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PROSPECTIVE CONTROLLED TRIAL OF INJECTION SCLEROTHERAPY IN PATIENTS WITH CIRRHOSIS AND RECENT VARICEAL HÆMORRHAGE
552 PROSPECTIVE CONTROLLED TRIAL OF INJECTION SCLEROTHERAPY IN PATIENTS WITH CIRRHOSIS AND RECENT VARICEAL HÆMORRHAGE A. W. CLARK D. WESTABY D. B. A. SILK J. L. DAWSON
B. R. D. MACDOUGALL K. J. MITCHELL L. STRUNIN
ROGER WILLIAMS
Liver Unit and Departments of Surgery and Anœsthesia, King’s College Hospital and Medical School, Denmark Hill, London
64 patients with cirrhosis and recent variceal hæmorrhage were studied in a prospective randomised trial of injection sclerotherapy by means of a flexible œsophageal sheath. 12 (33%) ofthe 36 patients in the sclerotherapy group, suffered further bleeds from varices compared with 19 (68%) ofthe 28 patients receiving standard medical treatment. The risk of bleeding per patient-month of follow up decreased more than threefold with sclerotherapy and the number of patients rebleeding after 2, 6, and 12 months was significantly reduced (p<0·05). 1-year survival without further bleeding improved significantly with sclerotherapy (46% compared with 6%, p<0·02), although the difference in overall survival assessed by cumulative life-table analysis was not statistically significant. The main complication of the technique was the development of œsophageal ulcers in some patients.
Summary
Introduction THE best treatment for recurrent variceal hxmorrhage in patients with cirrhosis and portal hypertension remains uncertain. Controlled trials have shown that portacaval anastomosis, the traditional method of treatment, does not improve long-term survival and the frequency of encephalopathy is high.l-3 The latter is almost certainly less with the selective distal splenorenal shunt of Warrenbut this operation is technically difficult and although such shunts may have a place in patients with well-preserved liver function, relatively few cases fall into this category. Interest in injection sclerotherapy of oesophageal varices was stimulated by Johnston and Rodgers,5 and our initial results with this technique, which we first used in 1973, were encouraging-155 of 25 patients discharged home and a 54% 1-year survival. Since then we have made several modifications to the technique, the most important of which was the development of a flexible oesophageal sheath used in conjunction with a fibreoptic endoscope. Here we describe the first analysis ofa prospective randomised controlled clinical trial of repeated injection sclerotherapy for the prevention of further haemorrhage from oesophageal varices compared with medical management alone.
Patients and Methods Between May, 1977, and November, 1979, 86 patients with portal hypertension and cirrhosis were admitted to the liver unit with acute variceal haemorrhage proven by endoscopy. 22 of these patients could not be included in the trial either because of rapid clinical deterioration and death within 48 h of admission (6 patients), previous surgery to the varices (3 patients), hepatitis-B antigen positive (3 patients), or because the referring consultant did not wish his patient to enter the trial (10 patients). The other 64 patients were randomly allocated by sealed envelope to the sclerotherapy group (36) or the control group (28) where they received supportive therapy only. The nature of the trial was
to all patients and relatives and approval was obtained from the ethical committee of the District Management Team. All patients were initially managed by standard medical treatment which included blood-transfusion, vasopressin, and a SengstakenBlakemore tube. Randomisation was done as soon as the initial episode of bleeding had been controlled and haemoglobin and bloodpressure remained stable; this varied between 48 h and 5 days. The severity of liver disease was graded A, B, or C by a modification of Child;s classification system.In the treatment group, injection sclerotherapy was repeated every 3-4 weeks until the oesophageal varices had either been obliterated or were too small to inject further. Thereafter, endoscopy was carried out at 3-monthly intervals and the varices reinjected as necessary. If there was any evidence of an oesophageal ulcer or stricture formation, injection was delayed. In the control group, patients were endoscoped every 3 months unless there were specific contraindications.
explained
Technique of Sclerotherapy Initially, only a 50-cm rigid oesophagoscope with a slot modification8 was available, but after 4 months this was replaced by a fibreoptic Olympus GIF-K oblique-viewing instrument, together with a flexible outer sheath.6 The sheath has a window (3 cm x 0-55 cm) near the distal end and is passed over the endoscope to a position where the varices just above the gastro-oesophageal junction protrude through the window. The vanx is injected via a flexible Olympus NM-3 needle passed down the biopsy channel of the endoscope. The sheath is immediately rotated to compress this varix and the nextvarix is allowed to protrude. This procedure is repeated until a ring of varices has been injected, usually three or four at the gastro-oesophageal junction, and the sheath is then advanced over the endoscope into the stomach to allow compression of the varices for another 5 minutes. A further injection is given at a more proximal level in the case of large varices extending high in the oesophagus. At the initial session 2-5 ml of 5% ethanolamine oleate are injected in each varix up to a maximum total of 20 ml, but at subsequent sessions, as the varices become smaller, the total amount needed may be reduced to only 5 ml. Sclerotherapy is best carried out under general anxsthesia9and for 24 h intravenous fluids only are allowed. Oral fluids are given the next day provided there is no retrosternal pain and the chest X-ray,is clear. On the third postsclerotherapy day most patients can be discharged. Results
sclerotherapy and control groups were similar in age, ratio, and type of underlying cirrhosis (table I). The severity of liver disease was also equally distributed with 25 (69%) poor-risk patients in categories Band C being treated by sclerotherapy compared with 19 (68%) in the control The
sex
group. 3 patients were withdrawn from each group. 2 of these showed progressive deterioration in hepatic function and a liver transplant was performed. The other 4 were withdrawn because their management had failed. 1 patient from the scleroTABLE I-COMPARISON OF THE TWO GROUPS AT ENTRY INTO THE TRIAL
553
therapy group bled from gastric varices after apparently complete obliteration ofoesophageal varices, and in another patient chronic oesophageal ulcer developed. Both patients
subsequently treated by percutaneous transhepatic embolisation of the coronary vein. Repeated episodes of variceal haemorrhage within single hospital admissions led to the withdrawal of 2 patients from the control group, 1 of whom was treated by oesophageal transection and the other were
by injection sclerotherapy. Frequency of Rebleeding and Survival Rates In 24 (67%) of the patients in the sclerotherapy group, there was no further bleeding over a mean follow-up period of9’ 5 monthand, in 3 of the 12 patients with further episodes of bleeding, the bleeding was from gastric varices, follow-up endoscopy having shown complete eradication ofoesophageal varices (table n). Haemorrhage from oesophageal varices in the other 9 patients occurred before there had been a
significant reduction in size of the vessels, and in 3 of these this was because of delays in sclerotherapy due to slow healing of oesophageal ulcers. The frequency ofrebleeding in the control group was much higher, occurring in 19 (68%) patients over a mean follow-up period of8’8months. Analysis of the frequency ofrebleeding over the follow-up period showed that in the control group with fifty episodes of rebleeding, the risk factor per patient month was 0 - 20, which was more than three times that of the sclerotherapy group with 21 episodes of rebleeding and a risk factor of only 0’ 06. Fig. 1 compares the number of patients in whom rebleeding occurred 0-2, 2-6 and 6-12 months after entering the trial; for each time interval there were significantly fewer patients from the sclerotherapy group
05). 1-year survival rate was calculated for 34 patients (17 in each group) who, on Nov. 1, 1979, had either been in the trial for more than 1 year or had died. In the sclerotherapy group 11patients (6507o) survived more than a year compared with 8 (46%) patients in the control group. Although with cumulative life tables the difference was not statistically significant (log rank sum test X2 2 - 147; 0-10>p<0’ 20), when the number of patients who had survived for 1 year or more without rebleeding was considered, the difference between the sclerotherapy (46%) and control groups (6%) was significant (p<0 02). Of the six deaths in the sclerotherapy group, one, which occurred early in the series, was directly attributable to the procedure (an oesophageal perforation with the rigid oesophagoscope). Two others were the direct result of variceal bleeding. In one, death followed haemorrhage from gastric varices 8 months after entering the trial when oesophageal varices seemed to have been completely eradicated after six courses of injections. The other had a massive bleed 18 days after the first course of sclerotherapy. The other three deaths were due to hepatic failure (2 patients) (p<0
The
=
TIME
INTERVAL AFTER ENTRY INTO TRIAL
(MONTHS)
No. patients with further episodes of bleeding in sclerotherapy (INJ) and control (CON) groups at different time intervals during follow up.
and an unrelated myocardial infarction (1 patient). In contrast, six of the nine deaths in the control group followed variceal haemorrhage. Minor complications from the procedure included retrosternal chest pain, pyrexia, and basal lung changes on the chest X-ray during the first 48 h after sclerotherapy which required only simple analgesia and physiotherapy. In 7% of the 145 sessions of sclerotherapy, there were potentially more-serious problems. In 10 patients oesophageal ulcers developed, and in 4 of these oesophageal strictures formed 2-8 weeks after healing of the ulcer which required dilatation. Discussion
-
TABLE
II-FREQUENCY OF REBLEEDING
IN THE TWO GROUPS DURING
FOLLOW UP
*3
patients bleedmg from gastric
varices.
Figures from our unit, which agree with another recently reported series,1O show that over 60% of patients admitted with bleeding from oesophageal varices suffer further episodes of bleeding during their admission, and during the next year the overall rebleeding rate rises to more than 90%. Although our results to date show that injection sclerotherapy does not stop further episodes of haemorrhage in all patients, the frequency ofrebleeding was reduced more than threefold compared with controls. Encouraging results have been published from two other centres where control of bleeding was achieved as an emergency procedure in 93% and 92% of patients, although both studies were uncontrolled. 5,11i More recently, a trial oflong-term sclerotherapy involving 31 patients demonstrated that varices could be eradicated by repeated injection without any further bleeding in these patients over a mean period of9’4 months. Our own experience with sclerotherapy carried out during active variceal bleeding showed that although haemorrhage may be stopped, the procedure is technically more difficult and oesophageal tamponade may be needed for 24 h after injection. This is likely to contribute to a higher morbidity
554 and mortality. In this trial sclerotherapy was undertaken only after bleeding had been controlled and blood-pressure stabilised, which in most cases was within 48-72 h of admission. The choice of 3-week intervals between courses of sclerotherapy for the first 6-9 weeks of treatment was based on a clinical impression that with longer time intervals the risk of further bleeding seemed greater, and with shorter intervals patient compliance became a problem. There was also a greater likelihood ofoesophageal ulceration. Most patients needed between three and four courses of sclerotherapy before all oesophageal varices were either eradicated or were too small to inject further as assessed by endoscopy. Thereafter, the frequency with which reinjection was necessary varied between 3 and 12 months, although in 3 patients no further sclerotherapy was needed for over a year. In the controls follow-up endoscopy over 3 to 30 months showed that the size of the oesophageal varices remained unchanged. There was no difference in frequency ofrebleeding episodes between alcoholic and non-alcoholic patients either in the sclerotherapy or control groups. The occurrence of bleeding from gastric varices in 3 patients after successful eradication of oesophageal varices has not been described before. These patients all had gastric varices as well as those in the oesophagus before entering the trial and there was no evidence that the gastric varices had increased in size after sclerotherapy. Indeed, Terblanche12 has described the disappearance of gastric varices presumably because of retrograde propagation of thrombus. The flexible oesophageal sheath for injection sclerotherapy, first described at King’s College Hospital,6 is an important addition to the technique. The varix, which protrudes through the window located at the distal end of the sheath, is easily approached and the flexible needle can be positioned accurately under direct vision before injecting the sclerosant. In addition to compression of the varix above and below the site of injection, so preventing dissemination of sclerosant, rotation of the sheath after injection assists further -compression and hxmostasis. The technique of maintaining compression of all varices by the sheath for several minutes after completion of injections has obviated the need for oesophageal balloon tamponade after the procedure. The development of an oesophageal ulcer is a more-serious complication, not only because of the stricture that can form but because further sclerotherapy has to be postponed until there is healing. During this time bleeding may occur, as happened in 2 patients in the present series. Damage to the oesophagus may result from injection of sclerosant into the submucosa rather than directly into the varix. This is supported by the following observation: with one exception, an oesophageal ulcer was found only in those who had had at least three courses of sclerotherapy, when varices which had already been sclerosed may have been inadvertently reinjected with consequent submucosal leakage of sclerosant. Since the flexible fibreoptic instrument was introduced, oesophageal perforation has not occurred. The distal end of the flexible sheath is also pliable and any resistance to passage of the sheath is easily detected. In his first 15 patients, Terblanchel2 had two cases of oesophageal perforation, with the rigid oesophagoscope, one fatal; Johnston and Rodgers5 reported three perforations with one death in 217 injection
procedures. Although in this first analysis of the trial the difference in overall survival with sclerotherapy was not statistically significant, this may emerge when more patients have been included with a longer follow up. Even so, injection sclero-
.
compares most favourably with the other recently introduced non-surgical technique-percutaneous transhepatic embolisation of varices. In 70% of patients in whom the technique was technically successful (25% of cases failed), follow-up studies showed that further episodes of haemorrhage occurred on average 5 months later due to the formation of new varices. 13I
therapy
We are indebted to the housemen and nursing staff of the Liver Unit who have devoted so much time to the care of these patients and we also thank our colleagues who have referred patients for inclusion in this study.
Requests for reprints should be addressed to R.W. REFERENCES 1.
Resnick RH, Iber FL, Ishihara AM, Chalmers TC, Zimmerman H. A controlled study of the therapeutic protacaval shunt. Gastroenterology 1974; 67: 843-57 2. Jackson FC, Perrin ED, Felix R, Smith WR. A clinical investigation of the portacaval shunt. Survival analysis ofthe therapeutic operation. Ann Surg 1971, 74: 672-701 3. Rueff B, Degos F, Degos JD, et al. A controlled study of therapeutic portacaval shuntin alcoholic cirrhosis. Lancet 1976; i: 655-59 4. Galambos JT, Warren WD, Rudman D. Selective and total shunts in the treatment of bleeding varices; a randomised controlled trial. N Engl J Med 1976; 295: 1088. 5. Johnston GW, Rodgers HW. A review of 15 years’ experience in the use of sclerotherapy in the control of acute haemorrhage from œsophageal varices. Br J Surg 1973; 60: 797-800. 6. Williams KGD, Dawson JL. Fibreoptic injection of oesophageal varices. Br Med J 1979; ii: 766-77. 7. 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 8. Bailey ME, Dawson JL. Modified œsophagoscope for injecting oesophageal varices Br Med J 1975; ii: 540. 9. Ward ME, Davies TDW, Strunin L. Anaesthesia for injection of bleeding varices Ann R Coll Surg Engl 1976; 58: 315-57. 10. Novis BH, Duys P, Barbezat GO, ClainJ, Bank S, TerblancheJ Fibreoptic endoscopy and the use of the Sengstaken tube in acute gastrointestinal hamorrhage in patients with portal hypertension and varices Gut 1976; 17: 258-63 11. Terblanche J, Northover JMA, Bornmann P. A prospective evaluation of injection sclerotherapy in the treatment of acute bleeding from oesophageal varices. Surgery 1979; 85: 239-45. 12. Terblanche J, Northover JMA, Bornmann P, et al. A prospective controlled trial of sclerotherapy in the long-term management of patients after oesophageal variceal bleeding Surg Gynecol Obst 1979; 148: 323-33 13. Smith-Laing G, Scott J, Dick RG, Sherlock S. A controlled trial of percutaneous transhepatic obliteration of gastro-œsophageal varices Gastroenterology 1979; 77: A42.
FETAL LOSS AFTER IMPLANTATION A
J.
Prospective Study
F. MILLER
E. WILLIAMSON
J. GLUE Departments of Obstetrics and Pœdiatrics, Southampton General Hospital Y. B. GORDON*
J. G. GRUDZINSKAS† A. SYKES
Department of Reproductive Physiology, St. Bartholomew’s Hospital, London The incidence of post-implantation pregnancy loss in 197 women was determined prospectively. The diagnosis of pregnancy was based on the detection of human chorionic gonadotropin in the urine during the luteal phase of each menstrual cycle. There were 152 conceptions in the 623 cycles studied with a pregnancy loss rate of 43%. 14 of the pregnancies ended in clinically recognised spontaneous abortions and in 50 the sole evidence of pregnancy was an increased concentration of urinary hCG. The maximum conception rate achieved was 36% in the first cycle after removal of an intra uterine device.
Summary
* Present address: Royal Free Hospital, London. &dag er; Present address: Royal North Shore Hospital, Sydney.
B. R. D. MACDOUGALL K. J. MITCHELL L. STRUNIN
ROGER WILLIAMS
Liver Unit and Departments of Surgery and Anœsthesia, King’s College Hospital and Medical School, Denmark Hill, London
64 patients with cirrhosis and recent variceal hæmorrhage were studied in a prospective randomised trial of injection sclerotherapy by means of a flexible œsophageal sheath. 12 (33%) ofthe 36 patients in the sclerotherapy group, suffered further bleeds from varices compared with 19 (68%) ofthe 28 patients receiving standard medical treatment. The risk of bleeding per patient-month of follow up decreased more than threefold with sclerotherapy and the number of patients rebleeding after 2, 6, and 12 months was significantly reduced (p<0·05). 1-year survival without further bleeding improved significantly with sclerotherapy (46% compared with 6%, p<0·02), although the difference in overall survival assessed by cumulative life-table analysis was not statistically significant. The main complication of the technique was the development of œsophageal ulcers in some patients.
Summary
Introduction THE best treatment for recurrent variceal hxmorrhage in patients with cirrhosis and portal hypertension remains uncertain. Controlled trials have shown that portacaval anastomosis, the traditional method of treatment, does not improve long-term survival and the frequency of encephalopathy is high.l-3 The latter is almost certainly less with the selective distal splenorenal shunt of Warrenbut this operation is technically difficult and although such shunts may have a place in patients with well-preserved liver function, relatively few cases fall into this category. Interest in injection sclerotherapy of oesophageal varices was stimulated by Johnston and Rodgers,5 and our initial results with this technique, which we first used in 1973, were encouraging-155 of 25 patients discharged home and a 54% 1-year survival. Since then we have made several modifications to the technique, the most important of which was the development of a flexible oesophageal sheath used in conjunction with a fibreoptic endoscope. Here we describe the first analysis ofa prospective randomised controlled clinical trial of repeated injection sclerotherapy for the prevention of further haemorrhage from oesophageal varices compared with medical management alone.
Patients and Methods Between May, 1977, and November, 1979, 86 patients with portal hypertension and cirrhosis were admitted to the liver unit with acute variceal haemorrhage proven by endoscopy. 22 of these patients could not be included in the trial either because of rapid clinical deterioration and death within 48 h of admission (6 patients), previous surgery to the varices (3 patients), hepatitis-B antigen positive (3 patients), or because the referring consultant did not wish his patient to enter the trial (10 patients). The other 64 patients were randomly allocated by sealed envelope to the sclerotherapy group (36) or the control group (28) where they received supportive therapy only. The nature of the trial was
to all patients and relatives and approval was obtained from the ethical committee of the District Management Team. All patients were initially managed by standard medical treatment which included blood-transfusion, vasopressin, and a SengstakenBlakemore tube. Randomisation was done as soon as the initial episode of bleeding had been controlled and haemoglobin and bloodpressure remained stable; this varied between 48 h and 5 days. The severity of liver disease was graded A, B, or C by a modification of Child;s classification system.In the treatment group, injection sclerotherapy was repeated every 3-4 weeks until the oesophageal varices had either been obliterated or were too small to inject further. Thereafter, endoscopy was carried out at 3-monthly intervals and the varices reinjected as necessary. If there was any evidence of an oesophageal ulcer or stricture formation, injection was delayed. In the control group, patients were endoscoped every 3 months unless there were specific contraindications.
explained
Technique of Sclerotherapy Initially, only a 50-cm rigid oesophagoscope with a slot modification8 was available, but after 4 months this was replaced by a fibreoptic Olympus GIF-K oblique-viewing instrument, together with a flexible outer sheath.6 The sheath has a window (3 cm x 0-55 cm) near the distal end and is passed over the endoscope to a position where the varices just above the gastro-oesophageal junction protrude through the window. The vanx is injected via a flexible Olympus NM-3 needle passed down the biopsy channel of the endoscope. The sheath is immediately rotated to compress this varix and the nextvarix is allowed to protrude. This procedure is repeated until a ring of varices has been injected, usually three or four at the gastro-oesophageal junction, and the sheath is then advanced over the endoscope into the stomach to allow compression of the varices for another 5 minutes. A further injection is given at a more proximal level in the case of large varices extending high in the oesophagus. At the initial session 2-5 ml of 5% ethanolamine oleate are injected in each varix up to a maximum total of 20 ml, but at subsequent sessions, as the varices become smaller, the total amount needed may be reduced to only 5 ml. Sclerotherapy is best carried out under general anxsthesia9and for 24 h intravenous fluids only are allowed. Oral fluids are given the next day provided there is no retrosternal pain and the chest X-ray,is clear. On the third postsclerotherapy day most patients can be discharged. Results
sclerotherapy and control groups were similar in age, ratio, and type of underlying cirrhosis (table I). The severity of liver disease was also equally distributed with 25 (69%) poor-risk patients in categories Band C being treated by sclerotherapy compared with 19 (68%) in the control The
sex
group. 3 patients were withdrawn from each group. 2 of these showed progressive deterioration in hepatic function and a liver transplant was performed. The other 4 were withdrawn because their management had failed. 1 patient from the scleroTABLE I-COMPARISON OF THE TWO GROUPS AT ENTRY INTO THE TRIAL
553
therapy group bled from gastric varices after apparently complete obliteration ofoesophageal varices, and in another patient chronic oesophageal ulcer developed. Both patients
subsequently treated by percutaneous transhepatic embolisation of the coronary vein. Repeated episodes of variceal haemorrhage within single hospital admissions led to the withdrawal of 2 patients from the control group, 1 of whom was treated by oesophageal transection and the other were
by injection sclerotherapy. Frequency of Rebleeding and Survival Rates In 24 (67%) of the patients in the sclerotherapy group, there was no further bleeding over a mean follow-up period of9’ 5 monthand, in 3 of the 12 patients with further episodes of bleeding, the bleeding was from gastric varices, follow-up endoscopy having shown complete eradication ofoesophageal varices (table n). Haemorrhage from oesophageal varices in the other 9 patients occurred before there had been a
significant reduction in size of the vessels, and in 3 of these this was because of delays in sclerotherapy due to slow healing of oesophageal ulcers. The frequency ofrebleeding in the control group was much higher, occurring in 19 (68%) patients over a mean follow-up period of8’8months. Analysis of the frequency ofrebleeding over the follow-up period showed that in the control group with fifty episodes of rebleeding, the risk factor per patient month was 0 - 20, which was more than three times that of the sclerotherapy group with 21 episodes of rebleeding and a risk factor of only 0’ 06. Fig. 1 compares the number of patients in whom rebleeding occurred 0-2, 2-6 and 6-12 months after entering the trial; for each time interval there were significantly fewer patients from the sclerotherapy group
05). 1-year survival rate was calculated for 34 patients (17 in each group) who, on Nov. 1, 1979, had either been in the trial for more than 1 year or had died. In the sclerotherapy group 11patients (6507o) survived more than a year compared with 8 (46%) patients in the control group. Although with cumulative life tables the difference was not statistically significant (log rank sum test X2 2 - 147; 0-10>p<0’ 20), when the number of patients who had survived for 1 year or more without rebleeding was considered, the difference between the sclerotherapy (46%) and control groups (6%) was significant (p<0 02). Of the six deaths in the sclerotherapy group, one, which occurred early in the series, was directly attributable to the procedure (an oesophageal perforation with the rigid oesophagoscope). Two others were the direct result of variceal bleeding. In one, death followed haemorrhage from gastric varices 8 months after entering the trial when oesophageal varices seemed to have been completely eradicated after six courses of injections. The other had a massive bleed 18 days after the first course of sclerotherapy. The other three deaths were due to hepatic failure (2 patients) (p<0
The
=
TIME
INTERVAL AFTER ENTRY INTO TRIAL
(MONTHS)
No. patients with further episodes of bleeding in sclerotherapy (INJ) and control (CON) groups at different time intervals during follow up.
and an unrelated myocardial infarction (1 patient). In contrast, six of the nine deaths in the control group followed variceal haemorrhage. Minor complications from the procedure included retrosternal chest pain, pyrexia, and basal lung changes on the chest X-ray during the first 48 h after sclerotherapy which required only simple analgesia and physiotherapy. In 7% of the 145 sessions of sclerotherapy, there were potentially more-serious problems. In 10 patients oesophageal ulcers developed, and in 4 of these oesophageal strictures formed 2-8 weeks after healing of the ulcer which required dilatation. Discussion
-
TABLE
II-FREQUENCY OF REBLEEDING
IN THE TWO GROUPS DURING
FOLLOW UP
*3
patients bleedmg from gastric
varices.
Figures from our unit, which agree with another recently reported series,1O show that over 60% of patients admitted with bleeding from oesophageal varices suffer further episodes of bleeding during their admission, and during the next year the overall rebleeding rate rises to more than 90%. Although our results to date show that injection sclerotherapy does not stop further episodes of haemorrhage in all patients, the frequency ofrebleeding was reduced more than threefold compared with controls. Encouraging results have been published from two other centres where control of bleeding was achieved as an emergency procedure in 93% and 92% of patients, although both studies were uncontrolled. 5,11i More recently, a trial oflong-term sclerotherapy involving 31 patients demonstrated that varices could be eradicated by repeated injection without any further bleeding in these patients over a mean period of9’4 months. Our own experience with sclerotherapy carried out during active variceal bleeding showed that although haemorrhage may be stopped, the procedure is technically more difficult and oesophageal tamponade may be needed for 24 h after injection. This is likely to contribute to a higher morbidity
554 and mortality. In this trial sclerotherapy was undertaken only after bleeding had been controlled and blood-pressure stabilised, which in most cases was within 48-72 h of admission. The choice of 3-week intervals between courses of sclerotherapy for the first 6-9 weeks of treatment was based on a clinical impression that with longer time intervals the risk of further bleeding seemed greater, and with shorter intervals patient compliance became a problem. There was also a greater likelihood ofoesophageal ulceration. Most patients needed between three and four courses of sclerotherapy before all oesophageal varices were either eradicated or were too small to inject further as assessed by endoscopy. Thereafter, the frequency with which reinjection was necessary varied between 3 and 12 months, although in 3 patients no further sclerotherapy was needed for over a year. In the controls follow-up endoscopy over 3 to 30 months showed that the size of the oesophageal varices remained unchanged. There was no difference in frequency ofrebleeding episodes between alcoholic and non-alcoholic patients either in the sclerotherapy or control groups. The occurrence of bleeding from gastric varices in 3 patients after successful eradication of oesophageal varices has not been described before. These patients all had gastric varices as well as those in the oesophagus before entering the trial and there was no evidence that the gastric varices had increased in size after sclerotherapy. Indeed, Terblanche12 has described the disappearance of gastric varices presumably because of retrograde propagation of thrombus. The flexible oesophageal sheath for injection sclerotherapy, first described at King’s College Hospital,6 is an important addition to the technique. The varix, which protrudes through the window located at the distal end of the sheath, is easily approached and the flexible needle can be positioned accurately under direct vision before injecting the sclerosant. In addition to compression of the varix above and below the site of injection, so preventing dissemination of sclerosant, rotation of the sheath after injection assists further -compression and hxmostasis. The technique of maintaining compression of all varices by the sheath for several minutes after completion of injections has obviated the need for oesophageal balloon tamponade after the procedure. The development of an oesophageal ulcer is a more-serious complication, not only because of the stricture that can form but because further sclerotherapy has to be postponed until there is healing. During this time bleeding may occur, as happened in 2 patients in the present series. Damage to the oesophagus may result from injection of sclerosant into the submucosa rather than directly into the varix. This is supported by the following observation: with one exception, an oesophageal ulcer was found only in those who had had at least three courses of sclerotherapy, when varices which had already been sclerosed may have been inadvertently reinjected with consequent submucosal leakage of sclerosant. Since the flexible fibreoptic instrument was introduced, oesophageal perforation has not occurred. The distal end of the flexible sheath is also pliable and any resistance to passage of the sheath is easily detected. In his first 15 patients, Terblanchel2 had two cases of oesophageal perforation, with the rigid oesophagoscope, one fatal; Johnston and Rodgers5 reported three perforations with one death in 217 injection
procedures. Although in this first analysis of the trial the difference in overall survival with sclerotherapy was not statistically significant, this may emerge when more patients have been included with a longer follow up. Even so, injection sclero-
.
compares most favourably with the other recently introduced non-surgical technique-percutaneous transhepatic embolisation of varices. In 70% of patients in whom the technique was technically successful (25% of cases failed), follow-up studies showed that further episodes of haemorrhage occurred on average 5 months later due to the formation of new varices. 13I
therapy
We are indebted to the housemen and nursing staff of the Liver Unit who have devoted so much time to the care of these patients and we also thank our colleagues who have referred patients for inclusion in this study.
Requests for reprints should be addressed to R.W. REFERENCES 1.
Resnick RH, Iber FL, Ishihara AM, Chalmers TC, Zimmerman H. A controlled study of the therapeutic protacaval shunt. Gastroenterology 1974; 67: 843-57 2. Jackson FC, Perrin ED, Felix R, Smith WR. A clinical investigation of the portacaval shunt. Survival analysis ofthe therapeutic operation. Ann Surg 1971, 74: 672-701 3. Rueff B, Degos F, Degos JD, et al. A controlled study of therapeutic portacaval shuntin alcoholic cirrhosis. Lancet 1976; i: 655-59 4. Galambos JT, Warren WD, Rudman D. Selective and total shunts in the treatment of bleeding varices; a randomised controlled trial. N Engl J Med 1976; 295: 1088. 5. Johnston GW, Rodgers HW. A review of 15 years’ experience in the use of sclerotherapy in the control of acute haemorrhage from œsophageal varices. Br J Surg 1973; 60: 797-800. 6. Williams KGD, Dawson JL. Fibreoptic injection of oesophageal varices. Br Med J 1979; ii: 766-77. 7. 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 8. Bailey ME, Dawson JL. Modified œsophagoscope for injecting oesophageal varices Br Med J 1975; ii: 540. 9. Ward ME, Davies TDW, Strunin L. Anaesthesia for injection of bleeding varices Ann R Coll Surg Engl 1976; 58: 315-57. 10. Novis BH, Duys P, Barbezat GO, ClainJ, Bank S, TerblancheJ Fibreoptic endoscopy and the use of the Sengstaken tube in acute gastrointestinal hamorrhage in patients with portal hypertension and varices Gut 1976; 17: 258-63 11. Terblanche J, Northover JMA, Bornmann P. A prospective evaluation of injection sclerotherapy in the treatment of acute bleeding from oesophageal varices. Surgery 1979; 85: 239-45. 12. Terblanche J, Northover JMA, Bornmann P, et al. A prospective controlled trial of sclerotherapy in the long-term management of patients after oesophageal variceal bleeding Surg Gynecol Obst 1979; 148: 323-33 13. Smith-Laing G, Scott J, Dick RG, Sherlock S. A controlled trial of percutaneous transhepatic obliteration of gastro-œsophageal varices Gastroenterology 1979; 77: A42.
FETAL LOSS AFTER IMPLANTATION A
J.
Prospective Study
F. MILLER
E. WILLIAMSON
J. GLUE Departments of Obstetrics and Pœdiatrics, Southampton General Hospital Y. B. GORDON*
J. G. GRUDZINSKAS† A. SYKES
Department of Reproductive Physiology, St. Bartholomew’s Hospital, London The incidence of post-implantation pregnancy loss in 197 women was determined prospectively. The diagnosis of pregnancy was based on the detection of human chorionic gonadotropin in the urine during the luteal phase of each menstrual cycle. There were 152 conceptions in the 623 cycles studied with a pregnancy loss rate of 43%. 14 of the pregnancies ended in clinically recognised spontaneous abortions and in 50 the sole evidence of pregnancy was an increased concentration of urinary hCG. The maximum conception rate achieved was 36% in the first cycle after removal of an intra uterine device.
Summary
* Present address: Royal Free Hospital, London. &dag er; Present address: Royal North Shore Hospital, Sydney.