Postgrad Med J (1991) 67, 606 - 612 © The Fellowship of Postgraduate Medicine, 1991

Review article

Bleeding peptic ulcer - endoscopic and pharmacologicalmanagement

S.C. Jones and A.T.R. Axon

Gastroenterology Unit, The General Infirmary, Leeds LSJ 3EX, UK.

Introduction

Upper gastrointestinal (GI) bleeding is a commonemergency, there is an annual incidence of 90patients per 100,000 population, ofwhom approxi-mately half are bleeding from duodenal or gastriculcer.

In spite of greater emphasis on early diagnosisand improvements in medical, surgical and inten-sive care, mortality is still around 10% and has notchanged significantly in the last 25 years.'`3 Thislack ofimprovement in outcome is partly the resultof a higher proportion of elderly patients in thepopulation.4 An analysis of causes of death in 484patients with acute upper GI bleeding showed that,in 60%, death was due to GI haemorrhage occurr-ing incidentally during a severe medical illness, i.e.they were unavoidable5 (Table I). The majority ofavoidable deaths occurred as a result of post-operative complications when surgery had beenperformed to terminate continuing or recurrenthaemorrhage. These deaths were virtually confinedto patients older than 60 years (Table II). Onegroup has shown that in patients aged more than 60years, early surgical intervention significantlyreduced mortality - 4% versus 15% in the delayedgroup,6 but, as many patients in need ofemergencysurgery are poor surgical risks, an early surgicalpolicy is still likely to be associated with a signi-ficant mortality from postoperative complications.Thus, ifan effective low-risk haemostatic treatmentwas available it should reduce mortality.

There are major difficulties in assessing the effectofdifferent treatments because ofvariation in causeof bleeding and the fact that the majority stopspontaneously. To document a 20% reduction inmortality with any therapy it has been estimatedthat 10,000 patients would need to be studied.7Usual endpoints used in trials have therefore beenrebleeding and need for emergency surgery in

addition to mortality. In most trials of endoscopicmethods for peptic ulcers, patients studied havebeen those with recent stigmata of haemorrhage -as treatment of these lesions which are at high riskof rebleeding should have the greatest impact onoutcome.

What is the bleeding lesion?

It is continued bleeding or rebleeding which leadsto operation or death in patients with peptic ulcer.Prospective studies have shown that endoscopicstigmata of recent haemorrhage help to predict

Table I Gastrointestinal haemorrhage - causes ofdeath- 55 of 484 (11.5%)

Unavoidable 7%malignancy 15medical disease 14moribund 4

Avoidable 4.5%postoperative 14exsanguination 2surgery contraindicated 6

From Dronfield 19795

Table II Gastrointestinal haemorrhage - patientsdying

Age Number % Potentially avoidable

<30 0 0 030-40 1 3 040-50 2 7 150-60 5 6 060-70 12 1 1 370-80 24 19 14> 80 1 1 20 4Total 55 11 22

From Dronfield 19795Correspondence: S.C. Jones, M.R.C.P.Accepted: 14 January 1991.

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BLEEDING PEPTIC ULCER 607

which patients are likely to rebleed. One largestudy8 showed that patients with an endoscopicallyvisible vessel in the base of the ulcer had a 57%likelihood of rebleeding, other stigmata 6%,whereas there was no rebleeding in individuals withno stigmata. Operative and post-mortem speci-mens show that the lesion responsible for rebleed-ing is an eroded artery which can usually bedemonstrated in the base of the ulcer. It followsthat the way to prevent avoidable deaths is toidentify some method whereby the artery can beoccluded, preferably permanently, at an early stagein the clinical presentation. Pharmacologicalmethods are unlikely to be successful in providingprimary haemostasis, but could be of benefit eitherby reducing the erosive action of gastric contentson arteries that have temporarily stopped bleedingor alternatively, by preventing fibrinolysis whichmight allow the artery to become permanentlyoccluded.

Endoscopic techniques for effecting arterialocclusion

Different techniques have been used endo-scopically in an attempt to occlude bleedinglesions, the most popular being thermal methodsand injection. The use of tissue adhesives9 and theendoscopic sewing machine'" have not yet beenadequately assessed.Thermal techniques produce either obliterative

or coaptive closure." Obliterative closure occurs bythe direct application ofheat to tissue which causesdessication and shrinkage with consequent narrow-ing of the lumen of the artery followed by throm-bosis. This mechanism is satisfactory for smallarteries, but is probably less effective for mediumsized and larger arteries. Coaptive closure, on theother hand, occurs when an artery is not onlyheated, but is compressed mechanically. The effectof this is to produce fusion of the opposing vesselwalls as they are compressed, the connective tissueblending into a single sheet. In order to producegood coaptive closure, the mechanical pressureused and the amount of heat generated should becontrolled; excessive heat leads to dessication ofthetissue which, in turn, leads to a less secure bonding.It follows that thermal techniques, where mechan-ical pressure is applied (such as a heater probe)should in theory be more effective than lasertherapy which produces obliterative closure.The injection ofadrenaline and sclerosing agents

into or around the vessel produces haemostasis byspasm or thrombosis respectively. Logically, adre-naline, which produces spasm, is more likely to besuccessful for initial haemostasis, but may be onlytemporary, whereas sclerosants may fail to arresthaemorrhage initially, but, if successful, provide

permanent haemostasis. A combination of thesetwo injections has been used in a number of studies,but there is a disadvantage with sclerosants in thatthey may themselves cause tissue damage and giverise to complications or rebleeding.

Endoscopic techniques

(a) Heater probe this produces direct thermalcoagulation by transferring heat to the tissue via ateflon coated probe. This is heated to 250°C by aninner coil and heat is transferred by conduction sothat no electricity enters the tissue. The probe isheld directly onto the bleeding vessel resulting incoaptive coagulation. The lesion is irrigated via thetip allowing the probe to remain in contact with thetissue.

(b) Monopolar electrocautery Electrocautery isa technique by which an electric current generatesheat. Monopolar units require a metal plate to be incontact with the patient to act as the returnelectrode, the electrical circuit being completed bycurrent flow through the body. Disadvantagesinclude tissue erosion due to sparking, lack ofcontrol over tissue heating, induced bleeding due tomechanical contact, thermal complications such asperforation, and possible electrical hazards.'2Older (dry) probes may adhere to tissue causingclot dislodgement.'3 Newer units (wet) permitcoagulation while under continued instillation ofwater so that adhesion of tissue to the probe isprevented.

(c) Bi-polar or multipolar In bi-polar or multi-polar units, the active and return electrodes arebuilt into the probe tip so that no patient returnelectrode is required. As a bipolar electrode wouldbe difficult to position endoscopically, a multipolarprobe has been developed (BICAP) which carries 6equally spaced microelectrodes and can contact thebleeding lesion from any direction. 14 This unit has a7 and 10 French probe (diameter 2.3 and 3.3 mm)and a maximum output of 50 watts. The power unitalso incorporates a water pump allowing irrigationof the target area. As the tissue heats and dries,electrical resistance increases and current flowdecreases. Sparking and tissue damage are mini-mized and deep tissue erosion avoided.'2 TheBICAP unit is portable.

(d) Microwave coagulator a monopolar elect-rode connected to a magnetron via a 2.7 mmcoaxial cable is introduced through a biopsy chan-nel. The electrode is inserted into the vessel andperivascular area and microwaves are then applied.The coagulated area is limited within a range of3 mm of the inserted electrode and shows littletendency to carbonization.'5

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608 S.C. JONES AND A.T.R. AXON

(e) Laser laser photocoagulation is achieved byconversion of light energy into thermal energy inthe tissue. Currently two types of laser are suitablefor the treatment of bleeding ulcers, the Argon andthe Neodymiun Yttrium Aluminium Garnet (NdYAG). The Argon laser is highly absorbed by redpigments such haemoglobin, and so causes onlysuperficial injury especially in the presence ofblood. The Nd YAG laser is poorly absorbedresulting in deep tissue penetration'6 and is there-fore theoretically advantageous when treatingactive bleeding from large vessels. It is not portable,and is complicated to work with and repair. Duringtreatment the tip of the fibre is positioned approxi-mately 10 mm away from the target and 6-8 shotsof laser energy are applied in a tight ring as close tothe bleeding point as possible, but avoiding it. Adirect hit of the bleeding point may precipitate oraggravate arterial haemorrhage.'7

(For costs of equipment see Appendix I.)

Studies using thermal techniques

Numerous trials have been performed using ther-mal techniques. Many of them are difficult tointerpret and not all have been controlled. It istechnically difficult to design studies which cannotbe criticized. The mortality rate from bleedingpeptic ulcer is low, so large numbers of patientsmust be recruited to give meaningful results. Thisproblem can be overcome to some extent if patientselection is made on the basis of endoscopicstigmata and if the endpoint is taken as rebleedingor surgery rather than death. A meta analysis ofthermocoagulation techniques has been under-taken.'8 In this particular study nearly 1500patients were assessed. Laser therapy improvedrebleeding, operation and death rate significantlycompared with no treatment. Electrocoagulationin a smaller number of patients showed an

improvement for rebleeding and operation, but thefigures for death were not significant. These dataconfirm the general impression given by a largenumber of studies that thermal techniques are

probably useful. The choice of which technique touse, however, is more difficult.

Laser therapy has been available for a longerperiod than most other techniques and has beensubjected to a larger number of trials."'-"" TheArgon laser is less effective than the Nd:YAG laser.However, the problems with laser therapy are thatthe technique itself is more difficult, access to thebleeding point is a greater problem, and specialtraining and support is necessary. The cost of theequipment is so much more than other forms ofthermal treatment that unless the results of thetechnique are superior there can be no justificationfor purchasing it for this purpose. In practice,

where the laser has been compared with otherforms of endoscopic treatment it has performedlittle better. A recent review,48 comparing differentstudies, concluded that laser therapy of arterialbleeding did not seem to be as effective as electro-coagulation or injection.The heater probe4954, monopolar55"-64 and bi-

polar44"65- appear from the literature to be equallyeffective. The heater probe has been written aboutwith the greatest enthusiasm, it is relatively simple,easily portable, there is no electrical contact withthe patient, and the amount ofenergy supplied witheach pulse can be accurately pre-set, reducing therisk of perforation. It can be applied tangentially,and since it remains in contact can remain on targetduring respiratory movement. The theoreticalability to apply pressure on the bleeding vessel mayprovide a coaptive seal which may be more effec-tive.

(f) Injection Injectable substances fall into twomain groups - vasocontrictors and sclerosants,which may be used alone or in combination.Sclerosants such as ethanol cause dehydrationwhich induces tissue contraction, blood coagula-tion, and necrosis of the vessel with subsequentfibrosis of the surrounding tissue.78 The onlyvasoconstrictor which has been evaluated in trialsis adrenaline which is thought to act by inducingvasospasm and platelet aggregation which com-bine to encourage thrombosis of the bleedingvessel.79A number oftrials ofinjection therapy have been

carried out.80-98 Significant benefit has been shownin some controlled studies.90-92 Hypertonic salineand ethanol, and pure ethanol injection gavegood initial haemostasis in several uncontrolledtrials.8"'81'8386'87 Similar success has been shown forpolidocanol alone99 and after preinjection withadrenaline.85 It is unclear which injection is thebest. Adrenaline alone seems to be effective anddoes not carry the risk of ulcer extension andperforation occasionally seen with other sclero-sants.The heater probe may be superior to injection

with pure alcohol in patients with spurting haemor-rhage.95 Some of the treatment failures with injec-tion in this paper were difficult to approach enfacewith the needle, there was no such problem inapplying the heat probe tangentially. Adrenaline-+ polidocanol performed better than adrenaline-+ laser in one study.97

(g) Application of tissue adhesives Applicationof clotting factors such as thrombin and fibrinogensolutions have not been shown conclusively to beeffective although further studies are needed.9Other tissue adhesives such as cyanoacrylate poly-mers were ineffective in a controlled study.'0'

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BLEEDING PEPTIC ULCER 609

(h) Haemoclips these were originally developedby Hayashi et al.'02 They were of two types, onebeing detachable and another connected to a longpolythene tube for peroral indwelling use. The clipswere modified by Hachisu et al.'03 and the clippingmanoeuvre was greatly simplified. Initial haemo-stasis was achieved in 24 out of 27 bleedingepisodes (88.9%) with a rebleeding rate of 16.7%.Clips, once planted, stayed longer than 24 days,average 9.4 days. Treated lesions included gastriculcers, duodenal ulcers, and stomal ulcers.

Pharmacological treatment

The pharmacological agents which have been usedto reduce mortality from peptic ulcer treatmentinclude H2 receptor antagonists, omeprazole,tranexamic acid, prostaglandins and somatostatin.

Acid reducing drugs

A meta-analysis of trials assessing H2 receptorantagonists"' (Table III) assessed 2,500 patients in27 trials. There was a reduction of30% in mortalitywhich just reached statistical significance. Therewas a trend towards reduction of rebleeding andneed for surgery, but the authors of the metaanalysis are very cautious in their interpretation ofthe results and feel that larger studies comprising atleast 10,000 patients are needed to confirm a usefulrole for these agents. More recently preliminaryresults of a trial using omeprazole have beenpublished.'05 Over 1,000 patients were studied, butno improvement in rebleeding, transfusion, opera-tion or death rate could be demonstrated.

Antifibrinolytics

A meta-analysis of the use of tranexamic acid inover 1,000 patients has produced more hopefulresults.' In this analysis rebleeding was reducedby 20-30%, surgery by 30-40%, and the deathrate came down by 40%, the results of surgery anddeath reached statistical significance at the 0.05level. Tranexamic acid is not a drug which has beenused extensively by gastroenterologists, but theresults of these studies suggest that it merits greaterinterest.

Prostaglandins and somatostatin

Controlled trials using prostaglandins have failedto show any benefit. 107"108 In both studies anaprostil

Table III Gastrointestinal haemorrhage - meta analysisH2RA - 27 trials 2,500 patients

Reduction % P

Rebleeding 10 n.s.Surgery 20 n.s.Death 30 0.02

Collins and Langman 1985'°, n.s. - not significant.

was tested against placebo in 219 patients. Somato-statin has also been studied."'0 In this study, fewerin the treated group required surgery and theresults did reach statistical significance. Similarresults were found in another study."' Other trialshave compared somatostatin with H2 receptorantagonists. Some showed significant improve-ment,"1-113 others no difference."4116 Somato-statin may therefore have a beneficial effect andmerits further study.

Conclusion

No unequivocal statement concerning the use ofendoscopic or pharmacological methods in gastro-intestinal haemorrhage is possible. The subject is adifficult one, many results are inconsistent anddifficult to interpret. At the present time there doesseem to be reasonable evidence to suggest thatendoscopic therapy using thermal techniques orinjection do probably reduce the incidence ofrebleeding and the need for surgery. This, in theory,may reduce mortality, but has not been shownconvincingly. There is little evidence to suggest thatthe use ofpharmacological drugs influences morta-lity to a greater extent although studies withsomatostatin and tranexamic acid merit furtherwork. Another approach which has not beensubjected to critical analysis is the possible advan-tages which may be gained from treating patients inspecialized bleeding units managed by experiencedgastroenterological teams of physicians and surg-eons. This approach is even more difficult to assessprospectively in randomized studies. However,figures ofmortality from gastrointestinal haemorr-hage vary widely from centre to centre and a morespecialized approach to the subject might lead to afall in the number of avoidable deaths which atpresent amounts to somewhere in the region of5%of all admissions with gastrointestinal haemorr-hage.

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Appendix

Endoscopic techniques - equipment costs (approx.) ex-cluding VAT

£Heat probe 6,730Monopolar electrocautery 4,000Multipolar probe (BICAP) 3,950

(7 and 10 French probe) 175Microwave coagulatorNdYAG laser 75,500Argon laser

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