- Email: [email protected]
Sclerosants for injection sclerosis of esophageal varices
Table 13. Long-term results after paravariceal endoscopic sclerotherapy of esophageal varices (N 1123, 1-1-69 to 1-1282). Department of Surgery, University of Bonn and Heinz Kalk-Clinic, Bad Kissingen, West Germany.
=
Fate Primary mortality Secondary mortality No follow-up Alive Total
Number
Percent
164 213 67 679 1123
15.0 34.0 19.0 6.0 60.0 100.0
patients after variceal bleeding of different etiologies. When paravariceal injection sclerotherapy is compared with intravariceal technique, no significant differences can be found in terms of hemostatic efficacy and interhospital mortality.I-8, 10-11 It appears that repeated injection procedures are beneficial, but the exact number and intervals are not defined. The complication rate is high in the severely ill patients and in cases of emergency, but it can be reduced by better • selection of patients. The complications are considerably low in elective and prophylactic treatment. The paravariceal technique seems to be superior to the intravariceal method in regard to recurrence of hemorrhage and long-term results. 5 Data on long-term survival, which is about 50% after 5 years in our patients, are not yet sufficient to judge the value of chronic intravariceal sclerotherapy. Since patent portal systemic shunts diminish the risk of bleeding to about 25%, the aim of long-term sclerotherapy must be to equal or keep within this rate. Retrospective data from our group encourages a controlled trial to solve the question of whether sclerotherapy might be able to replace portal systemic shunt operations. There is no doubt that endoscopic sclerotherapy is superior to every other conservative method for stop-
Sclerosants for injection sclerosis of esophageal varices Dennis M. Jensen, MD
Many different sclerosants and combinations have been used clinically for endoscopic sclerosis of esophageal varices (Table 1). Previous applications of these agents have included sclerosis of hemorrhoids or peripheral venous varicosities. The important considerations in choosing sclerosing agents are (1) safety and efficacy; (2) whether an intravariceal approach will be used; (3) availability in the United States and status From the University of California, Los Angeles, California. VOLUME 29, NO.4, 1983
ping variceal hemorrhage; this has been demonstrated in our prospective controlled randomized trial in comparing double balloon tamponade to sclerotherapy.12 The control trial of MacDougall et al. 13 has supported this, although it is different in the selection of patients. The question of prophylactic sclerotherapy has been investigated in a prospective controlled trial by US. 14 REFERENCES 1. Macbeth R. Treatment of esophageal varices in portal hypertension by means of sclerosing injection. Br Med J 1955;2:877. 2. Denck H. Zur Frage der zweckmabigen Behandlung blutender Osophagus-varizen. Wien Klin Wochenschr 1963;76:274. 3. Johnston GW, Rodgers HW. A review of 15 years experience in the use of sclerotherapy irr the control of acute hemorrhage from esophageal varices. Br J Surg 1973;60:797. 4. Raschke E, Paquet KJ. Management of hemorrhage from esophageal varices using endoscopic method. Ann Surg 1973;99:177. 5. Paquet KJ, Oberhammer E. Sclerotherapy of bleeding esophageal varices by means of endoscopy. Endoscopy 1978;10:7. 6. Terblanche J, Northover JMA, Bronman P, et al. A prospective evaluation of injection sclerotherapy in the treatment of acute bleeding from esophageal varices. Surg 1979;85:239. 7. Lewis J, Chung RS, Allison J. Sclerotherapy of esophageal varices. Ann Surg 1980;115:476. 8. Soehendra N. Fiberscopic sclerosing of esophageal varices. In: Demling L, Rosch W, eds. Operative Endoskpie Acron. Berlin, 1979. 9. Stelzner S, Lierse W. Der angiomuskulare Verschlub der Speiserohre. Langenbecks Arch Klin Chir 1981;321:35. 10. Clark AW, Westaby D, Wilk DP, et al. Prospective controlled trial of injection sclerotherapy in patient with cirrhosis and recent variceal hemorrhage. Lancet 1980;2:552. 11. Sivak MV Jr, Stout D, Skipper G. Endoscopic injection sclerosis of esophageal varices. Gastrointest Endosc 1981;27:52. 12. Paquet KJ, Feubner H. Sengstaken-tamponade or endoscopic sclerosis of the esophageal wall in acute variceal bleeding of patients with liver cirrhosis and portal hypertension. A prospective controlled randomized trial. Hepatology, 1983, in press. 13. MacDougall BRD, Westaby D, Theodossi A, Dawson JL, Williams R. Increased long-term survival in variceal hemorrhage using injection sclerotherapy. Lancet 1982;1:124. 14. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices-a prospective controlled randomized trial. Endoscopy 1982;14:4.
with the Federal Drug Administration; (4) case of injection through small gauge needles; (5) frequency of anaphylaxis; (6) side effects such as fever, pleural effusion, and chest pain; and (7) stability and shelf life of agent. The paravariceal agents (Table 1) are not readily available in the United States, nor is ethanolamine oleate. Fever, pleural effusions, and chest pains are more common with the fatty acid base sclerosants (morrhuate and ethanolamine) than with the aqueous agents (ethanol and tetradecyl). Ethanolamine is more viscous and more difficult to inject through a needle of 23-26 gauge than aqueous solutions. Anaphylactic reactions have been reported with the peripheral ve315
Table 1. Sclerosing agents. Generic drug Intravariceal Ethanol Sodium tetradecyl sulfate (Sotradecol) Ethanolamine oleate Sodium morrhuate Dextrose Diazepam (Valium) Cefazolin Thrombin Paravariceal Polidocanol (Aethoxysclerol) Liquid parafin Phenolized almond oil
Concentration (%)
Availability
33-95 0.5-1.5
US, Germany
5 5 50
UK
0.5-1
Germany
US, Germany
Germany
" Ubiquitous.
nous injection of morrhuate and ethanolamine, and some have been fatal. 1-3 Topical thrombin is made for topical, not intravenous, use. All the other intravariceal agents are available in sterile ampules or containers and are chemically stable. Although endoscopic injection sclerotherapy of esophageal varices has been used clinically for over 40 years,4 there are virtually no systemic comparative studies of sclerosing agents. In 1967, Blenkinsopp3 compared tetradecyl sulfate with 5% ethanolamine, using rat femoral veins. In that rat model, tetradecyl led to a higher rate of sclerosis than did ethanolamine. In mouse tail veins, Reiner 5 showed tetradecyl to be more thrombogenic than morrhuate. Other than these experiments, there has been very little scientific basis on which to choose the best sclerosant. To screen the promising and available sclerosing substances requires a large number of veins which can be both examined and resected. Such requirements obviously preclude systemic comparison in patients. Vein Response to Sclerosants
Using a reproducible model of canine portal hypertension,6 we systematically compared 14 substances for their ability to induce sclerosis in abdominal venous collaterals with intravenous administration. 7Also examined was the influence of physical factors such as vein size and contact time on efficacy of sclerosants. The most effective single agents (>60% of veins sclerosed) were 95% ethanol, 1.5% tetradecyl, and 5% ethanolamine. Ineffective single agents «25% sclerosis) were cefazolin, 50% dextrose, 24% ethanol, and the saline controls. 5% morrhuate, 47% ethanol, and 0.5% tetradecyl were of intermediate efficacy. Three different combinations of low concentrations of tetradecyl and ethanol were all at least 75% effective. The size of the vein did influence its sclerosability: smaller veins were slightly more likely to be sclerosed. Increasing 316
sclerosant contact time by vein compression above and below the injection site increased the effectiveness of the low concentration combinations, but not the single agents. The results indicate the sclerotherapy agents that should be further evaluated in canine and human esophageal varices. Effect of Sclerosants on Esophageal Varices in Dogs
In a canine model of esophageal varices, we compared nine sclerosing agents and combinations of agents to determine relative efficacy and safety.7 Varices were endoscopically injected intravariceally and followed weekly to determine rate of ulceration, erosion, and obliteration of the varix. Efficacy of sclerosis was defined as the ability to obliterate the varix after a single injection of the test sclerosant. Ten or more varices were injected with each agent (except 95% ethanol) and efficacy of sclerosis was expressed as a percent. Three groups of agents were defined. Agents statistically no more effective than saline control (group I) were cefazolin, 47% ethanol, 5% ethanol-. amine, and a combination of 0.5% tetradecyl plus thrombin plus 50% dextrose. Substances statistically more effective than saline injection (group II) were 1.5% sodium tetradecyl sulfate, 5% morrhuate, and a combination of 1% tetradecyl plus 32% ethanol and saline (TES). Two other agents with borderline efficacy (60 and 50%, respectively) compared with saline control (group III) were 95% ethanol and a combination of 0.75% tetradecyl plus 47% ethanol (TE). The effectiveness of sclerosants was inversely related to the frequency of esophageal damage. 95% ethanol was the most damaging with an 80% rate of severe ulceration. The frequency of ulceration with group II and III agents was 40% for 1.5% tetradecyl, 30% for morrhuate, 10% for TES, 80% for ethanol, and 0% for TE. Clinical Experience with Sclerosants
There are no randomized clinical trials of different sclerosing agents. However, Gibbert et al. B compared 5% morrhuate with 1.5% tetradecyl in similar patients and reported a higher incidence of esophageal ulcers, bleeding from ulcers, and deaths in the morrhuate group than the tetradecyl sclerosed patients. For an intravariceal technique we inject at each site up to 2 ml of TES (final concentration: 1% tetradecyl, 33% ethanol, and saline). For elective cases we inject up to 24 ml per session beginning circumferentially at the gastroesophageal junction and moving cephalad. Sclerotherapy is repeated every 4 to 7 days for three initial sessions, then once a month. For emergency cases we inject up to 50 ml initially and follow the same schedule or inject up to 24 ml and add another session within 48 hours. Emergency sclerotherapy and increased volume both correlate with more frequent esophageal ulcerations. GASTROINTESTINAL ENDOSCOPY
To be useful in clinical sclerotherapy, an agent must have a high sclerosis rate and low incidence of esophageal damage. Those two properties must be balanced and then considered with availability, cost, and ease of administration. In the present study, 95% ethanol caused too much damage for clinical use. The commercially available substances in the United States, 1.5% tetradecyl and 5% morrhuate, were effective, but damage was relatively frequent. In an attempt to maximize efficacy and minimize esophageal wall damage, we developed various combinations of low concentrations of tetradecyl and ethanol. TES proved slightly more effective than TE. Based upon the good efficacy (70%), low frequency of esophageal damage (10% ulcers), and availability, we have initiated clinical studies with TES. In our opinion, these data should assist clinicians who are evaluating or planning sclerotherapy trials.
VOLUME 29, NO. 4, 1983
REFERENCES 1. Lewis KM. Anaphylaxis due to sodium morrhuate. JAMA 1936;107:1298. 2. Shelley HJ. Allergic manifestations with injection treatment of varicose veins. JAMA 1939;112:1792-4. 3. Blenkinsopp WK. Comparison of tetradecyl sulfate of sodium with other sclerosants in rats. Br J Exp PathoI1968;49:197-201. 4. Crafoord C, Frenckner P. New surgical treatment of varicous veins of the esophagus. Acta Otolaryngol 1939;27:422-9. 5. Reiner L. The activity of anionic surface active compounds in producing vascular obliteration. Proc Soc Exp BioI Med 1946;62:49-54. 6. Jensen DM, Machicado GA, Tapia JI, et al. A reproducible canine model of esophageal varices. Gastroenterology 1983, in press. 7. Silpa ML, Jensen DM, Machicado GA, et al. Efficacy and safety of agents for variceal sclerotherapy (abstract). Gastrointest Endose 1982;28:152-3. 8. Gibbert V, Feinstat T, Burns M, Trudeau W. A comparison of the sclerosing agents sodium tetradecyl sulfate and sodium morrhuate in endoscopic injection sclerosis of esophageal varices (abstract). Gastrointest Endosc 1982;28:147.
317
=
Fate Primary mortality Secondary mortality No follow-up Alive Total
Number
Percent
164 213 67 679 1123
15.0 34.0 19.0 6.0 60.0 100.0
patients after variceal bleeding of different etiologies. When paravariceal injection sclerotherapy is compared with intravariceal technique, no significant differences can be found in terms of hemostatic efficacy and interhospital mortality.I-8, 10-11 It appears that repeated injection procedures are beneficial, but the exact number and intervals are not defined. The complication rate is high in the severely ill patients and in cases of emergency, but it can be reduced by better • selection of patients. The complications are considerably low in elective and prophylactic treatment. The paravariceal technique seems to be superior to the intravariceal method in regard to recurrence of hemorrhage and long-term results. 5 Data on long-term survival, which is about 50% after 5 years in our patients, are not yet sufficient to judge the value of chronic intravariceal sclerotherapy. Since patent portal systemic shunts diminish the risk of bleeding to about 25%, the aim of long-term sclerotherapy must be to equal or keep within this rate. Retrospective data from our group encourages a controlled trial to solve the question of whether sclerotherapy might be able to replace portal systemic shunt operations. There is no doubt that endoscopic sclerotherapy is superior to every other conservative method for stop-
Sclerosants for injection sclerosis of esophageal varices Dennis M. Jensen, MD
Many different sclerosants and combinations have been used clinically for endoscopic sclerosis of esophageal varices (Table 1). Previous applications of these agents have included sclerosis of hemorrhoids or peripheral venous varicosities. The important considerations in choosing sclerosing agents are (1) safety and efficacy; (2) whether an intravariceal approach will be used; (3) availability in the United States and status From the University of California, Los Angeles, California. VOLUME 29, NO.4, 1983
ping variceal hemorrhage; this has been demonstrated in our prospective controlled randomized trial in comparing double balloon tamponade to sclerotherapy.12 The control trial of MacDougall et al. 13 has supported this, although it is different in the selection of patients. The question of prophylactic sclerotherapy has been investigated in a prospective controlled trial by US. 14 REFERENCES 1. Macbeth R. Treatment of esophageal varices in portal hypertension by means of sclerosing injection. Br Med J 1955;2:877. 2. Denck H. Zur Frage der zweckmabigen Behandlung blutender Osophagus-varizen. Wien Klin Wochenschr 1963;76:274. 3. Johnston GW, Rodgers HW. A review of 15 years experience in the use of sclerotherapy irr the control of acute hemorrhage from esophageal varices. Br J Surg 1973;60:797. 4. Raschke E, Paquet KJ. Management of hemorrhage from esophageal varices using endoscopic method. Ann Surg 1973;99:177. 5. Paquet KJ, Oberhammer E. Sclerotherapy of bleeding esophageal varices by means of endoscopy. Endoscopy 1978;10:7. 6. Terblanche J, Northover JMA, Bronman P, et al. A prospective evaluation of injection sclerotherapy in the treatment of acute bleeding from esophageal varices. Surg 1979;85:239. 7. Lewis J, Chung RS, Allison J. Sclerotherapy of esophageal varices. Ann Surg 1980;115:476. 8. Soehendra N. Fiberscopic sclerosing of esophageal varices. In: Demling L, Rosch W, eds. Operative Endoskpie Acron. Berlin, 1979. 9. Stelzner S, Lierse W. Der angiomuskulare Verschlub der Speiserohre. Langenbecks Arch Klin Chir 1981;321:35. 10. Clark AW, Westaby D, Wilk DP, et al. Prospective controlled trial of injection sclerotherapy in patient with cirrhosis and recent variceal hemorrhage. Lancet 1980;2:552. 11. Sivak MV Jr, Stout D, Skipper G. Endoscopic injection sclerosis of esophageal varices. Gastrointest Endosc 1981;27:52. 12. Paquet KJ, Feubner H. Sengstaken-tamponade or endoscopic sclerosis of the esophageal wall in acute variceal bleeding of patients with liver cirrhosis and portal hypertension. A prospective controlled randomized trial. Hepatology, 1983, in press. 13. MacDougall BRD, Westaby D, Theodossi A, Dawson JL, Williams R. Increased long-term survival in variceal hemorrhage using injection sclerotherapy. Lancet 1982;1:124. 14. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices-a prospective controlled randomized trial. Endoscopy 1982;14:4.
with the Federal Drug Administration; (4) case of injection through small gauge needles; (5) frequency of anaphylaxis; (6) side effects such as fever, pleural effusion, and chest pain; and (7) stability and shelf life of agent. The paravariceal agents (Table 1) are not readily available in the United States, nor is ethanolamine oleate. Fever, pleural effusions, and chest pains are more common with the fatty acid base sclerosants (morrhuate and ethanolamine) than with the aqueous agents (ethanol and tetradecyl). Ethanolamine is more viscous and more difficult to inject through a needle of 23-26 gauge than aqueous solutions. Anaphylactic reactions have been reported with the peripheral ve315
Table 1. Sclerosing agents. Generic drug Intravariceal Ethanol Sodium tetradecyl sulfate (Sotradecol) Ethanolamine oleate Sodium morrhuate Dextrose Diazepam (Valium) Cefazolin Thrombin Paravariceal Polidocanol (Aethoxysclerol) Liquid parafin Phenolized almond oil
Concentration (%)
Availability
33-95 0.5-1.5
US, Germany
5 5 50
UK
0.5-1
Germany
US, Germany
Germany
" Ubiquitous.
nous injection of morrhuate and ethanolamine, and some have been fatal. 1-3 Topical thrombin is made for topical, not intravenous, use. All the other intravariceal agents are available in sterile ampules or containers and are chemically stable. Although endoscopic injection sclerotherapy of esophageal varices has been used clinically for over 40 years,4 there are virtually no systemic comparative studies of sclerosing agents. In 1967, Blenkinsopp3 compared tetradecyl sulfate with 5% ethanolamine, using rat femoral veins. In that rat model, tetradecyl led to a higher rate of sclerosis than did ethanolamine. In mouse tail veins, Reiner 5 showed tetradecyl to be more thrombogenic than morrhuate. Other than these experiments, there has been very little scientific basis on which to choose the best sclerosant. To screen the promising and available sclerosing substances requires a large number of veins which can be both examined and resected. Such requirements obviously preclude systemic comparison in patients. Vein Response to Sclerosants
Using a reproducible model of canine portal hypertension,6 we systematically compared 14 substances for their ability to induce sclerosis in abdominal venous collaterals with intravenous administration. 7Also examined was the influence of physical factors such as vein size and contact time on efficacy of sclerosants. The most effective single agents (>60% of veins sclerosed) were 95% ethanol, 1.5% tetradecyl, and 5% ethanolamine. Ineffective single agents «25% sclerosis) were cefazolin, 50% dextrose, 24% ethanol, and the saline controls. 5% morrhuate, 47% ethanol, and 0.5% tetradecyl were of intermediate efficacy. Three different combinations of low concentrations of tetradecyl and ethanol were all at least 75% effective. The size of the vein did influence its sclerosability: smaller veins were slightly more likely to be sclerosed. Increasing 316
sclerosant contact time by vein compression above and below the injection site increased the effectiveness of the low concentration combinations, but not the single agents. The results indicate the sclerotherapy agents that should be further evaluated in canine and human esophageal varices. Effect of Sclerosants on Esophageal Varices in Dogs
In a canine model of esophageal varices, we compared nine sclerosing agents and combinations of agents to determine relative efficacy and safety.7 Varices were endoscopically injected intravariceally and followed weekly to determine rate of ulceration, erosion, and obliteration of the varix. Efficacy of sclerosis was defined as the ability to obliterate the varix after a single injection of the test sclerosant. Ten or more varices were injected with each agent (except 95% ethanol) and efficacy of sclerosis was expressed as a percent. Three groups of agents were defined. Agents statistically no more effective than saline control (group I) were cefazolin, 47% ethanol, 5% ethanol-. amine, and a combination of 0.5% tetradecyl plus thrombin plus 50% dextrose. Substances statistically more effective than saline injection (group II) were 1.5% sodium tetradecyl sulfate, 5% morrhuate, and a combination of 1% tetradecyl plus 32% ethanol and saline (TES). Two other agents with borderline efficacy (60 and 50%, respectively) compared with saline control (group III) were 95% ethanol and a combination of 0.75% tetradecyl plus 47% ethanol (TE). The effectiveness of sclerosants was inversely related to the frequency of esophageal damage. 95% ethanol was the most damaging with an 80% rate of severe ulceration. The frequency of ulceration with group II and III agents was 40% for 1.5% tetradecyl, 30% for morrhuate, 10% for TES, 80% for ethanol, and 0% for TE. Clinical Experience with Sclerosants
There are no randomized clinical trials of different sclerosing agents. However, Gibbert et al. B compared 5% morrhuate with 1.5% tetradecyl in similar patients and reported a higher incidence of esophageal ulcers, bleeding from ulcers, and deaths in the morrhuate group than the tetradecyl sclerosed patients. For an intravariceal technique we inject at each site up to 2 ml of TES (final concentration: 1% tetradecyl, 33% ethanol, and saline). For elective cases we inject up to 24 ml per session beginning circumferentially at the gastroesophageal junction and moving cephalad. Sclerotherapy is repeated every 4 to 7 days for three initial sessions, then once a month. For emergency cases we inject up to 50 ml initially and follow the same schedule or inject up to 24 ml and add another session within 48 hours. Emergency sclerotherapy and increased volume both correlate with more frequent esophageal ulcerations. GASTROINTESTINAL ENDOSCOPY
To be useful in clinical sclerotherapy, an agent must have a high sclerosis rate and low incidence of esophageal damage. Those two properties must be balanced and then considered with availability, cost, and ease of administration. In the present study, 95% ethanol caused too much damage for clinical use. The commercially available substances in the United States, 1.5% tetradecyl and 5% morrhuate, were effective, but damage was relatively frequent. In an attempt to maximize efficacy and minimize esophageal wall damage, we developed various combinations of low concentrations of tetradecyl and ethanol. TES proved slightly more effective than TE. Based upon the good efficacy (70%), low frequency of esophageal damage (10% ulcers), and availability, we have initiated clinical studies with TES. In our opinion, these data should assist clinicians who are evaluating or planning sclerotherapy trials.
VOLUME 29, NO. 4, 1983
REFERENCES 1. Lewis KM. Anaphylaxis due to sodium morrhuate. JAMA 1936;107:1298. 2. Shelley HJ. Allergic manifestations with injection treatment of varicose veins. JAMA 1939;112:1792-4. 3. Blenkinsopp WK. Comparison of tetradecyl sulfate of sodium with other sclerosants in rats. Br J Exp PathoI1968;49:197-201. 4. Crafoord C, Frenckner P. New surgical treatment of varicous veins of the esophagus. Acta Otolaryngol 1939;27:422-9. 5. Reiner L. The activity of anionic surface active compounds in producing vascular obliteration. Proc Soc Exp BioI Med 1946;62:49-54. 6. Jensen DM, Machicado GA, Tapia JI, et al. A reproducible canine model of esophageal varices. Gastroenterology 1983, in press. 7. Silpa ML, Jensen DM, Machicado GA, et al. Efficacy and safety of agents for variceal sclerotherapy (abstract). Gastrointest Endose 1982;28:152-3. 8. Gibbert V, Feinstat T, Burns M, Trudeau W. A comparison of the sclerosing agents sodium tetradecyl sulfate and sodium morrhuate in endoscopic injection sclerosis of esophageal varices (abstract). Gastrointest Endosc 1982;28:147.
317