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Experimental Control of Gastrointestinal Hemorrhage via the Endoscope: A New Era Dawns
Vol. 70, No.2 Printed in U.S.A.
1976 Copyright © 1976 by The Williains & Wilkins Co.
GASTROENTEROLOGY 70:272 ~277 ,
CLINICAL TRENDS AND TOPICS EXPERIMENTAL CONTROL OF GASTROINTESTINAL HEMORRHAGE VIA THE ENDOSCOPE: A NEW ERA DAWNS RONALD
M.
KATON,
Department of Medicine, Portland, Oregon
M.D. (Divi~ion
of Gastroenterology),
In 1870 John Tyndall demonstrated that light could be made to follow curves. He illuminated the interior of a tank of water and allowed a jet of water to escape from its side. The light was clearly seen to emerge and to follow the descending curve of the stream. 1 The birth of modern day flexible fiberoptic instruments occurred some 93 years later in 1963 when Hirschowitz 2 described the first fiberesophagoscope. In the last 12 years that has been a veritable explosion in fiberoptic endoscopy, and excellent instruments have become available for panendoscopy3-S (esophagogastroduodenoscopy), colonoscopy,6, 7 and cannulation of the biliary and pancreatic ducts. 8-1o Whereas diagnostic endoscopy is entering its adolescence, therapeutic endoscopy is still in its infancy. Only endoscopic polypectomyll and foreign body extraction l2 have been perfected sufficiently to be clinically applicable. Vaterian papillotomy l3 is being evaluated in Japan. Panendoscopy has now been clearly shown to be a safe and highly accurate method of diagnosis in the patient with acute upper gastrointestinal hemorrhage. 14-16 An exact etiological diagnosis has enabled the clinician to employ more selectively the techniques available, including antacids, nasogastric tubes, vasopressin infusion (by peripheral vein or selectively catheterized artery), balloon tamponade, or emergency operation. Unfortunately, none of the methods is entirely satisfactory. Antacids, although useful in prevention of stress ulcers, 17 cannot control active hemorrhage. Intravenous vasopressin, although of temporary benefit in perhaps 50% of patients with bleeding esophageal varices, 18 has significant hemodynamic side effects. 19 Selective intraarterial vasopressin in a well controlled study20 provided temporary control of both variceal and non-variceal bleeders, but had no effect on mortality. In addition, this technique requires considerable technical skill and expense and carries several risks including arrhythmia, acute myocardial infarction, bacteremia, embolization, thrombosis, and water retention with hyponatremia. 20 Balloon tamponade, although effective in up to 75 % of variceal bleeders, carries significant risk including esophageal necrosis and asphyxiation. 21 Emergency surgery in an acute gastrointestinal bleeder is associated with a very high mortality. Thus, despite early diagnosis now available in 90% of
Univ e r~ity
of Oregon Health Sciences Center,
acute bleeders, continued bleeding or early recurrence remains a major threat. Mortality has not been dramatically reduced, and runs between 4 15 and 8%.14 The endoscopist has become increasingly frustrated with his inability to control directly the observed bleeding lesion(s). Intensive research in many United States centers is presently evaluating several techniques for safe and effective direct transendoscopic control of active gastrointestinal hemorrhage. I will outline the various physical, electrical, and chemical modalities being tested with emphasis on the areas I believe are most promising. Pertinent research data already available will be described. Finally, I will try to set some guidelines for investigation in this important area and enter a strong plea for carefully controlled animal investigation before cautious application in humans.
Received August 20, 1975. Accepted September 3, 1975. 272
Experimental Modalities for Endoscopic Control of Hemorrhage (Table 1) Topical Agents Tissue adhesives. These remarkable substances set (harden) extremely rapidly from a liquid state by polymerization, evaporation of a solvent from the dispersed polymer, or a combination of both. Three of the most promising chemical groups include: (1) alkyl-2cyanoacrylates, 22,23 (2) polyurethane adhesives, 24 (3) epoxy resins. 25 Because the cyanoacrylates have been studied most extensively, most of the comments to follow will refer to this group of adhesives. The monomeric form is prepared from formaldehyde which is condensed with alkyl cyanoacetate to form alkyl-2cyanoacrylate polymers. Distillation of the polymer forms the monomeric alkyl-2-cyanoacrylate, which is a thin, colorless liquid. Figure 1 shows the setting reaction of the alkyl-2cyanoacrylate monomer. The chain growth polymerization of the monomer results in solidification. This is initiated by nucleophilic reagents, such as weak bases, water, or alcohoL 26 Because of the rapid setting (4 to 8 sec) and extreme strength of the ensuing bond, these polymers have obvious potential as hemostatic agents. Matsumot0 23 has had experience with these substances in traumatic combat wounds. Dotter et aL 27 injected isobutyl 2cyanoacrylate into the hypogastric artery of a patient
CLINICAL TRENDS AND TOPICS
February 1976 TABLE
1. Experimental modalities for endoscopic control of
hemorrhage I. Topical agents A. Tissue adhesives B. Adjunctive agents 1. Iced saline or water 2. Compressed air 3. Vasopressin 4. Norepinephrine, epinephrine 5. Prostaglandin E, II. Injected agents or other mechanical devices A. Norepinephrine (intramucosal) B. Sclerosing agents (intravariceai) C. Balloon tamponade D. Hemociips, suture devices III. Thermal agents A. Electrosurgery B. Laser photocoagulation C. Cryosurgery
H
C==N
I I C=C I I H C-OR II
H
TraceofB
o
l
(Initiator)
C==N
I I B-C-C G I I H
°
C-OR
CN
CN
I I~ B-CH - C - C H _C v 2 I 2 I C0 2 R
~ Monon",
Polymer (brittle solid)
C0 2 R
H<±lBO
(Termination)
CN
CN
I
I
B-CH - C - C H -C-H
I
I
°
Alkyl(=R)-2cyanoacrylate monomer (liquid)
2
Monomer (Exothermic)
2
I
+ BO
C0 2 R CO,R Low molecular weight polymer (powdery solid) FIG. 1. Setting reaction of the alkyl-2-cyanoacrylates. Courtesy of D.R. Charles (ed): Medical Engineering. Chicago, Year Book Medical Publishers, Inc., 1974, p 1124.
with massive pelvic hemorrhage. Bleeding ceased, but the patient died 3 days later of advanced carcinomatosis. Many limitations must be overcome before human application, however. First of all, certain of these monomers, especially methyl cyanoacrylate, have displayed considerable histotoxicity in the rat. 28 The higher homologues of cyanoacrylate such as N-butyl, isobutyl, and the monomer mixture of 95% heptyl and 5% methyl cyanoacrylate monomer markedly decrease histotoxicity but unfortunately have a prolonged period of biodegradability in tissue. 23 The threat of carcinogenesis is very real, since Oppenheimer et al. 29 in 1958 produced sarcomas in rats and mice by embedding plastic films subcutaneously in the abdominal wall. These authors found cellophane, polyethylene, nylon, Dacron, polymethyl methacrylate, polystyrene, polyvinyl chloride, Saran, silicone, and Vinyin N all induced tumor in varying degrees. There was a long latent period before
273
tumor development, usually 1 to 2 years. The problems of histotoxicity and carcinogenesis must be solved by suitable animal experiments before human investigation. Suitable aerosolized forms of monomer could then be applied under direct vision endoscopically. Excessive moisture or blood would have to be eliminated from the lesion(s) before application, because this would lead to an excess of powdery, low molecular weight polymers with poor cohesive strength (see fig. 1). The endoscopist would have to take suitable precautions against inadvertent contact with his eyes or skin. Despite the existing problems, the relatively low cost, potential ease of application, and the ability to coat all types of lesions and multiple lesions quickly makes these agents particularly attractive. Adjunctive agents given intragastrically. Although there have been no controlled studies with any of these agents, one or all of them may prove to cause temporary hemostasis. Kiselow et al.,30 in a small uncontrolled group of patients, noted that 7 of 13 (54%) massive bleeding episodes ceased after intragastric instillation of levarterenol (norepinephrine) 8 mg in 100 mg of saline. In addition to norepinephrine, iced saline, or water, vasopressin and prostaglandin E 131 may have an effect by decreasing mucosal blood flow. Compressed air may have a local drying effect. The agents would be relatively easily applied and safe for the endoscopist but side effects could occur. Saline overload would be detrimental to patients with congestive heart failure or cirrhosis. Excessive water would cause hyponatremia. Absorption of norepinephrine or vasopressin could produce systemic cardiovascular effects such as tachycardia, angina, or myocardial ischemia. Compressed air could produce explosion or air embolism. Despite their limitations and probably incomplete and temporary benefit, these agents may dry the mucosa sufficiently to allow the more permanent modalities such as tissue adhesives, electrocoagulation, and lasers to have their desired effect.
Injected Agents and Other Mechanical Devices Transendoscopic needles are now available which allow the injection of substances into the mucosa. Norepinephrine could reduce local blood supply around a lesion, but the threat of tissue necrosis due to this agent 32 would seem to make this hazardous. Sclerosing agents 33 such as ethylolamine oleate (Veristab) have met with some success in treating vericeal bleeding. Puncturing a varix with a needle is not esthetically appealing, however, and this procedure would be difficult in an acutely bleeding patient. Zimmon 34 has reported an instance in which tamponade with a transendoscopic balloon successfully controlled hemorrhage from duodenal ulcer. The difficulty in employing such a device, and its use in relatively few bleeding lesions, make it impractical for general use. Hemoclips are now available (Olympus Corporation of America) which can be applied via the endoscope to a bleeding vessel. These would require great skill to position and would not be applica-
274
CLINICAL TREN DS AND TOPICS
ble to bleeding from varices or diffuse lesions such as esophagitis, gastritis, or stress ulcers .
Thermal Agents Primary agents. 1. Electrosurgery. Modern electrosurgical units employ high frequency currents (1 million cycles per sec) to obtain a local tissue heating effect. Such currents may provide electrocutting (severing of tissue by a thin wire or blade electrode), electrocoagulation (heating, desiccation, and destruction of tissue using an energized ball), or both. Although similar thermal effects can be induced by lower frequencies, muscle and nerve stimulation (electrical shock) can occur below 100,000 cycles per sec. 3S Colonoscopic polypectomy utilizing high frequency currents has been accepted as a useful therapeutic procedure with a complication rate of only 0.9% for bleeding and 0.23% for perforation. 7 Only one death has been reported in 3793 reported cases. 4 Because of these statistics, and the ready availability of electrosurgical units, it may be tempting for the endoscopist to employ the coagulating electrode to actively bleeding patients . P app 36 used electrocoagulation in an uncontrolled series of 25 patients with various upper gastrointestinal bleeding lesions. 83 % were initially controlled, but 4 re-bled after coagulation to yield an over-all success rate of 18 out of 25 (70%). Blackwood and Silvis 37 attempted electrocoagulation in a patient with hemorrhagic gastritis , but he died. The authors suggested that the bleeding was increased by the procedure. Experimental work suggests extreme caution before further application to humans. Blackwood and Silvis 38 demonstrated the production of gastric ulcers in dogs via the brief application of the Bovie electrosurgical probe to the gastric mucosa. The dogs displayed intermittent bleeding through the period of ulceration, until healing (mean time 15.9 days). In another paper Blackwood and Silvis 39 describe difficulty in controlling the depth of electrosurgicallesions in dogs, even with very fine adjustments of amperage and application times of electrosurgical currents. They concluded by urging basic changes in electrosurgical generators so that better control of size and depth of lesions could be obtained. Papp et al. 40 noted transmural coagulation necrosis in canine gastric mucosa when the Cameron Miller power unit was set at 6.5 and 7 or when the duration was longer than 1 sec. They concluded that the safest electrocoagulation was at a setting of 5 or 5.5 for 1 sec. In addition to the risks to the patient of perforation, increasing hemorrhage, or producing a gastric ulcer, the endoscopist should be aware of the risks to himself including low frequency electrical shock and high frequency burns.41 On the basis of the data available, electrocoagulation would appear to have potential value, but clinical application should be deferred pending further animal work and modification of existing equipment in order to allow precise predictability of depth and extent of electrocoagulation induced lesions. 2. Laser photocoagulation. The major feature of the laser is its capacity to produce coherent light; that is a beam of light with parallel rays at a single wavelength
Vol. 70, N o. 2
(monochromatic) . Because these light rays can be fo cused to a very small spot, they permit extremely high· power densities in very small regions (high degree of focusability).42 Photons (smallest obtainable units of light energy) are absorbed by pigments in the underlying tissue, causing thermal interactions. The thermal damage which occurs is the basis of the coagulation of biological tissues (photocoagulation). 43 All laser systems have a stimulating external source, such as electricity, that acts as a pump. The lasing material (a rod of ruby or a gas-filled tube) is formed as a reflecting cavity so that the beam is fired through one partially reflective end of the cavity. The output power of the laser depends on the amplification of light radiation by the process of stimulated emission. Thus, the term laser (light amplification by stimulated emission of radiation). 42 Table 2 lists the four types of lasers which could be used for photocoagulation. Francois and Combie 42 provide a well written chapter on laser characteristics for those interested in more detail. Laser photocoagulation has been employed in several areas of medicine including ophthalmology (retinal detachment, hemorrhage, uveitis, choreoretinitis) ," tumor therapy (especially melanoma)"s and tattoo removal. 46 In 1967 Ketchon et al. 47 demonstrated that laser irradiation could produce small vessel thrombosis. In 1970 Goodale et al. 48 used an unfocused continuous wave carbon dioxide laser via a hollow rigid endoscope in an attempt to control bleeding from experimentally induced gastric erosions in dogs. Both mechanically induced abrasions and HCI jet erosions were observed to stop bleeding in 3 to 5 sec after laser application. The rate of bleeding in the 2-min control period before laser treatment was reduced by 87% in the post-treatment period . When killed 7 days later, all 14 dogs treated with the laser showed evidence of regenerating mucosa at the site of the experimentally produced lesions, and a thin laser-induced coagulum on the surface of the lesions . No dog was noted to have recurrent bleeding after treatment nor was blood noted in the stomach of any animal at autopsy. In 1975 Dwyer et al. 49 reported the coupling of a flexible fiberoptic filament to a fiberoptic endoscope . The filament transmitted a continuous wave argon ion laser at 4800 and 5145 A. In their experiment, erosions were created in the gastric mucosa of rats and dogs, with either scalpel incisions or multiple biopsy forcep bites. Laser photocoagulation was applied and continued until cessation of bleeding was observed. In dogs, venous oozing in an area 15 mm in diameter was observed to stop in under 30 sec with 350 mw of incident laser power. Arterial pumpers required up to 1.5 min at 500 mw. No quantitative blood loss measurements nor control pe ~ TABLE
1. 2. 3. 4.
2. Ty pes of lasers
Continuous wave gas lasers (Argon, Helium-neon, Krypton) Pulsed solid state lasers (Ruby, Neodymium) Burst laser (Pulsed argon laser) Dye lasers or liquid lasers
February 1976
CLINICAL TRENDS AND TOPICS
riods were reported. All 9 dogs employed survived without evidence of gastric perforation, and no histological studies were performed. Rat gastric mucosa, 48 hr after laser treatment, showed early healing of the scalpel induced ulceration. There was edema and a proteinaceous coagulum covering the mucosal edge of the ulcer. There was slight extravasation of red blood cells in the submucosa and slight inflammatory reaction in the tunica serosa. Although these experim~nts do not prove the efficacy or safety of laser photocoagulation, the authors have provided an important link between laser delivery and modern fiberoptic panendoscopy. Waitman et a1. 50 and Silverstein et a1. 51 have also reported successful coupling of argon laser delivery systems with fiberscopes . Waitman 50 produced paired gastric mucosal defects (8 to 10 mm in diameter) in dogs. The resulting bleeding continued for 1 hr or longer in control (non-laser treated) sites, whereas in lesions exposed to laser photocoagulation, bleeding ceased in only 2 to 3 min. Silverstein et a1. 51 report a 12-w (high energy) argon laser system which can photocoagulate a 20 mm 2 eroded area in 1 sec. Dogs with three induced gastric erosions (1.5 cm) were given 5 to 10 laser pulses of I-sec duration in two of the three lesions. The dogs were killed at 0, 4, 7, 10, and 14 days for histological study. Acutely the erosions (control) extended through only 1/ 2 of fundal gland thickness, whereas lasered erosions extended 2/:! of the fundal gland thickness. Both lasered and non-lasered lesions re-epithelialized in 4 to 7 days. However, in the lasered group fundal glands had not yet returned to the lasered areas after 2 weeks and small gaps in muscularis mucosa were noted beneath some lesions. Neither of these findings was seen in controls. Silverstein et a1. 51 also report an automatically. inserted filter which protects the examiner's eyes from laserinduced blindness. More extensive animal studies are needed to be certain of the safety of lasers with respect to the gastrointestinal tract and contiguous organs (heart, lungs, liver, spleen, etc.). Although it may ultimately prove effective and safe, it is relatively expensive and demanding in technical ability. The need for trained laser engineers and hazards to the endoscopist may limit its regular clinical application. 3. Cryosurgery. With this modality local tissue necrosis can be produced by rapidly achieved, profoundly low temperatures. Since 1963 experimentation has been performed at the Memorial Sloan-Kettering Cancer Center with the use of liquid nitrogen as the refrigerant. 52 Stainless steel probes were cooled to -80°C or lower and applied to certain tissues. By a repetition of freezing and cooling of tissue two or more times unique effects were achieved. Localized tissue necrosis appeared over a period of hours, becoming complete in from 1 to 3 days. A sharply demarcated slough developed with little surrounding inflammation. Histology of the necrotic area resembled an ischemic infarct with ghost cells. In 1 to 6 weeks the slough was discarded, leaving a clean granulating base which healed by re-epithelization. There was a striking absence of
275
significant bleeding during or after the cryosurgery, . perhaps attributable to rapid development of local capillary thrombosis. Fortunately, large arteries and veins seem quite resistant to cryonecrosis. Although most experiments were aimed at local destruction of various tumors, certain hemorrhagic conditions such as menometrorrhagia and bladder hemorrhage were treated with some success. Such steel probes or "cryojets" could theoretically be divised to be passed via the fiberoptic endoscope for direct application of liquid nitrogen. This modality seems worthy of further study in this regard.
Ideal Characteristics of Therapeutic Modality and Criteria for Evaluation Given this imposing array of possible therapeutic agents one needs to formulate certain "ideal" characteristics of the agent(s) being tested as well as criteria for evaluating effectiveness and safety. The method should be relatively inexpensive, readily available and relatively easily applied by the "average" endoscopist via existing or slightly modified endoscopes. Both the Olympus Corporation of America and American Cystoscope Makers, Inc. have prototype instruments with large channels (5 mm in diameter) . Such instruments would be necessary for many of the techniques to be tested. The therapeutic agent should be effective in most if not all of the major types of gastrointestinal bleeding. Therefore, the research employed should involve the experimental induction of as many types of gastrointestinallesions as is feasible . There presently exist methods to induce hemorrhagic gastritis, stress ulcer, chronic peptic ulcer, acute arterial bleeding, and esophageal varices. The procedure should be extensively tested in appropriate animals in a controlled fashion. The experimental design should include enough objective data to determine its efficacy in stopping hemorrhage. Gross measurements, clinical data, and laboratory parameters including radioactive chromium labeling 53 should be employed to assess blood loss. Follow-up examinations including endoscopy should be included to assess the duration of effectiveness and the gross nature of lesions produced by the modality as well as healing of experimentally induced or therapeutically induced lesions. Histological studies at several time intervals should be evaluated during the early post-treatment period (lst month), looking for the depth and nature of tissue injury and rate of healing. To obtain full thickness specimens of esophagus, stomach, and duodenum would involve sacrifice of animals . Injury to contiguous organs should be assessed by appropriate laboratory tests (i .e. , liver function, amylase, renal function) and autopsy studies. This might be particularly applicable to laser therapy. Late follow-up should exclude the possibility of carcinogenesis (especially tissue adhesives). Only after extensive animal experiments have conclusively found a new therapeutic agent to be superior to a control group, and free of severe short- or long-term morbidity and mortality should human investigation
276
CLINICAL TRENDS AND TOPICS
begin. The modality should be tested against a control group which would include one of the presently accepted methods of treatment for the particular lesion. For example, in bleeding esophageal varices the use of adhesives or laser photocoagulation might be compared to the Sengstaken-Blakemore tube. The same careful comparison as in animal studies should be made including autopsy study in the event of death. The endoscopist must be fully aware of all the hazards associated with the modality to prevent serious injury to himself or his technical assistants. Appropriate "failsafe" devices should be devised to prevent serious burns, electrical shock, eye injuries, and skin histotoxicity. Before application of the primary agent, topical application or infusion of an adjunctive agent may be necessary to obtain clear visibility of the bleeding site. Excessive moisture will especially impair the efficacy of tissue adhesives and electrocoagulation. Those agents though to affect mucosal blood flow should be quantitatively assessed by a technique such as aminopyrine clearance. 54 It is obvious that success in this area will only be accomplished through the close cooperation of the gastroenterologist, surgeon, pathologist, pharmacologist, physiologist, chemical and electrical engineer, and perhaps others. It is reasonable to believe that by 1980 at the latest the endoscopist will have available for routine use a safe, effective treatment for acute gastrointestinal hemorrhage. The controlled or noncontrolled use of any therapeutic modality in humans before thorough animal investigation would be counterproductive and should be discouraged. REFERENCES l. The endoscopic revolution ... a new era III diagnosis? Roche Medical Image, Summer 1961. 2. Hirschowitz BE: A fiberoptic flexible esophagoscope. Lancet 2:388, 1963 3. Belber JP: Endoscopic examination of the duodenal bulb: A comparison with x-ray. Gastroenterology 61:55-61, 1971 4. Shearman DTC, Warwick RR, McLeod IB, et al: Clinical evaluation of the Olympus duodenoscope. Lancet 1:726-729, 1971 5. Salmon PR, Brown P, Htut T, et al: Endoscopic examination of the duodenal bulb; Clinical evaluation of forward- and side-viewing fiberoptic systems in 200 cases. Gut 13: 170-175, 1972 6. Shinya H, Wolff W, Geffen A: Colonofiberoscopy-a new and valuable diagnostic modality. Gastroenterology 60:878, 1971 7. Overholt BF: Colonoscopy. A review. Gastroenterology 68: 1308-1320, 1975 8. Vennes, JA, Silvis SE: Endoscopic visualization of bile and pancreatic ducts. Gastrointest Endosc 18: 149-152, 1972 9. Cotton PB, Salmon PR, Beals JSM, et al: Endoscopic trans-papillary radiographs of pancreatic and bile ducts. Gastrointest Endosc 19:60-62, 1972 10. Katon RM, Lee TG, Parent JA, et al: Endoscopic retrograde cholangiopancreatography (ERCP)-experience with 100 cases. Am J Dig Dis 19:295-306, 1974 1l. Wolff WI, Shiny a H: Polypectomy via the fiberoptic clonoscope. N Engl J Med 288:329-332, 1973 12. Olsen H, Lawrence W, Bernstein R: Fiberendoscopic removal of foreign bodies from the upper gastrointestinal tract. Gastrointest Endosc 21:58-60, 1974 13. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphinc-
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terotomy of the ampulla of Vater. Gastrointest Endosc 20: 148-151, 1974 14. Katon RM, Smith FW: Panendoscopy in the early diagnosis of acute upper gastrointestinal bleeding. Gastroenterology 65:728-734, 1973 15. Cotton PB, Rosenberg MT, Waldrom RPI, et al: Early endoscopy of oesophagus, stomach and duodenal bulb in patients with haematemesis and melena. Br Med J 2:505-509, 1973 16. Davis FL, Graham DY: The source of hemorrhage in acute major upper gastrointestinal bleeding (abstr). Gastroenterology 68:A-46, 1975 17. Silen W: Stress ulcers. Viewpoints. on Digestive Disease 3:5,1971 18. Shaldon S, Sherlock S: The use of vasopressin (Pitressin) in the control of bleeding from oesopbageal varices. Lancet 2:222, 1960 19. Erickson S: Hemodynamic effects of vasopressin. Acta Chiurgica Scand 414:3, 1971 20. Conn HO, Ramsby GR, Storrer EH, et al: Intraarterial vasopressin in the treatment of upper gastrointestinal hemorrhage: A prospective controlled trial. Gastroenterology 68:211, 1974. 2l. Pitcher JL: Safety and effectiveness of the modified SengstakenBlakemore rube: A prospective study. Gastroenterology 61:291, 1971 22. Lowry ML: Synthetic adhesives-a new hemostatic agent. Arch Surg 60:793, 1950. 23. Matsumoto T, Hardaway PM, Heisterkamp A, et al: Higher homologous cyanoacrylate tissue adhesives in surgery of internal organs. Arch Surg 94:861, 1967 24. Macoomb RK: Polyurethane foam (Ostamer): Its use in experimental animals and in the investigation of tissue reactions. S Forum 11:454, 1960 25. Skeist I (ed): Handbook of Adhesives. New York, Reinhold Publishing Corp, 1962 26. Charles DR (ed): Surgical adhesives and coatings. In Medical Engineering. Chicago, Year Book Medical Publishers, Inc., 1974, 1123-1130 27. Dotter CT, Goldman ML, Rosch J: Instant selective arterial occlusion with isobutyl 2-cyanoacrylate. Rad 114:227-230, 1975. 28. Woodward SC, Herrman JB, Cameron JL, et al: Histotoxicity of cyanoacrylate tissue adhesive in the rat. Ann Surg 162: 113-121, 1964 29. Oppenheimer BS, Oppenheimer ET, Stout AP, et al: The latent period in carcinogenesis by plastics in rats and its relation to the presarcomatous stage. Cancer 11:204-213, 1958 30. Kiselow MC, Wagner M: Intragastric instillation of Levarterenol. Arch Surg 107:387-389, 1973 3l. Wilson DE, Levine RA: Decreased canine gastric mucosal blood flow induced by prostaglandin E,: A mechanism for its inhibitory effect on gastric secretion. Gastroenterology 56: 1268, 1969. 32. Friedberg CK: Diseases of the Heart. Philadelphia, W.B. Saunders Co., 1966 33. Johnston GW, Rodgers HW: A review of 15 years experience in the use of sclerotherapy in the control of acute haemorrhage from oesophageal varices. Br J Surg 60:797-800, 1973 34. Zimmon DS: A device for balloon tamponade of the duodenal bulb at endoscopy. Gastrointest Endosc 20:31-33, 1973 35. Curtiss LE: High frequency currents in endoscopy. Gastrointest Endosc 20:9-12, 1973 36. Papp JP: Electrocoagulation in upper gastrointestinal hemorrhage: A two year experience (abstr). Gastroenterology 68:A-183, 1975 37. Blackwood WD, Silvis SE: Electrocoagulation of hemorrhagic gastritis. Gastrointest Endosc 18:53-55, 1971 38. Blackwood WD, Silvis SE: Observations on the healing of gastric lesions produced by gastroscopic electrosurgery. Gastroenterology 64:370-374, 1973 39. Blackwood WD, Silvis SE: Standardization of electrosurgical lesions. Gastrointest Endosc 21:22-24, 1974.
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CLINICAL TRENDS AND TOPICS
40. Papp JP, Fox JM, Willis HS : Experimental electrocoagulation of dog gastric mucosa (abstr). Gastroenterology 68:A-183, 1975 41. Wald AS, Mozzia VDB, Spencer FC : Accidental burns associated with electrosurgery. JAMA 217:916-921, 1971 42. Ray CE (ed): Medical Engineering. Chapter 78. Chicago, Year Book Medical Publishing Co., 1974, p 1063-1065 43. Francois J: Symposium on light coagulation-Argon laser and Xenon arc. Baltimore, Williams & Wilkins, 1973 44. Yahr WZ, Strully KS: J Assoc Adv Med Instr 1:28, 1966. 45 . Goldman L: Melanoma with vesiculobullous metastatic lesions. Arch Derm 93:233-4, 1966 46. Goldman L, Rockwell J , Meyer R, et al: Laser treatment of tattoos. JAMA 201:163-166, 1967 47 . Ketcham AS, Hoye RC, Riggle GC : Asurgeon's appraisal of laser. Surg Clin North Am 47: 1249- 1263, 1967 48. Goodale RL, Okada A, Gonzales R, et al: Rapid endoscopic control of bleeding gastric erosions by laser radiation. Arch Surg 101:211-214, 1970
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49 . Dwyer RM, Haverback BJ, Bass M , et al : Laser-induced hemostasis in the canine stomach. JAMA 231-489-489, 1975. 50. Waitman AM, Spira I, Chrysanthou CP, et al: Application of fiberoptic-coupled argon laser in the control of experimentally produced gastric bleeding (abstr). Gastroenterology 68:A-192, 1975 51. Silverstein F, Rubin CE, Auth D: Fiberendoscopic control of experimental gastric bleeding by laser photocoagulation (abstr). Gastroenterology 68:A-189, 1975. 52. Cahan WG: Five years of cryosurgical experience: Benign and malignant tumors with hemorrhagic conditions. In Cryosurgery. Edited by "Rand RW, Renfret AP, vonLeden H . Springfield, Ill., Charles C Thomas, 1968, p 358-409 53. Gray ST, Sterling K: The taggin of red cells and plasma proteins with radioactive chromium . J Clin Invest 29:1604, 1950 54. Jacobson ED, Linford RH, Grossman MI: Gastric secretion in relation to mucosal blood flow studied by a clearance technique. J Clin Invest 45:1-13, 1966.
1976 Copyright © 1976 by The Williains & Wilkins Co.
GASTROENTEROLOGY 70:272 ~277 ,
CLINICAL TRENDS AND TOPICS EXPERIMENTAL CONTROL OF GASTROINTESTINAL HEMORRHAGE VIA THE ENDOSCOPE: A NEW ERA DAWNS RONALD
M.
KATON,
Department of Medicine, Portland, Oregon
M.D. (Divi~ion
of Gastroenterology),
In 1870 John Tyndall demonstrated that light could be made to follow curves. He illuminated the interior of a tank of water and allowed a jet of water to escape from its side. The light was clearly seen to emerge and to follow the descending curve of the stream. 1 The birth of modern day flexible fiberoptic instruments occurred some 93 years later in 1963 when Hirschowitz 2 described the first fiberesophagoscope. In the last 12 years that has been a veritable explosion in fiberoptic endoscopy, and excellent instruments have become available for panendoscopy3-S (esophagogastroduodenoscopy), colonoscopy,6, 7 and cannulation of the biliary and pancreatic ducts. 8-1o Whereas diagnostic endoscopy is entering its adolescence, therapeutic endoscopy is still in its infancy. Only endoscopic polypectomyll and foreign body extraction l2 have been perfected sufficiently to be clinically applicable. Vaterian papillotomy l3 is being evaluated in Japan. Panendoscopy has now been clearly shown to be a safe and highly accurate method of diagnosis in the patient with acute upper gastrointestinal hemorrhage. 14-16 An exact etiological diagnosis has enabled the clinician to employ more selectively the techniques available, including antacids, nasogastric tubes, vasopressin infusion (by peripheral vein or selectively catheterized artery), balloon tamponade, or emergency operation. Unfortunately, none of the methods is entirely satisfactory. Antacids, although useful in prevention of stress ulcers, 17 cannot control active hemorrhage. Intravenous vasopressin, although of temporary benefit in perhaps 50% of patients with bleeding esophageal varices, 18 has significant hemodynamic side effects. 19 Selective intraarterial vasopressin in a well controlled study20 provided temporary control of both variceal and non-variceal bleeders, but had no effect on mortality. In addition, this technique requires considerable technical skill and expense and carries several risks including arrhythmia, acute myocardial infarction, bacteremia, embolization, thrombosis, and water retention with hyponatremia. 20 Balloon tamponade, although effective in up to 75 % of variceal bleeders, carries significant risk including esophageal necrosis and asphyxiation. 21 Emergency surgery in an acute gastrointestinal bleeder is associated with a very high mortality. Thus, despite early diagnosis now available in 90% of
Univ e r~ity
of Oregon Health Sciences Center,
acute bleeders, continued bleeding or early recurrence remains a major threat. Mortality has not been dramatically reduced, and runs between 4 15 and 8%.14 The endoscopist has become increasingly frustrated with his inability to control directly the observed bleeding lesion(s). Intensive research in many United States centers is presently evaluating several techniques for safe and effective direct transendoscopic control of active gastrointestinal hemorrhage. I will outline the various physical, electrical, and chemical modalities being tested with emphasis on the areas I believe are most promising. Pertinent research data already available will be described. Finally, I will try to set some guidelines for investigation in this important area and enter a strong plea for carefully controlled animal investigation before cautious application in humans.
Received August 20, 1975. Accepted September 3, 1975. 272
Experimental Modalities for Endoscopic Control of Hemorrhage (Table 1) Topical Agents Tissue adhesives. These remarkable substances set (harden) extremely rapidly from a liquid state by polymerization, evaporation of a solvent from the dispersed polymer, or a combination of both. Three of the most promising chemical groups include: (1) alkyl-2cyanoacrylates, 22,23 (2) polyurethane adhesives, 24 (3) epoxy resins. 25 Because the cyanoacrylates have been studied most extensively, most of the comments to follow will refer to this group of adhesives. The monomeric form is prepared from formaldehyde which is condensed with alkyl cyanoacetate to form alkyl-2cyanoacrylate polymers. Distillation of the polymer forms the monomeric alkyl-2-cyanoacrylate, which is a thin, colorless liquid. Figure 1 shows the setting reaction of the alkyl-2cyanoacrylate monomer. The chain growth polymerization of the monomer results in solidification. This is initiated by nucleophilic reagents, such as weak bases, water, or alcohoL 26 Because of the rapid setting (4 to 8 sec) and extreme strength of the ensuing bond, these polymers have obvious potential as hemostatic agents. Matsumot0 23 has had experience with these substances in traumatic combat wounds. Dotter et aL 27 injected isobutyl 2cyanoacrylate into the hypogastric artery of a patient
CLINICAL TRENDS AND TOPICS
February 1976 TABLE
1. Experimental modalities for endoscopic control of
hemorrhage I. Topical agents A. Tissue adhesives B. Adjunctive agents 1. Iced saline or water 2. Compressed air 3. Vasopressin 4. Norepinephrine, epinephrine 5. Prostaglandin E, II. Injected agents or other mechanical devices A. Norepinephrine (intramucosal) B. Sclerosing agents (intravariceai) C. Balloon tamponade D. Hemociips, suture devices III. Thermal agents A. Electrosurgery B. Laser photocoagulation C. Cryosurgery
H
C==N
I I C=C I I H C-OR II
H
TraceofB
o
l
(Initiator)
C==N
I I B-C-C G I I H
°
C-OR
CN
CN
I I~ B-CH - C - C H _C v 2 I 2 I C0 2 R
~ Monon",
Polymer (brittle solid)
C0 2 R
H<±lBO
(Termination)
CN
CN
I
I
B-CH - C - C H -C-H
I
I
°
Alkyl(=R)-2cyanoacrylate monomer (liquid)
2
Monomer (Exothermic)
2
I
+ BO
C0 2 R CO,R Low molecular weight polymer (powdery solid) FIG. 1. Setting reaction of the alkyl-2-cyanoacrylates. Courtesy of D.R. Charles (ed): Medical Engineering. Chicago, Year Book Medical Publishers, Inc., 1974, p 1124.
with massive pelvic hemorrhage. Bleeding ceased, but the patient died 3 days later of advanced carcinomatosis. Many limitations must be overcome before human application, however. First of all, certain of these monomers, especially methyl cyanoacrylate, have displayed considerable histotoxicity in the rat. 28 The higher homologues of cyanoacrylate such as N-butyl, isobutyl, and the monomer mixture of 95% heptyl and 5% methyl cyanoacrylate monomer markedly decrease histotoxicity but unfortunately have a prolonged period of biodegradability in tissue. 23 The threat of carcinogenesis is very real, since Oppenheimer et al. 29 in 1958 produced sarcomas in rats and mice by embedding plastic films subcutaneously in the abdominal wall. These authors found cellophane, polyethylene, nylon, Dacron, polymethyl methacrylate, polystyrene, polyvinyl chloride, Saran, silicone, and Vinyin N all induced tumor in varying degrees. There was a long latent period before
273
tumor development, usually 1 to 2 years. The problems of histotoxicity and carcinogenesis must be solved by suitable animal experiments before human investigation. Suitable aerosolized forms of monomer could then be applied under direct vision endoscopically. Excessive moisture or blood would have to be eliminated from the lesion(s) before application, because this would lead to an excess of powdery, low molecular weight polymers with poor cohesive strength (see fig. 1). The endoscopist would have to take suitable precautions against inadvertent contact with his eyes or skin. Despite the existing problems, the relatively low cost, potential ease of application, and the ability to coat all types of lesions and multiple lesions quickly makes these agents particularly attractive. Adjunctive agents given intragastrically. Although there have been no controlled studies with any of these agents, one or all of them may prove to cause temporary hemostasis. Kiselow et al.,30 in a small uncontrolled group of patients, noted that 7 of 13 (54%) massive bleeding episodes ceased after intragastric instillation of levarterenol (norepinephrine) 8 mg in 100 mg of saline. In addition to norepinephrine, iced saline, or water, vasopressin and prostaglandin E 131 may have an effect by decreasing mucosal blood flow. Compressed air may have a local drying effect. The agents would be relatively easily applied and safe for the endoscopist but side effects could occur. Saline overload would be detrimental to patients with congestive heart failure or cirrhosis. Excessive water would cause hyponatremia. Absorption of norepinephrine or vasopressin could produce systemic cardiovascular effects such as tachycardia, angina, or myocardial ischemia. Compressed air could produce explosion or air embolism. Despite their limitations and probably incomplete and temporary benefit, these agents may dry the mucosa sufficiently to allow the more permanent modalities such as tissue adhesives, electrocoagulation, and lasers to have their desired effect.
Injected Agents and Other Mechanical Devices Transendoscopic needles are now available which allow the injection of substances into the mucosa. Norepinephrine could reduce local blood supply around a lesion, but the threat of tissue necrosis due to this agent 32 would seem to make this hazardous. Sclerosing agents 33 such as ethylolamine oleate (Veristab) have met with some success in treating vericeal bleeding. Puncturing a varix with a needle is not esthetically appealing, however, and this procedure would be difficult in an acutely bleeding patient. Zimmon 34 has reported an instance in which tamponade with a transendoscopic balloon successfully controlled hemorrhage from duodenal ulcer. The difficulty in employing such a device, and its use in relatively few bleeding lesions, make it impractical for general use. Hemoclips are now available (Olympus Corporation of America) which can be applied via the endoscope to a bleeding vessel. These would require great skill to position and would not be applica-
274
CLINICAL TREN DS AND TOPICS
ble to bleeding from varices or diffuse lesions such as esophagitis, gastritis, or stress ulcers .
Thermal Agents Primary agents. 1. Electrosurgery. Modern electrosurgical units employ high frequency currents (1 million cycles per sec) to obtain a local tissue heating effect. Such currents may provide electrocutting (severing of tissue by a thin wire or blade electrode), electrocoagulation (heating, desiccation, and destruction of tissue using an energized ball), or both. Although similar thermal effects can be induced by lower frequencies, muscle and nerve stimulation (electrical shock) can occur below 100,000 cycles per sec. 3S Colonoscopic polypectomy utilizing high frequency currents has been accepted as a useful therapeutic procedure with a complication rate of only 0.9% for bleeding and 0.23% for perforation. 7 Only one death has been reported in 3793 reported cases. 4 Because of these statistics, and the ready availability of electrosurgical units, it may be tempting for the endoscopist to employ the coagulating electrode to actively bleeding patients . P app 36 used electrocoagulation in an uncontrolled series of 25 patients with various upper gastrointestinal bleeding lesions. 83 % were initially controlled, but 4 re-bled after coagulation to yield an over-all success rate of 18 out of 25 (70%). Blackwood and Silvis 37 attempted electrocoagulation in a patient with hemorrhagic gastritis , but he died. The authors suggested that the bleeding was increased by the procedure. Experimental work suggests extreme caution before further application to humans. Blackwood and Silvis 38 demonstrated the production of gastric ulcers in dogs via the brief application of the Bovie electrosurgical probe to the gastric mucosa. The dogs displayed intermittent bleeding through the period of ulceration, until healing (mean time 15.9 days). In another paper Blackwood and Silvis 39 describe difficulty in controlling the depth of electrosurgicallesions in dogs, even with very fine adjustments of amperage and application times of electrosurgical currents. They concluded by urging basic changes in electrosurgical generators so that better control of size and depth of lesions could be obtained. Papp et al. 40 noted transmural coagulation necrosis in canine gastric mucosa when the Cameron Miller power unit was set at 6.5 and 7 or when the duration was longer than 1 sec. They concluded that the safest electrocoagulation was at a setting of 5 or 5.5 for 1 sec. In addition to the risks to the patient of perforation, increasing hemorrhage, or producing a gastric ulcer, the endoscopist should be aware of the risks to himself including low frequency electrical shock and high frequency burns.41 On the basis of the data available, electrocoagulation would appear to have potential value, but clinical application should be deferred pending further animal work and modification of existing equipment in order to allow precise predictability of depth and extent of electrocoagulation induced lesions. 2. Laser photocoagulation. The major feature of the laser is its capacity to produce coherent light; that is a beam of light with parallel rays at a single wavelength
Vol. 70, N o. 2
(monochromatic) . Because these light rays can be fo cused to a very small spot, they permit extremely high· power densities in very small regions (high degree of focusability).42 Photons (smallest obtainable units of light energy) are absorbed by pigments in the underlying tissue, causing thermal interactions. The thermal damage which occurs is the basis of the coagulation of biological tissues (photocoagulation). 43 All laser systems have a stimulating external source, such as electricity, that acts as a pump. The lasing material (a rod of ruby or a gas-filled tube) is formed as a reflecting cavity so that the beam is fired through one partially reflective end of the cavity. The output power of the laser depends on the amplification of light radiation by the process of stimulated emission. Thus, the term laser (light amplification by stimulated emission of radiation). 42 Table 2 lists the four types of lasers which could be used for photocoagulation. Francois and Combie 42 provide a well written chapter on laser characteristics for those interested in more detail. Laser photocoagulation has been employed in several areas of medicine including ophthalmology (retinal detachment, hemorrhage, uveitis, choreoretinitis) ," tumor therapy (especially melanoma)"s and tattoo removal. 46 In 1967 Ketchon et al. 47 demonstrated that laser irradiation could produce small vessel thrombosis. In 1970 Goodale et al. 48 used an unfocused continuous wave carbon dioxide laser via a hollow rigid endoscope in an attempt to control bleeding from experimentally induced gastric erosions in dogs. Both mechanically induced abrasions and HCI jet erosions were observed to stop bleeding in 3 to 5 sec after laser application. The rate of bleeding in the 2-min control period before laser treatment was reduced by 87% in the post-treatment period . When killed 7 days later, all 14 dogs treated with the laser showed evidence of regenerating mucosa at the site of the experimentally produced lesions, and a thin laser-induced coagulum on the surface of the lesions . No dog was noted to have recurrent bleeding after treatment nor was blood noted in the stomach of any animal at autopsy. In 1975 Dwyer et al. 49 reported the coupling of a flexible fiberoptic filament to a fiberoptic endoscope . The filament transmitted a continuous wave argon ion laser at 4800 and 5145 A. In their experiment, erosions were created in the gastric mucosa of rats and dogs, with either scalpel incisions or multiple biopsy forcep bites. Laser photocoagulation was applied and continued until cessation of bleeding was observed. In dogs, venous oozing in an area 15 mm in diameter was observed to stop in under 30 sec with 350 mw of incident laser power. Arterial pumpers required up to 1.5 min at 500 mw. No quantitative blood loss measurements nor control pe ~ TABLE
1. 2. 3. 4.
2. Ty pes of lasers
Continuous wave gas lasers (Argon, Helium-neon, Krypton) Pulsed solid state lasers (Ruby, Neodymium) Burst laser (Pulsed argon laser) Dye lasers or liquid lasers
February 1976
CLINICAL TRENDS AND TOPICS
riods were reported. All 9 dogs employed survived without evidence of gastric perforation, and no histological studies were performed. Rat gastric mucosa, 48 hr after laser treatment, showed early healing of the scalpel induced ulceration. There was edema and a proteinaceous coagulum covering the mucosal edge of the ulcer. There was slight extravasation of red blood cells in the submucosa and slight inflammatory reaction in the tunica serosa. Although these experim~nts do not prove the efficacy or safety of laser photocoagulation, the authors have provided an important link between laser delivery and modern fiberoptic panendoscopy. Waitman et a1. 50 and Silverstein et a1. 51 have also reported successful coupling of argon laser delivery systems with fiberscopes . Waitman 50 produced paired gastric mucosal defects (8 to 10 mm in diameter) in dogs. The resulting bleeding continued for 1 hr or longer in control (non-laser treated) sites, whereas in lesions exposed to laser photocoagulation, bleeding ceased in only 2 to 3 min. Silverstein et a1. 51 report a 12-w (high energy) argon laser system which can photocoagulate a 20 mm 2 eroded area in 1 sec. Dogs with three induced gastric erosions (1.5 cm) were given 5 to 10 laser pulses of I-sec duration in two of the three lesions. The dogs were killed at 0, 4, 7, 10, and 14 days for histological study. Acutely the erosions (control) extended through only 1/ 2 of fundal gland thickness, whereas lasered erosions extended 2/:! of the fundal gland thickness. Both lasered and non-lasered lesions re-epithelialized in 4 to 7 days. However, in the lasered group fundal glands had not yet returned to the lasered areas after 2 weeks and small gaps in muscularis mucosa were noted beneath some lesions. Neither of these findings was seen in controls. Silverstein et a1. 51 also report an automatically. inserted filter which protects the examiner's eyes from laserinduced blindness. More extensive animal studies are needed to be certain of the safety of lasers with respect to the gastrointestinal tract and contiguous organs (heart, lungs, liver, spleen, etc.). Although it may ultimately prove effective and safe, it is relatively expensive and demanding in technical ability. The need for trained laser engineers and hazards to the endoscopist may limit its regular clinical application. 3. Cryosurgery. With this modality local tissue necrosis can be produced by rapidly achieved, profoundly low temperatures. Since 1963 experimentation has been performed at the Memorial Sloan-Kettering Cancer Center with the use of liquid nitrogen as the refrigerant. 52 Stainless steel probes were cooled to -80°C or lower and applied to certain tissues. By a repetition of freezing and cooling of tissue two or more times unique effects were achieved. Localized tissue necrosis appeared over a period of hours, becoming complete in from 1 to 3 days. A sharply demarcated slough developed with little surrounding inflammation. Histology of the necrotic area resembled an ischemic infarct with ghost cells. In 1 to 6 weeks the slough was discarded, leaving a clean granulating base which healed by re-epithelization. There was a striking absence of
275
significant bleeding during or after the cryosurgery, . perhaps attributable to rapid development of local capillary thrombosis. Fortunately, large arteries and veins seem quite resistant to cryonecrosis. Although most experiments were aimed at local destruction of various tumors, certain hemorrhagic conditions such as menometrorrhagia and bladder hemorrhage were treated with some success. Such steel probes or "cryojets" could theoretically be divised to be passed via the fiberoptic endoscope for direct application of liquid nitrogen. This modality seems worthy of further study in this regard.
Ideal Characteristics of Therapeutic Modality and Criteria for Evaluation Given this imposing array of possible therapeutic agents one needs to formulate certain "ideal" characteristics of the agent(s) being tested as well as criteria for evaluating effectiveness and safety. The method should be relatively inexpensive, readily available and relatively easily applied by the "average" endoscopist via existing or slightly modified endoscopes. Both the Olympus Corporation of America and American Cystoscope Makers, Inc. have prototype instruments with large channels (5 mm in diameter) . Such instruments would be necessary for many of the techniques to be tested. The therapeutic agent should be effective in most if not all of the major types of gastrointestinal bleeding. Therefore, the research employed should involve the experimental induction of as many types of gastrointestinallesions as is feasible . There presently exist methods to induce hemorrhagic gastritis, stress ulcer, chronic peptic ulcer, acute arterial bleeding, and esophageal varices. The procedure should be extensively tested in appropriate animals in a controlled fashion. The experimental design should include enough objective data to determine its efficacy in stopping hemorrhage. Gross measurements, clinical data, and laboratory parameters including radioactive chromium labeling 53 should be employed to assess blood loss. Follow-up examinations including endoscopy should be included to assess the duration of effectiveness and the gross nature of lesions produced by the modality as well as healing of experimentally induced or therapeutically induced lesions. Histological studies at several time intervals should be evaluated during the early post-treatment period (lst month), looking for the depth and nature of tissue injury and rate of healing. To obtain full thickness specimens of esophagus, stomach, and duodenum would involve sacrifice of animals . Injury to contiguous organs should be assessed by appropriate laboratory tests (i .e. , liver function, amylase, renal function) and autopsy studies. This might be particularly applicable to laser therapy. Late follow-up should exclude the possibility of carcinogenesis (especially tissue adhesives). Only after extensive animal experiments have conclusively found a new therapeutic agent to be superior to a control group, and free of severe short- or long-term morbidity and mortality should human investigation
276
CLINICAL TRENDS AND TOPICS
begin. The modality should be tested against a control group which would include one of the presently accepted methods of treatment for the particular lesion. For example, in bleeding esophageal varices the use of adhesives or laser photocoagulation might be compared to the Sengstaken-Blakemore tube. The same careful comparison as in animal studies should be made including autopsy study in the event of death. The endoscopist must be fully aware of all the hazards associated with the modality to prevent serious injury to himself or his technical assistants. Appropriate "failsafe" devices should be devised to prevent serious burns, electrical shock, eye injuries, and skin histotoxicity. Before application of the primary agent, topical application or infusion of an adjunctive agent may be necessary to obtain clear visibility of the bleeding site. Excessive moisture will especially impair the efficacy of tissue adhesives and electrocoagulation. Those agents though to affect mucosal blood flow should be quantitatively assessed by a technique such as aminopyrine clearance. 54 It is obvious that success in this area will only be accomplished through the close cooperation of the gastroenterologist, surgeon, pathologist, pharmacologist, physiologist, chemical and electrical engineer, and perhaps others. It is reasonable to believe that by 1980 at the latest the endoscopist will have available for routine use a safe, effective treatment for acute gastrointestinal hemorrhage. The controlled or noncontrolled use of any therapeutic modality in humans before thorough animal investigation would be counterproductive and should be discouraged. REFERENCES l. The endoscopic revolution ... a new era III diagnosis? Roche Medical Image, Summer 1961. 2. Hirschowitz BE: A fiberoptic flexible esophagoscope. Lancet 2:388, 1963 3. Belber JP: Endoscopic examination of the duodenal bulb: A comparison with x-ray. Gastroenterology 61:55-61, 1971 4. Shearman DTC, Warwick RR, McLeod IB, et al: Clinical evaluation of the Olympus duodenoscope. Lancet 1:726-729, 1971 5. Salmon PR, Brown P, Htut T, et al: Endoscopic examination of the duodenal bulb; Clinical evaluation of forward- and side-viewing fiberoptic systems in 200 cases. Gut 13: 170-175, 1972 6. Shinya H, Wolff W, Geffen A: Colonofiberoscopy-a new and valuable diagnostic modality. Gastroenterology 60:878, 1971 7. Overholt BF: Colonoscopy. A review. Gastroenterology 68: 1308-1320, 1975 8. Vennes, JA, Silvis SE: Endoscopic visualization of bile and pancreatic ducts. Gastrointest Endosc 18: 149-152, 1972 9. Cotton PB, Salmon PR, Beals JSM, et al: Endoscopic trans-papillary radiographs of pancreatic and bile ducts. Gastrointest Endosc 19:60-62, 1972 10. Katon RM, Lee TG, Parent JA, et al: Endoscopic retrograde cholangiopancreatography (ERCP)-experience with 100 cases. Am J Dig Dis 19:295-306, 1974 1l. Wolff WI, Shiny a H: Polypectomy via the fiberoptic clonoscope. N Engl J Med 288:329-332, 1973 12. Olsen H, Lawrence W, Bernstein R: Fiberendoscopic removal of foreign bodies from the upper gastrointestinal tract. Gastrointest Endosc 21:58-60, 1974 13. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphinc-
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terotomy of the ampulla of Vater. Gastrointest Endosc 20: 148-151, 1974 14. Katon RM, Smith FW: Panendoscopy in the early diagnosis of acute upper gastrointestinal bleeding. Gastroenterology 65:728-734, 1973 15. Cotton PB, Rosenberg MT, Waldrom RPI, et al: Early endoscopy of oesophagus, stomach and duodenal bulb in patients with haematemesis and melena. Br Med J 2:505-509, 1973 16. Davis FL, Graham DY: The source of hemorrhage in acute major upper gastrointestinal bleeding (abstr). Gastroenterology 68:A-46, 1975 17. Silen W: Stress ulcers. Viewpoints. on Digestive Disease 3:5,1971 18. Shaldon S, Sherlock S: The use of vasopressin (Pitressin) in the control of bleeding from oesopbageal varices. Lancet 2:222, 1960 19. Erickson S: Hemodynamic effects of vasopressin. Acta Chiurgica Scand 414:3, 1971 20. Conn HO, Ramsby GR, Storrer EH, et al: Intraarterial vasopressin in the treatment of upper gastrointestinal hemorrhage: A prospective controlled trial. Gastroenterology 68:211, 1974. 2l. Pitcher JL: Safety and effectiveness of the modified SengstakenBlakemore rube: A prospective study. Gastroenterology 61:291, 1971 22. Lowry ML: Synthetic adhesives-a new hemostatic agent. Arch Surg 60:793, 1950. 23. Matsumoto T, Hardaway PM, Heisterkamp A, et al: Higher homologous cyanoacrylate tissue adhesives in surgery of internal organs. Arch Surg 94:861, 1967 24. Macoomb RK: Polyurethane foam (Ostamer): Its use in experimental animals and in the investigation of tissue reactions. S Forum 11:454, 1960 25. Skeist I (ed): Handbook of Adhesives. New York, Reinhold Publishing Corp, 1962 26. Charles DR (ed): Surgical adhesives and coatings. In Medical Engineering. Chicago, Year Book Medical Publishers, Inc., 1974, 1123-1130 27. Dotter CT, Goldman ML, Rosch J: Instant selective arterial occlusion with isobutyl 2-cyanoacrylate. Rad 114:227-230, 1975. 28. Woodward SC, Herrman JB, Cameron JL, et al: Histotoxicity of cyanoacrylate tissue adhesive in the rat. Ann Surg 162: 113-121, 1964 29. Oppenheimer BS, Oppenheimer ET, Stout AP, et al: The latent period in carcinogenesis by plastics in rats and its relation to the presarcomatous stage. Cancer 11:204-213, 1958 30. Kiselow MC, Wagner M: Intragastric instillation of Levarterenol. Arch Surg 107:387-389, 1973 3l. Wilson DE, Levine RA: Decreased canine gastric mucosal blood flow induced by prostaglandin E,: A mechanism for its inhibitory effect on gastric secretion. Gastroenterology 56: 1268, 1969. 32. Friedberg CK: Diseases of the Heart. Philadelphia, W.B. Saunders Co., 1966 33. Johnston GW, Rodgers HW: A review of 15 years experience in the use of sclerotherapy in the control of acute haemorrhage from oesophageal varices. Br J Surg 60:797-800, 1973 34. Zimmon DS: A device for balloon tamponade of the duodenal bulb at endoscopy. Gastrointest Endosc 20:31-33, 1973 35. Curtiss LE: High frequency currents in endoscopy. Gastrointest Endosc 20:9-12, 1973 36. Papp JP: Electrocoagulation in upper gastrointestinal hemorrhage: A two year experience (abstr). Gastroenterology 68:A-183, 1975 37. Blackwood WD, Silvis SE: Electrocoagulation of hemorrhagic gastritis. Gastrointest Endosc 18:53-55, 1971 38. Blackwood WD, Silvis SE: Observations on the healing of gastric lesions produced by gastroscopic electrosurgery. Gastroenterology 64:370-374, 1973 39. Blackwood WD, Silvis SE: Standardization of electrosurgical lesions. Gastrointest Endosc 21:22-24, 1974.
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CLINICAL TRENDS AND TOPICS
40. Papp JP, Fox JM, Willis HS : Experimental electrocoagulation of dog gastric mucosa (abstr). Gastroenterology 68:A-183, 1975 41. Wald AS, Mozzia VDB, Spencer FC : Accidental burns associated with electrosurgery. JAMA 217:916-921, 1971 42. Ray CE (ed): Medical Engineering. Chapter 78. Chicago, Year Book Medical Publishing Co., 1974, p 1063-1065 43. Francois J: Symposium on light coagulation-Argon laser and Xenon arc. Baltimore, Williams & Wilkins, 1973 44. Yahr WZ, Strully KS: J Assoc Adv Med Instr 1:28, 1966. 45 . Goldman L: Melanoma with vesiculobullous metastatic lesions. Arch Derm 93:233-4, 1966 46. Goldman L, Rockwell J , Meyer R, et al: Laser treatment of tattoos. JAMA 201:163-166, 1967 47 . Ketcham AS, Hoye RC, Riggle GC : Asurgeon's appraisal of laser. Surg Clin North Am 47: 1249- 1263, 1967 48. Goodale RL, Okada A, Gonzales R, et al: Rapid endoscopic control of bleeding gastric erosions by laser radiation. Arch Surg 101:211-214, 1970
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49 . Dwyer RM, Haverback BJ, Bass M , et al : Laser-induced hemostasis in the canine stomach. JAMA 231-489-489, 1975. 50. Waitman AM, Spira I, Chrysanthou CP, et al: Application of fiberoptic-coupled argon laser in the control of experimentally produced gastric bleeding (abstr). Gastroenterology 68:A-192, 1975 51. Silverstein F, Rubin CE, Auth D: Fiberendoscopic control of experimental gastric bleeding by laser photocoagulation (abstr). Gastroenterology 68:A-189, 1975. 52. Cahan WG: Five years of cryosurgical experience: Benign and malignant tumors with hemorrhagic conditions. In Cryosurgery. Edited by "Rand RW, Renfret AP, vonLeden H . Springfield, Ill., Charles C Thomas, 1968, p 358-409 53. Gray ST, Sterling K: The taggin of red cells and plasma proteins with radioactive chromium . J Clin Invest 29:1604, 1950 54. Jacobson ED, Linford RH, Grossman MI: Gastric secretion in relation to mucosal blood flow studied by a clearance technique. J Clin Invest 45:1-13, 1966.