaken. Previous treatments to control bleeding include balloon tamponade and vasoactive drugs. Although tamponade may be effective in controlling haemorrhage in

Correspondence to." Dr. S.A. Jenkins, Department of Surgery, Universityof Liverpool,5th Floor, U.C.D., Royal Liverpool Hospital, Prescot Street,

Liverpool, L7 8XP, U.K. The study has been presented to the Surgical Research Society (U.K.), the British Society of Gastroenterologyand 3rd World Congress of Hepatic, Pancreatic and Biliary Surgery and published in abstract form in the Brititsh Journal of Surgery, Gut and World Journal of Hepatic, Pancreatic and Biliary Surgery.

SOMATOSTATININ VARICEALBLEEDING 70-80% of patients, rebleeding recurs rapidly in about half and the complication rate of 20-25%, even in experienced hands, is high (1-5). The conventional vasoactive drug to control variceal haemorrhage is vasopressin, which is however only successful in about half of the patients. Moreover, in approximately 25% of cases, its administration is associated with undesirable sideeffects, some of which can be fatal (6,7). As a result, there has been increased interest in other vasoactive drugs to control variceal bleeding. Somatostatin, a naturally occurring peptide first isolated from the hypothalamus in 1972 (8), lowers portal pressure in experimental animals (9,10) and in man (11,12). Furthermore, early controlled clinical trials, admittedly with relatively small numbers of patients, indicated that somatostatin was a safe and effective treatment for the control of the acute variceal haemorrhage (13-15). Therefore we decided to compare somatostatin with emergency injection sclerotherapy for the control of acute variceal bleeding in a prospective randomised controlled trial. A 5-day trial period was chosen for two reasons. First, we wished to assess the efficacy of somatostatin and injection sclerotherapy in both the control of the acute variceal haemorrhage and the prevention of early rebleeding. Second, it has been the policy in our unit that patients undergoing endoscopic sclerotherapy to control an acute bleed receive a second injection 5 days later.

129 and patients previously included in the trial or who had undergone injection sclerotherapy in the previous 7 days. Eighty patients satisfying the entry criteria were randomised by sealed-envelope technique to receive either somatostatin (Stilamin, Serono Laboratories Ltd.), or immediate injection sclerotherapy. In order to maintain approximately the same number of patients in each group, the opaque envelopes containing the allocated treatment were prepared in blocks of 12 (somatostatin 6, injection sclerotherapy 6). The time at which treatment was commenced was defined as the zero time. Thirtyone patients were excluded from the study because of prior treatment at the referring hospital (balloon tamponade in 7 patients: vasopressin in 1 patient) or because endoscopic examination revealed bleeding from oesophageal ulcers (14 patients), oesophagitis (8 patients) secondary to previous injection sclerotherapy or gastric varices and oesophageal varices (1 patient). During the study period, 11 patients were not entered into the trial because bleeding was classed as insignificant. The study was approved by the Ethical Committee of the Royal Liverpool Hospital. Verbal consent was obtained from the patients or, if they were confused and encephalopathic, from their next of kin.

Treatment protocols Somatostatin

Methods Entry to the trial was confined to patients with an upper gastrointestinal bleed (haematemesis and/or melaena) who on admission had an endoscopically proven, haemodynamically-significant variceal bleed. Endoscopy was performed as soon as possible (see Table 3) after admission and treatment commenced thereafter. In those patients not actively bleeding at the time of their endoscopy, a diagnosis of recent variceal bleeding was based on the presence of fresh blood in the oesophagus, blood clot adherent to the varices and the absence of any other sources of upper gatrointestinal bleeding. A significant variceal bleed was defined as: (a) a systemic disturbance (pulse rate greater than 100 beats/min, systolic blood pressure less than 100 mgHg) requiring transfusion of blood and other intravenous fluids to restore the vital signs; or (b) the necessity to transfuse 2 units or more of blood per 24 h to maintain haemoglobin levels. Excluded from the trial were patients in whom oesophageal varices were not the source of bleeding, those transferred from other hospitals with an oesophageal balloon in place or already being treated with vasoactive drugs,

Patients randomised to receive somatostatin received a constant infusion of 250/~g/h for 5 days. As soon as the infusion was established a bolus dose of 250/~g was administered over 2 min and repeated once daily. Great care was taken to ensure that the infusion was uninterrupted by, for example, overlapping of infusion bags. If the infusion of somatostatin was interrupted accidentally, a futher bolus dose of 250/~g was administered as soon as it was re-established. Occasionally if bleeding was very severe on entry to the trial, balloon tamponade was instituted to prevent exsanguination or aspiration of blood into the lung, until definitive treatment could be organised. The balloon was removed as soon as possible, and no later than 12 h. However, reinsertion of the balloon to treat continued or recurrent haemorrhage constituted a treatment failure.

Injection sclerotherapy Injection sclerotherapy was carried out using a fibreoptic endoscope and overtube immediately after the diagnostic endoscopy. Ethanolamine oleate (2-3 ml) was injected intravariceally into each variceal column. Occasionally, if significant oozing persisted after two 10-min periods of compression with the overtube, balloon tam-

! 30 ponade of the oesophagus was instituted, but the balloon was then removed within 12 h. The need to reinsert the balloon for recurrent bleeding constituted a treatment failure. Five days after somatostatin infusion or injection sclerotherapy, the trial was stopped, all patients underwent a further endoscopy and definitive elective treatment instituted unless contraindicated.

Balloon tamponade If oozing persisted after injection sclerotherapy or rebleeding occurred in any patients a Minnesota tube was inserted (gastric balloon 300 ml water, oesophageal balloon 40 mmHg; air) for a maximum period of 12 h. Success of treatment Successful control of haemorrhage was defined as the cessation of bleeding assessed endoscopically 15-20 min after the start of the somatostatin treatment or following I0 min compression with the overtube after injection sclerotherapy, by the absence of overt signs and by stable haematocrit and haemoglobin levels without need for blood transfusions over a 5-day period. Failure to control bleeding or recurrent haemorrhage (further haematemesis and malaena accompanied by either a systemic disturbance or a fall in the haemoglobin level) in the 5 days following admission was regarded as a failure of treatment. The time from entry into the trial (time years) to failure of treatment was recorded. Patients were also followed up for 28 days to determine mortality. Statistical analysis The results of the trial are expressed in three ways: (1) comparison of the efficacy of somatostatin and injection sclerotherapy with reference to control of variceal bleeding, mortality and complications were made using a two-tailed Fisher's exact test; (2) percentage differences in rebleeding and mortality rates between the two treatments were determined together with the 95% confidence interval (16). (3) Since those calculations did not take into account the time to rebleeding or time to death, Cox's proportional hazards model (17) was used to estimate the relative risks of rebleeding and of dying for both somatostatin and injection sclerotherapy. Rebleeding was censored at 5 days or at death, if earlier, and mortality was censored at 28 days. This model was in addition used to identify and adjust the relative risks for independent prognostic factors. Sample size estimation was based on an expected efficacy in controlling bleeding of 95% in the injection sclerotherapy group (based on our experience with the

R. SHIELDSet al. technique in the 2 years prior to commencing the trial) and of 75% in the somatostatin group. Using a twotailed significance test at the 5% level, it was estimated that there would be a strong probability for detecting a difference between the two groups of 20% (90% power) with a sample size of 62 in each treatment arm. The relative efficacies of injection sclerotherapy and somatostatin in terms of control of bleeding and mortality were evaluated progressively as each patient was entered into the trial using angular transformation of a binomial proportion (which has a constant variance in the sense of the proportion of successes and failures). Such an analysis allows for early closure of the trial if one treatment is clearly superior to the other over and above the expected difference between the treatments used to calculate the sample size. However, if the difference in efficacy between the treatments is far less than that expected, a detailed analysis taking into account factors which may affect outcome is necessary. On this basis our interim analysis for the first 40 patients entered into the trial was written into the protocol to allow a more detailed comparison of the efficacies of injection sclerotherapy and somatostatin in the control of bleeding and mortality, taking into account any prognostic factors which might bias outcome. At that point the failure of injection sclerotherapy to control variceal haemorrhage and prevent rebleeding was 9.5% compared to 13.6% in the.somatostatin group. It was apparent at that point that the efficacy of injection sclerotherapy in controlling haemorrhage and preventing rebleeding was 90.5%, less than originally assumed, whereas somatostatin was more effective than anticipated with a success rate of 86.4%, although it must be accepted that with this number of patients there is a chance of a type II error. Since there was very little difference between injection sclerotherapy and somatostatin in controlling the acute variceal bleed, using tables of exact confidence limits for differences in proportions (18), it was calculated that had the trial continued with the same low failure rate a total sample size of 80 would stand a good chance of showing equivalence to within 15% and a type II error of less than 20%.

Results

Forty-one patients were randomised to receive endoscopic injection sclerotherapy and 39 to somatostatin. The aetiology of the portal hypertension, age and sex, ratio of index (first) were similar in the two groups (Table 1). The ratio of index (first) to interval bleeds was

SOMATOSTATIN IN VARICEAL BLEEDING

131

TABLE 1 Clinical and demographic features of patients

Causes of portal hypertension Extrahepatic Intrahepatic Alcohol-related Cryptogenic Primary biliary cirrhosis Chronic active hepatitis Sarcoidosis Haemochromatosis with hepatocellular carcinoma Age (years) Median (range) Male/Female Type of bleed Index bleeds (first varicial bleed) Interval bleeds (second or subsequent variceal bleeds at least 14 days after the last course of injection sclerotherapy) Child's Grade A B C

TABLE 2 Blood transfusion requirements (median; range) for patients randomised to injection sclerotherpy or somatostatin

Injection sclerotherapy (n=41)

Somatostatin (n = 39)

4 37 26 6 3 1 0

1 38 28 3 4 2 1

1

0

59 (32-76) 26 : 15

57 (39-76)

23

26

18

13

7 17 17

6 8 25

28 : 11

similar in the two groups and in those patients with interval bleeding in w h o m sclerotherapy had not been undertaken for at least 3 weeks beforehand. There were m o r e patients in the s o m a t o s t a t i n group with severe liver dysfunction graded according to Child's criteria (19) (Table 1). Child's grading was achieved by the following scoring system: bilirubin (#mol/l < 34 = I, 3 4 51 = 2, > 51 = 3; albumin (g/l) > 35 = 1, 30-35 = 2, < 30 = 3; ascites, absent = 1, minimal = 2, gross = 3; encephalopathy, a b s e n t = l , m i n i m a l = 2 , s e v e r e = 3 ; nutrition, excellent= 1, i n a d e q u a t e = 2 , p o o r = 3 . Patients with a cumulative score of < 5 were classified as Child's A, 6 - 9 as Child's B and > 9 as Child's C. The n u m b e r of patients actively bleeding at the time of endoscopy in the injection sclerotherapy g r o u p (25/41, 61%) was similar to that in the s o m a t o s t a t i n group (26/39, 69%), as were the transfusion requirements before and during the trial period (Table 2). Finally there were no significant differences in the time from onset of bleeding to admission to hospital, the ratio of patients transferred from other hospitals to those admitted directly to the Royal Liverpool Hospital, and the time for transfer or the time from admission to the Royal Liverpool Hospital to start of treatment (Table 3).

Injection sclerotherapy Injection sclerotherapy initially controlled variceal bleeding in 40 of the 41 patients (98%). One patient was

Units of blood transfused after start of haemorrhage until end of trial period Units of blood transfused before the start of treatment Units of blood transfused during the trial period (120 h)

Injection sclerotherapy (n=41)

Somatostatin (n = 39)

7 (2-19)

6 (4-24)

5 (2-16)

5 (2-13)

1 (0-9)

1 (0-12)

TABLE 3 Time-related variables in patients randomised to either injection sclerotherapy or somatostatin: median (range) Injection sclerotherapy (n=41) Time from onset of bleed to admission to hospital (h) Number of patients transferred from other hospitals Transfer time from referring hospital to Royal Liverpool Hospital (h) Time from admission at Royal Liverpool Hospital to start of treatment (h) Time from onset of bleed to start of treatment (h)

2 (0-6) 17 (41%)

Somatostatin (n = 39) 1.5 (0-8) 19 (49%)

4 (2-21)

4 (I.5-7)

1.25 (0.75-8)

1.25 (0.75-6.25)

4 (I.5-15.25)

5 (1-12.25)

randomised to receive injection sclerotherapy, but bleeding was so severe that sclerotherapy was impossible and the patient died despite balloon t a m p o n a d e . Since patients satisfying the entry criteria were randomised on an 'intention to treat basis', the inability to inject the varices was considered to be a treatment failure. In the 40 patients in w h o m bleeding was initially controlled, 6 rebled during the 5-day trial period and were treated by balloon t a m p o n a d e and somatostatin infusion. Although h a e m o r r h a g e was controlled in 5, only one survived. Thus, the overall control of bleeding in the injection sclerotherapy group was 34/41 (83%). One patient aspirated during balloon t a m p o n a d e and died. O n e patient complained of severe chest pain after removal of the Minnesota tube inserted to control continuous oozing after injection sclerotherapy and underwent an X-ray for a suspected oesophageal perforation. Unfortunately, the patient aspirated during this investigation and died shortly afterwards. T w o patients did not experience any further h a e m o r r h a g e but died of progressive liver failure. One remaining patient continued to bleed despite further periods of balloon t a m p o n ade and underwent an emergency oesophageal transection which controlled the haemorrhage. However,

132

R. SHIELDS et al. TABLE 4

this patient also developed progressive liver failure and died.

Initial and overall control of variceal bleeding by injection sclerotherapy and somatostatin

Somatostatin

Variceal bleeding was initially controlled (as defined above) by somatostatin infusion in 38 out of the 39 patients. The patient randomised to somatostatin who continued to bleed was treated with balloon tamponade in an attempt to control the haemorrhage. However, bleeding was not controlled and the patient died of hypovolaemic shock. Of the 38 patients in whom bleeding was controlled initially, 30 experienced no further bleeding. Eight patients rebled. Consequently the overall success rate of somatostatin infusion was 77% (30/39 patients). Of the patients who rebled during the trial, one underwent injection sclerotherapy alone which controlled the haemorrhage. The remaining 7 patients were treated by balloon tamponade which controlled bleeding in 4 patients, but 3 aspirated during the period of tamponade and subsequently died. The remaining 3 patients in this group were treated by injection sclerotherapy and further periods of tamponade but continued to bleed and all underwent an emergency oesophageal transection which controlled the haemorrhage. However, all these patients subsequently developed liver failure and died.

Initial control of bleeding No further bleeding over 5-day period

Injection sclerotherapy

Somatostatin

Significance

40/41 (98%)

38/39 (97%) p= 1.0

34/41 (83%)

30/39(77%)

p=0.58

Comparison of the efficacy of the two treatments was made using a two-tailed Fisher's exact test.

the patient had mild, moderate or severe liver disease or was actively bleeding at the time of endoscopy (Table 5). The Kaplan-Meier plots for time to rebleeding (Fig. 1) were similar for both groups of patients, almost all recurrent haemorrhages occurring in the first 24 h after initiation of therapy. The estimated difference in rebleeding rates between injection sclerotherapy and somatostatin infusion over the 5-day trial period was 6%. However, the 95% confiTABLE 5 Overall control of variceal bleeding by either injection sclerotherapy or somatostatin related to the severity of the liver disease or active bleeding at the time of entry into the study

Comparison of rebleeding between treatments There were no statistically significant differences between injection sclerotherapy and somatostatin in either the initial control rate (to stop bleeding) or the overall success rate (no further bleeding) during the 5-day trial period (Table 4). Similarly there were no significant differences between the two treatments in the overall success rate, whether

Child's classification A B C Actively bleeding at time of diagnostic endoscopy

Injection sclerotherapy

Somatostatin

Significance

7/7 (100%) 15/17 (88%) 12/17 (71%)

5/6 (83%) 8/8 (100%) 17/25 (68%)

p=0.46 p=0.91 p=l.0

19/25 (76%)

19/26 (73%)

p= 1.0

Statistical comparisons were made using a two-tailed Fisher's exact test.

100-

.......

80-

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1

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% 40-

20-

0 •

0



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,



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,

,



48 TIME

I

72

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96



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120

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Fig. 1. Kaplan-Meier plots for time to rebleeding after initiation of therapy in the somatostatin (......) and injection sclerotherapy ( Time zero indicates the commencement of therapy.

) groups.

133

SOMATOSTATIN IN VARICEAL BLEEDING

Comparison of mortality between treatments

dence intervals suggest that injection sclerotherapy could be 23.5% more effective or 11.5% less effective than somatostatin in controlling acute variceal haemorrhage (type II error 0.8). Similarly, using Cox's proportional hazard model, the relative risk of rebleeding in patients receiving somatostatin was 1.39 greater than in those receiving injection sclerotherapy. However, the 95% confidence intervals suggest that the relative risk of rebleeding in patients treated with somatostatin compared to injection sclerotherapy could be as much as 3.73 or as low as 0.52. The only prognostic factor shown to be independently associated with the risk of rebleeding was the degree of liver dysfunction according to Child's grading; all other variables such as aetiology, sex, age, referral patterns, active bleeding at the time of diagnostic endoscopy, use of balloon tamponade and blood transfusion requirements had no significantly independent prognostic effect on outcome. Patients with mild to moderate liver disease (Child's A and B) had a much better prognosis than those with severe liver dysfunction (Child's C). The Kaplan-Meier curves for time to rebleeding for either mild to moderate or severe liver dysfunction clearly show that the majority of patients who rebled during the trial period belonged to Child's C (Fig. 2). Since there were more patients with severe liver dysfunction in the somatostatin group the relative risk of rebleeding in the two groups was readjusted to take into account the Child's grading. This reduced the relative risk of rebleeding in the somatostatin group compared to injection sclerotherapy from 1.39 to 0.98 (95% confidence interval 0.37-2.67).

The main cause of death in both groups was hepatic failure (Table 6). There was no significant difference in the overall mortality between the groups as a whole or when related to the severity of liver disease according to the Child's grading (Table 7). The Kaplan-Meier plot of survival curves over the TABLE 6 Causes of death in patients receiving injection sclerotherapy or somatostatin Causes of death

Injection sclerotherapy

Somatostatin

Liver failure Aspiration secondary to balloon tamponade Aspiration of contrast during barium swallow Cardiac arrest secondary to hypovolaemic shock Septicaemia Pulmonary oedema

5

6

1

3

1

0

1 0 0

1 1 I

TABLE 7 Overall mortality and mortality related to Child's grading in patients receiving injection sclerotherapy or somatostatin Injection sclerotherapy Overall mortality Mortality related to Child's grading A

Somatostatin

Significance

8/41 (19.5%) 12/39 (30.7%) p=0.31 0/7 (0%)

0/6 (0%)

p= 1

B

2/17 (12%)

0/8 (0%)

p= 1

C

6/17 (35%)

12/35(48%)

p=0.5

Statistical comparison between the two treatments was made by a two-tailed Fisher's exact test.

100-

l

1

............ iiiiiiiiiiiiiiiiiiiiiii*iiiiiiiiiiiii*iill...........................

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60-

% 40-

20-

i

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48

I

72

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96

J

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120

T I M E : hours

Fig. 2. Kaplan-Meier plots for time to rebleeding after injection sclerotherapy ( - - ) or somatostatin (......) in patients with mild to moderate liver disease (Child's A and B). Rebleeding in patients with Child's Grade C liver function in the somatostatin ( - - - ) and injection sclerotherapy ( ) groups are plotted separately. Time zero indicates the commencement of therapy.

134

R. SHIELDSet al. the only significant prognostic factor with respect to mortality was the Child's grading, those patients with severe or moderate liver disease having a much greater chance of dying than those with mild hepatic dysfunction (Fig. 4). Because there were more patients with severe liver dysfunction in the somatostatin group, the relative risk of dying was readjusted to take into account the Child's grading. With this adjustment the relative risk of dying on somatostatin treatment compared to injection sclerotherapy was reduced from 1.6 to 1.03 (95% confidence limits 0.42; 2.47). Sixty out of the 80 patients survived their variceal bleed and were discharged from hospital (hospital stay median 23, range 16-26 days). All surviving patients were placed on an elective injection sclerotherapy programme and all, apart from one, were alive at 60 days. The patient who died re-presented with a minor bleed and advanced liver failure and died on day 44 after his first admission for acute variceal bleeding.

first month for patients treated with somatostatin or injection sclerotherapy (Fig. 3) indicated that most deaths occurred during the first 5 days and were related to either failure to control bleeding or early rebleeding (somatostatin n = 5, injection sclerotherapy n=3). In 5 of these patients death resulted directly from complications arising from balloon tamponade instituted in an attempt to control persistent or recurrent bleeding (Table 6). The major cause of death in the remaining 12 patients who died within 28 days of their variceal bleed was progressive hepatic/renal failure, which may have been precipitated in two by a recurrent variceal bleed after the 5-day trial period. The onset of liver failure was indicated by a progressive increase in serum bilirubin levels, confusion and disorientation (treated with lactulose and neomycin), accumulation of ascites (treated with spironolactone, therapeutic paracentesis and transfusion of albumin) and by a gradual decrease in urine output (treated with renal dopamine). The treatments instituted to reverse the progressive hepatic/renal failure were similar in both groups of patients. Mortality in patients treated with injection sclerotherapy was estimated as 11.2% less than in those treated with somatostatin. However, the 95% confidence limits indicate that the mortality in the injection sclerotherapy group could be as much as 28.2% less, or 9.4% more, than in the somatostatin group (type II error 0.76). Moreover, the overall estimate of dying in the somatostatin group compared to the injection sclerotherapy groups, using Cox's proportional hazard model, was 1.60. However, the 95% confidence limits indicate that the relative risk of dying in the somatostatin group could be as much as 3.93 times greater or 0.66 less than in the injection sclerotherapy group. As with rebleeding,

Complications of treatment The majority of complications in both groups were minor and resolved spontaneously (Table8). Some patients complained of retrosternal pain after injection sclerotherapy which was always accompanied by pyrexia and pleural effusions. In the somatostatin group 4 patients experienced severe nausea after bolus administrations, but this resolved spontaneously within 2-3 min. Hypocalcaemia was detected in 1 patient by daily full blood biochemical analyses and oesophageal ulcers were diagnosed by repeat endoscopy at the end of the 5-day trial period. The only major complication was aspiration during a barium swallow for a suspected oesophageal perforation in one patient who received injection sclero-

100...: ....................... !....................

t.~ I

80...........................

!

60-

Survival

%

40-

20-

O"

i

0

i

i

i

i

i

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7

I

i

,

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i

i

I

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14

'

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i

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21

i

i

i

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28

T I M E : days

Fig. 3. Kaplan-Meiersurvival plots for patients randomised to receive somatostatin (......) or injection sclerotherapy ( the commencementof therapy.

). Time zero indicates

135

SOMATOSTATIN IN VARICEAL B L E E D I N G 100-

80-

i ............

~ ...... ; ......

i

. . . . . . . . . -,"

60" Survival

%

40.

20.

0

7

14

21

28

T I M E : days

Fig. 4. Kaplan-Meier survival plots for patients in the sclerotherapy group ( - - ) or somatostatin group (......) with mild to moderate liver disease (Child's A and B). The survival of patients with severe liver disease (Child's C) in either the somatostatin group ( - - - ) or injection sclerotherapy group ( ) are plotted separately. Time zero indicates the commencement of therapy. TABLE 8 Complications associated with somatostatin or injection sclerotherapy Complications

Oesophageal ulcers Pyrexia, retrosternal pain or pulmonary effusion Aspiration after barium swallow for suspected perforation leading to death Nausea Hypocalcaemia Total

Injection sclerotherapy

Somatostatin

8

0

3

0

I 0 0

0 4 1

12/41 (29%)

5/39 (13%)

Significance

p=0.068

Statistical comparison was by a two-tailed Fisher's exact test.

therapy. Although this complication may not be considered to be directly associated with injection sclerotherapy, we have included it since we were unable to ascertain whether or not the patient did have a perforation of the oesophagus and because the investigation would not have been carried out if perforation was not suspected.

variceal haemorrhage where success is defined as the stopping of bleeding, and the prevention of recurrent bleeding during a 5-day period. Somatostatin and injection sclerotherapy were equally effective in patients actively bleeding at the time of the diagnostic endoscopy and in patients with mild, moderate or severe hepatic dysfunction (Child's A, B, C). Therefore the results of the present study suggest that somatostatin may be as effective in controlling acute variceal haemorrhage as injection sclerotherapy, the failure rates for both treatments being 23% and 17%, respectively. These results confirm that somatostatin is an effective initial treatment for the control of acute variceal haemorrhage, with a control rate in accord with previous reports (13-15, 21-28) (Table 9). In these controlled trials the efficacy of somatostatin ranged from 53 to 100% with a mean of approximately 70%. The variation in success rates of somatostatin may be due to several factors, including the aetiology and severity of the liver disease,

TABLE 9 Efficacy of-somatostatin in controlling variceal bleeding in controlled clinical trials Author

Number of variceal bleeds treated with somatostatin

Overall success

Kravetz et al. (13) Jenkins et al. (14) Testoni et al. (15) Bagarini et al. (21) Loperfido et al. (22) Cardona et al. (23) Averginos et al. (24) Jarmillo et al. (25) Saari et al. (26) Burroughs et al. (27) Valenzuela et al. (28)

30 17 16 24 52 20 20 20 28 61 48

16 (53%) 17 (100%) 16 (100%) 16 (67%) 30 (68%) 10 (50%) 17 (86%) 11 (58%) 18 (66%) 39 (64%} 31 (65%)

Discussion The high success rate of injection sclerotherapy in controlling acute variceal haemorrhage has led to the view that this treatment modality should be regarded as the "gold standard" against which all the other forms of therapies are compared (20). The results of this randomised controlled clinical trial suggest that there is no significant difference between somatostatin infusion and injection sclerotherapy in the control of appreciable

136 severity of the bleeding, time of randomisation in the trials, differences in the dosing regimen and duration of therapy. Nevertheless, overall the results of these clinical trials do suggest that somatostatin is a relatively effective treatment for the control of the acute variceal bleed. A most important determinant of outcome in the treatment of acute variceal bleeding is survival. In this study, there was no significant difference in the mortality of patients treated with somatostatin (30.7%) compared to those treated with injection sclerotherapy (19.5%). Furthermore, it is well documented that most deaths from variceal bleeding occur in patient's with severe liver dysfunction (Child's C). Since it turned out that the somatostatin group contained more patients with Child's C liver disease, adjustment for this factor was made using Cox's proportional hazard model and it was clear that the relative risk of dying was similar in the two groups, i.e. 1.03 (80% power). In the present study no major complications were observed with somatostatin therapy. Although more complications were observed with injection sclerotherapy, these were of little consequence apart from one death because of aspiration during a barium swallow for a suspected oesophageal perforation. The lack of any major side-effects of somatostatin infusion in this study is in accord with previous observations (13-15, 21-23) and confirms the safety of the treatment. The relative safety of somatostatin is in marked contrast to the 10-25% morbidity and mortality associated with other initial treatments for the control of acute variceal haemorrhage such as vasopressin (6,7) and balloon tamponade (29,30). The precise mode of action of somatostatin in stopping and preventing recurrent variceal bleeding has not yet been established. The rapid effect in reducing portal pressure in experimental animals and in man led to the suggestion that the hormone acted directly in the smooth muscle of the splanchnic blood vessels (9). However, this hypothesis rests on the assumption that a reduction in portal pressure is the critical mode of action of vasoactive agents in controlling variceal haemorrhage. However, vasopressin, which markedly reduces portal pressure, is not as effective in controlling acute variceal haemorrhage as somatostatin (14). Recently, evidence has been accumulating that a reduction in collateral blood flow including that through the varices, and not portal pressure per se, may be the more important determinant in controlling variceal haemorrhage. In portal hypertensive rats, vasopressin reduces portal pressure more than somatostatin, but the latter had a more pronounced effect on collateral blood flow (32). Similarly, in man, although vasopressin lowers portal pressure more than somatostatin, somatostatin reduces azygos blood flow

R. SHIELDSetal. to a much greater extent than vasopressin (33). These observations strongly suggest that, to control variceal bleeding, vasoactive agents should reduce blood flow through the collateral circulation, including the varices. This hypothesis offers some explanation, at least in part, why somatostatin may be more effective than vasopressin in controlling the acute variceal bleed. In addition, somatostatin has a further potential advantage over other vasoactive drugs in the management of bleeding oesophageal varices. Somatostatin, by inhibiting gastric secretion (28), may reduce the risk of rebleeding by preventing clot dissolution at the site of haemostasis on the varices. Erosion of the varices by reflux of gastric contents not thought to be important in precipitating a variceal bleed pet" se (erosive theory), but it may be an important factor in preventing rebleeding. In conclusion, therefore, somatostatin appears to be a safe and relatively effective treatment for acute variceal haemorrhage, and may have a particular role in centres without the facilities or expertise for emergency injection sclerotherapy. Although glypressin (34-36) or combined nitroglycerin therapy (37-39) have been suggested as safe efficacious treatments for the control of bleeding oesophageal varices, the controlled trials have provided conflicting reports on the superiority of these treatment regimens with respect to both the control of bleeding and reduction in side-effects. Thus, at this point in time somatostatin would appear to be the vasoactive treatment of choice for bleeding oesophageal varices, since it appears to be as effective or better than all other treatments with which it has been compared and has fewer side-effects (40). A 5-day treatment period would also appear to be the optimum for evaluating the efficacy of the drug (27,41), since divergence of somatostatin and the control groups begins to emerge at 24 h and is progressive thereafter. Finally, this trial was carried out in a major referral centre for bleeding oesophageal varices which has considerable expertise in performing emergency injection sclerotherapy. In hospitals with a limited experience of emergency injection sclerotherapy, the results might have been worse with this treatment modality; on the other hand, somatostatin does not require such expertise for its administration.

Acknowledgements This study was supported by grants from the Mersey Regional Health Authority and Serono Laboratories Ltd. We would like to thank the junior medical and nursing staff of the Professional Surgical Unit, Royal Liverpool Hospital, who helped with the care of the patients and Mr. K. Tweedie for help with the trial design.

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SOMATOSTATIN IN VARICEAL BLEEDING

References

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17:21-26.

A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices.

Since previous reports have suggested that somatostatin may be of value in the control of acute variceal haemorrhage, we compared its efficacy with th...
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