Consesus On Management Of Peptic Ulcer Disease



Contents
1. H.Pylori Related Peptic Ulcer Disease
    Helicobacter Pylori and Its Role in peptic Ulcer Disease
    How is H. Pylori Infection Diagnosed
    Treatment Of H.Pylori
2. Non-H.Pylori Related Peptic Ulcer Disease
    A. Non-Steroidal Anti-Inflammatory Drugs and peptic Ulcer Disease
        Risk Factors for NSAID Induced Ulcers
        Prevention
        Treatment of NSAID Induced Ulcers
        Risk of Ulcer Complications Associated with Individual Non-Aspirin NSAID use
        Relative risk of UGIB Associated with individual NSAID'S
    B. Refractory Ulcer
        Definition
        Management
    C. Long Term Maintenance Therapy
        Indication
    D. Stress Ulcer
        Aetiology and Risk Factors
        Management
        prophylaxis
        1. Sucralfate
        2. Antisecretory agents
3. Role of Endoscopy in Peptic Ulcer Disease
    Diagnosis of Peptic Ulcer
    Medical Management of Bleeding peptic Ulcer
    Prognostic Stigmata of Bleeding Peptic Ulcer
    Endoscopic Haemostasis of Bleeding Peptic Ulcer
    Endoscopic Management of Benign Peptic Pyloric Stricture
4. Role of Surgery in Peptic Ulcer Disease
    A. Surgery for Uncomplicated Duodenal Ulcer
    B. Surgery for Complication of Duodenal Ulcer
        1. Bleeding
        2. Perforation
        3. Stenosis
    C. Surgery for Uncomplicated Gastric Ulcer
    D. Surgery for Complications of Gastric Ulcer
    E. Laparoscopic Surgery in peptic Ulcer Disease
5. References
6. Expert Commitee
7. Appendix 1
    Appendix 2
    Appendix 3



                 EXPERT COMMITTEE Chairperson:  Dato’ Dr (Mrs) S T Kew Secretary    :  Dr Tan Soon Seng                              Dr Zainal Ariffin Hashim H.pylori Related Peptic Ulcer Disease A Prof K L Goh (Chairman) A Prof N Parasakthi A Prof Mahendra Raj A Prof Isa Ros A Prof Mazlam Mohd Zawawi Non-H.pylori Related Peptic Ulcer Disease Dato’ Dr (Mrs) S T Kew (Chairman) - NSAID & Peptic Ulcer Disease Dato’ Dr F K Chan - Refractory Ulcers Dr Andrew Chua - Long Term Maintenance Therapy Dr K Inbasegaran - Stress Ulcers Role of Endoscopy in Peptic Ulcer Disease Dr T P Yin (Chairman) A Prof Damien Wong Dr Anand Bhupalan Role of Surgery in Peptic Ulcer Disease Dato’ Dr J C Mehta (Chairman) Dato’ P Kandasami Mr Robert Jalleh Mr K T Ong Mr Ng Chuan Wai


1. H.Pylori related Peptic Ulcer Disease

Helicobacter Pylori and its Role in Peptic Ulcer Disease:
Evidence strongly suggests a causal relationship between H. pylori and peptic ulcer disease: H pylori is found in the majority of ulcer patients (>90% of duodenal ulcers and 70-90% of gastric ulcers), H. pylori causes chronic gastritis which is strongly correlated with peptic ulcer disease and H.pylori eradication results in marked reduction or abolition of ulcer recurrence. H.pylori eradication is recommended in H.pylori positive peptic ulcer patients.

There is no convincing data of an association between H.pylori and non ulcer dyspepsia at this point in time. H.pylori eradication cannot be routinely recommended in H.pylori positive NUD patients.

How is H.Pylori Infection Diagnosed?
Following the above recommendations, biopsy tests for H.pylori when ulcer disease is diagnosed at endoscopy should be performed.

For routine diagnosis, a rapid urease test and/or histological examination where expertise is available is recommended. H.pylori is invariably found in the gastric antrum. Sampling error due to uneven distribution of the bacteria is minimized if two biopsies from the antrum are taken.

Routine testing for successful H.pylori eradication is probably not necessary. Patients with complicated ulcers especially when discontinuation of acid-suppressing maintenance therapy is contemplated should be assessed for H.pylori eradication. Testing of eradication should be done not earlier than 4 weeks after completion of the eradication regime.

When assessing for H.pylori status following treatment, where endoscopy is not indicated (eg. uncomplicated duodenal ulcer), a radiolabelled carbon urea breath test is recommended where available. When endoscopy is indicated at follow-up (eg. to confirm gastric ulcer healing), an endoscopy biopsy test is recommended; both antral and body biopsies should be taken for testing.

A positive serological test for H.pylori reflects exposure to H.pylori. Laboratory based ELISA tests are acceptable methods of diagnosis but kits vary in their sensitivity and specificity. Furthermore, antibody titres decrease slowly over months after successful eradication. Post-treatment assessment of H.pylori status using serology is impractical and therefore not routinely recommended. Rapid qualitative blood tests (office based tests) may become useful tests in the future but need further evaluation.

Treatment of H.Pylori
At this present point in time, treatment to eradicate H.pylori is recommended in patients with peptic ulcers and proven H.pylori infection.

Treatment with any single agent is ineffective. Combination therapy with two or three drugs are needed.

Several treatment regimes are recommended: The bismuth triple therapy regime consisting of colloidal bismuth subcitrate and 2 antibiotics, metronidazole and tetracycline or amoxycillin for 2 weeks, is well established and gives consistent eradication rates of 80-90%. Side-effects have been reported in about 30% of patients in clinical trials and are normally minor.

Triple therapy with H2 antagonists and two antibiotics; metronidazole and amoxycillin or tetracycline have also been used: eradication rates of greater than 80% have been recorded. Similar side-effects as for the bismuth triple therapy are experienced by patients.

Omeprazole and amoxycillin or clarithomycin for 2 weeks achieves eradication rates of up to 80%; however, eradication rates have been inconsistent. Dual therapy regimes are well tolerated.

Recent studies indicate that a one week treatment with omeprazole 20mg daily or bd, with 2 of the following antibiotics: metronidazole or amoxycillin or clarithromycin achieves consistent eradication rates of greater than 90%. These regimes also appear to be well tolerated.

Newer drugs and regimes will constantly become available. Treatment regimes should not only be safe but simple to take and cheap.

Reinfection following successful eradication appears to be low in our community and will not nullify the effect of successful eradication. As with other bacterial infections, emergence of antibiotic resistance particularly to nitroimidazoles may pose therapeutic problems. Indiscriminate use of antibiotics to treat H.pylori may increase the problem of antibiotic resistance.
 

Appendix 1

Therapeutic regimes that have been used for eradication of H.pylori include:
 

-Colloidal bismuth subcitrate 1 tablet (120mg) qid or 2 (240mg) tablets bd 
         - Amoxycillin 500mg tds or 
           Tetracycline 500mg tds 
         - Metronidazole 400mg tds                                                   for 2 weeks
-Omeprazole 40mg daily or 20mg bd 
         - Amoxycillin 500mg tds 
           or Clarithromycin 500mg tds                                               for 2 weeks
-Omeprazole 20mg daily or bd and 2 of the following: 
         - Metronidazole 400mg bd 
         - Amoxycillin 500mg bd 
         - Clarithromycin 250mg or 500mg bd                                      for 1 week
-Histamine - 2 receptor antagonist  
                  (eg. Ranitidine 300mg daily or Famotidine 40mg daily) 
        - Amoxycillin 500mg tds 
        - Metronidazole 400 mg tds                                                   for 2 weeks

 

2. Non-H.pylori Related Peptic Ulcer Disease
A. Non-steroidal Anti-inflammatory Drugs and Peptic Ulcer Disease

NSAID’s including Aspirin are among the most commonly prescribed drugs. The association of gastroduodenal mucosal damage and NSAID use is well documented, with relative risk of developing adverse gastrointestinal events approximately three times in users compared to non-users.

NSAID induced gastropathy may either take the form of acute mucosal petechiae, haemorrhages or erosions; or less acute, larger submucosal ulcers of the stomach or duodenum.

All NSAID’s are capable of inducing mucosal injury, and there is no consistent difference in the degree of mucosal damage among the various NSAID’s. In several case control studies, the odds ratios of some NSAID’s in causing upper gastrointestinal bleeding and perforation are lower than others (See Appendix 2 & 3).

Newer NSAID’s which are acid-insoluble, pro-drug, parenterally administered, or enteric coated formulation do not appear to reduce potential for causing gastrointestinal damage especially with long term use. With short term use, however, gastric mucosal injury from a topical effect is decreased with enteric coated formulations.

Risk Factors for NSAID Induced Ulcers

Include: Elderly persons (>65 years)
            Severe co-morbid conditions
            Past history of peptic ulcer disease or upper gastrointestinal bleeding
            Arthritis related disability, the greater the disability the greater the risk
            Possibly smoking

NSAID related risk factors

Dose dependence relationship - higher dosage of NSAID increases risk2 or more NSAID’sNSAID given with steroidNSAID given with anticoagulantHighest risk in the first month of therapy

Prevention

The best approach of NSAID induced gastropathy is prevention. If the clinical situation only requires analgesia, then physical therapy, paracetamol or other non-opiate analgesics should suffice. NSAID’s are used only when they are absolutely indicated. The least ulcerogenic agent at the lowest therapeutically effective dose is recommended.

An agent for prophylaxis should be considered in persons at significantly increased risk of NSAID induced gastropathy. The only effective prophylaxis proven to protect against both gastric and duodenal ulcers is prostaglandin analogue (eg. Misoprostol). The dose recommended for prophylaxis is 400 - 800 ug/day in divided doses.

H2 receptor antagonists in standard doses reduces risks of NSAID induced duodenal ulcers but not gastric ulcers. Use of H2RA is reasonable as prophylaxis if such agent has previously healed NSAID induced duodenal ulcers in the same patients.

Proton pump inhibitor (eg. Omeprazole) used prophylactically reduces risks of NSAID induced gastropathy in the short term.

Treatment of NSAID induced ulcers

First step in the treatment of NSAID induced ulcers is the withdrawal or reduction of dose to the lowest minimum of NSAID. For NSAID induced duodenal ulcers and smaller gastric ulcers, full dose of H2RA should be prescribed for a minimum of 8 weeks. For larger gastric ulcers, proton pump inhibitor (eg. Omeprazole at 20 - 40 mg/day) for 8 weeks is recommended. Alternatively full dose of H2RA for up to 12 weeks is as effective in healing larger NSAID induced gastric ulcers. Prostaglandin analogue (eg. Misoprostol at 800 ug/day in divided doses) is also effective in healing NSAID induced GU and possibly DU.

If the clinical situation requires the continued administration of NSAID in the presence of healed ulcer, concurrent administration of anti-secretory drugs or prostaglandin analogue is recommended.

  Appendix 2

.

No. of Cases 

Hospital  Controls

Community Controls

Odds ratio  (95% CI)*

Azapropazone

22

2

2

31.5 (10.3-96 9)

Diclofenac

71

30

31

4.2 (2.6-6.8)

Ibuprofen

88

61

75

2.0 (1.4-2.8)

Indomethacin

57

16

14

11.3 (6.3-20.3)

Ketoprofen

31

2

4

23.7 (7.6-74.2)

Naproxen

90

23

21

9.1 (5.5-15.1)

Piroxicam

57

13

11

13.7 (7.1-26.3)

Any non-aspirin NSAID

411

169

182

4.5 (3.6-5.6)

Not on NSAID or aspirin

457

807

657

1.0

*All odds ratios from unconditional logistic regression model with terms for aspirin use, smoking, alcohol, previous peptic ulcer, and history of dyspepsia. For azaproprazone, to obtain convergence, aspirin use was not included.

Risks of ulcer complications associated with individual non-aspirin NSAID use during previous 3 months

Ref : Langman MJS, Weil J, Wainwright P: Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 343:1075-78, 1994.

 Appendix 3

.

Cases (n= 862)

Controls (n= 9017)

Adjusted relative risk (95% CI)

NSAID current use . . .
No use

615

8222

1.0

Ibuprofen

20

74

2.9 (1.7-5.0)

Other*

13

39

2.9 (1.5-5.6)

Naproxen

15

46

3.1 (1.7-5.9)

Diclofenac

25

53

3.9 (2.3-6.5)

Ketoprofen

14

20

5.4 (2.6-11.3)

Indomethacin

20

24

6.3 (3.3-12.2)

Multiple NSAIDs

33

43

8.9 (5.4-14.7)

Piroxicam

20

11

18.0 (8.2-39.6)

Azapropazone

11

4

23.4 (6.9-79.5)

Only patients with no history of peptic ulcer were included.
*Mefenamic acid, fenbufen, fenoprofen, flurbiprofen, diflunisal, sulindac, tenoxicam, tiaprofenic acid, etodolac, and nabumetone.
Among current users of the four NSAID’s listed were 4 people with unknown daily dose.

Relative Risk of UGIB Associated with Individual NSAID’S
ef :Gatrcia Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 343:769-72, 1994.

B. Refractory Ulcer
Refractory ulcer, non-healing ulcer, resistant ulcer, and slow to heal ulcer are some of the terms used to describe ulcers that are difficult to heal. Though there is no consensus on the terminology, with current available therapies, truly non-healing ulcers are rare, the term "Slow-to-heal" ulcers may be a more accurate description of such ulcers.

Definition
Refractory ulcers are peptic ulcers that do not heal following at least 3 months of treatment with H2 receptor antagonist or proton pump inhibitor at standard doses recommended for ulcer healing.

Malignancy must be excluded conclusively in all ulcers that are slow to heal.

Certain factors have been known to be associated with delay in healing of ulcers, attempts should be made to elucidate such factors in the management of these patients.
1. Smoking.
2. Non-compliance with recommended therapies.
3. Usage (including surreptitious use) of NSAIDs, and steroid.
4. Gastrinoma, as Zollinger-Ellison syndrome or Multiple endocrine adenomatosis, typically manifests
    as non-healing ulcers.
5. Non-peptic ulcers:
    a. Crohn’s Disease.
    b. Lymphoma.
    c. Behcet’s disease.
    d. Metastatic ulcerated lesions (to upper GIT)
    e. ulcerated leiomyoma, leiomyosarcoma.

Management
1. Where specific diagnosis has been made, appropriate therapies should be given.
2. Repeat upper GI endoscopy and multiple biopsies of ulcers (at least 6 biopsies at edges of ulcers)
    must be obtained at each and every endoscopy until healing is complete and documented.
3. All patients should be advised to stop smoking.
4. Stop or reduce the use of NSAID’s and steroid when this is feasible. Consider alternative in place of
    NSAID’s.

Options for treatment include:
1. Proton pump inhibitor offers the best option for treatment. A higher dose of proton pump inhibitor is
    usually necessary and it may be necessary to continue treatment for at least 3 months. Surgical
    option should be considered if ulcer remained unhealed after 6 months of therapy.
2. Should relapses occur following termination of treatment, maintenance therapy with proton pump
    inhibitor at dosages comparable to that used for ulcer healing may be necessary to prevent relapses.

C. Long Term Maintenance Therapy

Indication
Long term maintenance therapy is desirable to prevent recurrence only in selected high risk patients:
1. Patients with known history of complicated ulcers which are non H pylori related or have failed
    H.Pylori eradication.
2. Patients with known history of ulcer disease on NSAID therapy
3. Patients with underlying conditions predisposing to ulcer recurrence.

With respect to complicated ulcers in patients who have H.Pylori eradicated the data is not clear. Long term maintenance therapy may be given until further results are available.

The most thoroughly investigated drugs which have been used in the long term maintenance therapy of ulcer disease are the H2-receptor antagonists. There is conclusive evidence that H2-receptor antagonists substantially reduce the frequency of symptomatic relapse, and reduce the recurrence of duodenal ulcer haemorrhage. The proton pump inhibitors have been shown to be an effective and safe alternative to the H2-receptor antagonists. Other substances such as sucralfate, prostaglandin analogues or antacids are not used to the same extent as the H2-receptor antagonists for long term therapy.

An alternative option which may be more cost effective to long term maintenance therapy is intermittent treatment. There is yet no evidence to prove that intermittent therapy is a safe and effective alternative to continuous maintenance therapy. Until more conclusive data is available, continuous therapy is preferred.

In patients with no contraindications, surgery is an alternative to long term maintenance therapy.

D. Stress Ulcers
The term stress ulcers is used to describe a group of mucosal lesions of the oesophagus, stomach or duodenum that occur in the critically ill or otherwise stressed patient. The type of lesions that occur can vary from small petechial haemorrhages and erosions to deep ulcerations and occasional perforations. The true incidence of stress ulcers as diagnosed endoscopically varies from 20% to 50% in all intensive care patients not receiving prophylaxis for stress ulcers. However only about 2% of them develop clinically significant bleeding which requires active resuscitation and surgical or medical therapy.

Aetiology and Risk Factors
The development of stress ulcers appears to be dependent on three factors: namely the presence of gastric acid and pepsin, reduction of mucosal blood flow from any cause such as hypotension and increased mucosal permeability brought about by lack or decreased local cytoprotection.

There are certain well known risk factors in the critically ill that are closely associated with the development of stress ulcers. These include the following:
1.  Mechanical ventilation for more than 48 hours
2.  Presence of sepsis
3.  Hypotension or hypovolaemic shock
4.  Acute respiratory failure, in particular ARDS
5.  Coagulopathy
6.  Steroid therapy
7.  Multiple trauma
8.  Severe head injury
9.  Burns of more than 25% body surface area
10.Hepatic failure
11.Acute renal failure with sepsis.

The most significant risk factors are mechanical ventilation, sepsis, prolonged hypovolaemia and coagulopathy. In a number of patients multiple risk factors may be present.

Management
The management of clinically significant bleeding will depend on the severity. The cause of the bleeding must be confirmed endoscopically as soon as possible and blood loss replaced appropriately. Other measures will include the administration of Oxygen, increasing intraluminal pH with H2 receptor antagonists or antacids and appropriate surgical and medical intervention described elsewhere in this document.
 
Prophylaxis
The most important prophylaxis is to ensure that the critically ill patient receives optimal supportive therapy. This includes adequate tissue oxygenation, maintenance of adequate intravascular volume and good perfusion pressures. These measures may require fluid loading, use of inotropes as well as vasodilators. Enteral feeding has been shown to reduce significantly the incidence of gastrointestinal bleeding and this should be started as soon as possible in the critically ill patients as long as there is no contraindication.Pharmacological prophylaxis should be used in patients with risk factors whether single or multiple.

In general, the pharmacological prophylaxis is directed towards the reduction of the volume of gastric acid secretion thereby reducing its acidity (ie increase in pH) or offering mucosal protection (cytoprotective effect).

1. Sucralfate
Sucralfate is a non absorbable aluminium salt of sucrose octasulphate that has no effect on gastric secretion or acidity. Its mechanism of action is multiple including binding to pepsin and bile salts, cytoprotective effect, binding to exposed proteins among others. It has been shown to be as effective as Histamine-2 receptor antagonists in the prevention of stress ulcers and has no significant side effects. As it does not affect acidity, it does not increase the incidence of nosocomial pneumonia. The recommended dosage is 1 gm dissolved in 10 ml aliquots of water administered via a nasogastric tube every 6 hours. Currently it is the preferred choice for stress ulcer prophylaxis.

2. Antisecretory agents:
a. Histamine-2 receptor antagonists
The Histamine-2 receptor antagonists decrease gastric acid secretion as well as increase the pH. Long term use has been shown to produce bacterial overgrowth and a significantly increased incidence of nosocomial pneumonia. This is more common in intubated and ventilated patients. Bolus dosing of Histamine-2 receptor antagonists while effective in reducing acid secretion is not effective in maintaining the pH above 4 at all times. A continuous infusion will maintain the pH above 4 at all times, but may not be practical at most times.

Suggested dosages are as follows:

Intermittent bolusa.
a. Cimetidine - 200 mg i.v. 6 hourly
b. Ranitidine - 50 mg i.v. 8 hourly

Continuous infusiona.
a. Cimetidine - 50-100 mg hourly after a bolus of 200 mg
b. Ranitidine - 6.25 - 12 mg hourly after a bolus of 50 mg

It would be preferable to monitor and maintain the intragastric pH at all times.

b. Proton pump inhibitors
Drugs belonging to this class of agents (eg. omeprazole) have been shown to reduce gastric secretions to very low levels. They have been shown to be effective in stress ulcer prophylaxis, but they also cause a higher than usual incidence of nosocomial pneumonia by the same mechanisms. The suggested dosage is 40 mg once daily.

Prophylactic therapy, though not totally preventing the occurrence of stress ulcers, prevents the progression, reduces the severity and expedites healing. In general, prophylactic therapy does not change the mortality of the critically ill; the mortality is ultimately dependent on the underlying disease process. Over the last two decades the incidence of stress ulcer related bleeding has decreased dramatically independent of stress ulcer prophylaxis. This is attributed to improvement in the management of the critically ill with inotropic drugs, vasodilators and adequate intravascular volume replacement resulting in improved tissue oxygenation and perfusion.
 
3. Role Of Endoscopy In Peptic Ulcer Disease

Diagnosis of Peptic Ulcer
Endoscopy is the investigation of choice in the evaluation of patients suspected of peptic ulcers. In the era of Helicobacter pylori infection this role is further enhanced as endoscopy allows direct proof of the infection to be made. Double contrast barium meal is an alternative investigation if endoscopy is not available. This investigation suffers from the inability to allow histological diagnosis when required and is unable to provide information on Helicobacter pylori status. Re-endoscopy is recommended for gastric ulcers to confirm healing.

Medical Management of Bleeding Peptic Ulcer
Acid suppression with H2 receptor antagonists and proton pump inhibitors are given in bleeding peptic ulcers to initiate ulcer healing. There is no evidence from clinical trials that these drugs are helpful in arresting ulcer bleeding, or in reducing transfusion requirement, emergency surgery and mortality.

Gastric lavage or the use of pharmacological agents like vasopressin, somatostatin and tranxenamic acid has not been proven to be effective as well.

80% of all bleeding peptic ulcers stop spontaneously. The reduction in morbidity and mortality in the small group of patients that continue to bleed or rebleed is the prime objective of current endoscopic and surgical approach.

Following resuscitation measures endoscopy is to be performed as soon as possible for actively bleeding patients. For the stable patient who appears to have stopped bleeding, the timing of endoscopy can vary considerably depending on the clinical situation. It is preferable to perform endoscopy within 24 hours if small lesions are not to be missed.

Prognostic Stigmata Of Bleeding Peptic Ulcer
The appearance of peptic ulcer at index bleed allows us to make prediction of its natural history and behaviour, and the indication for endoscopic haemostatic intervention. A clean base ulcer has a 5% rebleeding rate, and can be observed for a day and discharge without intervention in the majority of cases. A flat spot and adherant clot ulcers have a 10% and 20% rebleeding rates respectively and is advisable to be observed in a general ward for two to three days without endoscopic therapeutic intervention. The ulcer with non bleeding visible vessel and actively bleeding features have a rebleeding rate of 40 to 50% and will require active endoscopic haemostatic intervention, and where available, these patients are best observed in an intensive care unit or high dependency unit setting.

Endoscopic Haemostasis of Bleeding Peptic Ulcer
Injection of bleeding ulcer with dilute adrenaline (1:10,000), using aliquots of 0.5 ml each injection, around and into the bleeding spot, is efficacious in 84 - 94% of cases. This technique requires very little learning curve and is cost effective, with minimal complications. Other techniques like heater probe, bipolar and laser add little to reduction of mortality rate, although some trials suggested that heater probe has advantage over bipolar probe. Laser therapy suffers from high cost and immobility of the equipment. Haemoclip as a new method of endoscopic haemostasis may in future prove to be superior to other techniques. There is no agreement whether endoscopic haemostasis should be repeated if rebleeding occurs. The recommendation of the committee is that all such patients be offered surgical treatment except in specialised endoscopy unit.

Endoscopic Management of Benign Peptic Pyloric Stricture
According to published data, balloon dilatation through the endoscope achieved successful dilatation in the majority of cases with minimal complications. Improvement is however temporary and repeated dilatation may be required for long term relief. Endoscopic dilatation is recommended for patients who refuse surgery and for those whose general condition precludes surgery.

4. Role Of Surgery In Peptic Ulcer Disease

Despite the introduction of acid-reducing and Helicobacter pylori eradication therapies in the treatment of peptic ulcer disease, there remains a definite role for surgery in the management of peptic ulcer disease especially when dealing with its complications.

A. Surgery for Uncomplicated Duodenal Ulcer
Where surgery is indicated, the recommended operations include truncal vagotomy and drainage (either posterior gastroenterostomy or pyloroplasty) with its acceptably low morbidity and recurrence rates.

Highly selective vagotomy (parietal cell vagotomy/proximal gastric vagotomy) is encouraged in those familiar with this procedure for its superior results if its completeness can be assured.

B. Surgery for Complications of Duodenal Ulcer
The common complications are bleeding, perforation and stenosis.

1. Bleeding
It is recommended that a joint approach between physician/gastroenterologist and surgeon be adopted in the management of bleeding duodenal ulcer. This is to reduce the morbidity and mortality associated with delayed surgical intervention.

1.1 Resuscitation
Rigorous resuscitation with monitoring should be initiated immediately until haemodynamic stability is achieved.

1.2 Diagnosis
Early endoscopic diagnosis preferably within 24 hours is essential. Those inappropriate for endoscopic techniques of haemostasis are then selected for surgery.

1.3 Surgical indications
Early surgery should be considered in the presence of any one of these criteria:
a. Hypovolaemic shock on admission (<90mmHg)
b. Age 65 or more
c. Resuscitation requirement of 4 units blood in the first 24 hours
d. Signs of continuing haemorrhage
e. History of a previous admission for an ulcer complication
f.  Ulcer size >2cm or with stigmata of recent haemorrhage (despite endoscopic haemostatic
    techniques)
g. Co-morbid factors

The majority of clinically significantly bleeding ulcers are posterior ulcers. Underruning of the bleeding ulcer alone or together with truncal vagotomy and pyloroplasty is a safe and expedient option in the poor risk patients. Anterior ulcer may be excised and incorporated into the pyloroplasty.

In the presence of a large duodenal ulcer, partial gastrectomy is recommended for its lower risk of rebleeding but there is an increased risk of duodenal leak compared to vagotomy and pyloroplasty. If vagotomy and pyloroplasty is inappropriate or has been performed previously, partial gastrectomy is the preferred option.

2. Perforation
The first-choice operation is simple omental patch closure with meticulous peritoneal toilet. A definitive ulcer-treating procedure should only be considered in the haemodynamically stable patient and in the absence of gross contamination. Truncal vagotomy and drainage is recommended and highly selective vagotomy should be reserved for those familiar with the technique.

In cases where gross duodenal distortion or large perforation prevents satisfactory patch closure, partial gastrectomy is recommended.

Simple closure alone should be followed by long-term ulcer therapy or Helicobacter pylori eradication where indicated.

3. Stenosis
Duodenal stenosis not responding to medical or endoscopic therapy requires surgery. The recommended operation is truncal vagotomy with a drainage procedure.

C. Surgery for Uncomplicated Gastric Ulcer

Surgery is indicated in the presence of:
1. Refractory ulcer
2. Large gastric ulcers (>3cm)
3. Suspicion of malignancy

Gastrectomy incorporating the ulcer is the operation of choice. A prepyloric ulcer can be treated as a duodenal ulcer.

D. Surgery for Complications of Gastric Ulcer

1. Bleeding
The preferred option is partial gastrectomy including the ulcer. Other choices include ulcer excision or underrunning of the bleeding point with or without vagotomy (followed by ulcer therapy).

2. Perforation
Gastric resection is ideal if feasible. If malignancy can be confidently excluded or the patient is too ill, ulcer excision with omental patch followed by ulcer therapy is acceptable.

E. Laparoscopic Surgery In Peptic Ulcer Disease
Major advances have been made in the application of laparoscopic techniques in both elective and emergency ulcer surgery. These include highly selective vagotomy, posterior truncal vagotomy with anterior seromyotomy, vagotomy and gastrojejunostomy or pyloroplasty, laparoscopic repair of perforated ulcer and gastrectomy. Although the feasibility of these procedures has been established, further considerations including efficacy, cost-effectiveness and training need to be made before they can be advocated in Malaysia.

References:

1. H. Pylori related Peptic Ulcer Disease
1. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. Journal of American Medical
    Association 1994; 272: 65-71.
2. Rauws EAJ, Tytgat GNJ. Eradication of Hlicobacter pylori cures duodenal ulcer. Lancet 1990; 335:
    1233-5.
3. Marshall BJ. Helicobacter pyloi Quadrennial review, World Congress of Gastroenterology 1994. Am J
    Gastroenterol 1994; 89: S116-128.
4. Talley NJ. A critique of therapeutic trials in Helicobacter pylori positive functional dyspepsia.
    Gastroenterology 1994; 106: 1174-83.
5. Cutler AF. Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and
    non-invasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995; 109: 136-41.
6. Goh KL, Parasakthi N, Peh SC, Chin SC. Reinfection and ulcer relapse in South-East Asian patients
    following successful Helicobacter pylori eradication: Results of a two year follow-up. Gastroenterology
    1995; 108: A103.
7. Goddard A, Logan R. One-week low dose triple therapy: new standards for Helicobacter pylori. Eur J
    Gastroenterol Hepatol 1995; 7: 1-3.
 
2.  Non-H.pylori Peptic Ulcer Disease
a. NSAID’s and Peptic Ulcer Disease

1.  Griffin MR, Ray WA, Shafner W: Nonsteroidal Anti-inflammatory Drug Use and Increased Risk for
     Peptic Ulcer Disease in Elderly Persons. Ann Intern Med 114:257-263, 1991.
2.  Chamberlain CE: Acute Haemorrhagic Gastritis. Gastro Clin N Am 22: (4) 843-73, 1993.
3.  Taha AS, Dahill S, Sturrock RD: Predicting NSAID related ulcers - assessment of clinical and
     pathological risk factors and importance of differences in NSAID. Gut 35:891-95, 1994.
4.  Schoen RT, Vender RJ: Mechanisms of Nonsteroidal Anti-inflammatory Drug-Induced Gastric
     Damage. Am J Med 86:449-58, 1989.
5.  Taha AS, Russell RI: Helicobacter pylori and non-steroidal anti-inflammatory drugs: uncomfortable
     partners in peptic ulcer disease. Gut 34:580-3, 1993.
6.  Langman MJS, Weil J, Wainwright P: Risks of bleeding peptic ulcer associated with individual
     non-steroidal anti-inflammatory drugs. Lancet 343:1075-78, 1994.
7.  Garcia Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with
     individual non-steroidal anti-inflammatory drugs. Lancet 343:769-72, 1994.
8.  Holvoet J, Terriere L, Van Hee W: Relation of upper gastrointestinal bleeding to non-steroidal
     anti-inflammatory drugs and aspirin: a case control study. Gut 32:730-4, 1991.
9.  Laporte JR, Cerne X, Vidal X: Upper gastrointestinal bleeding in relation to previous use of analgesics
     and non-steroidal anti-inflammatory drugs. Lancet 337:85-9, 1991.
10.Gabriel SE, Jaakimainen L, Bombardier C: Risk of serious gastrointestinal complications related to
     use of nonsteroidal anti-inflammatory drugs. Ann Intern Med 115:787-96, 1991.
11.Weil J, Colin-Jones D, Langman M: Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ
     310:827-30, 1995.
12.Cryer B, Feldman M: Effects of nonsteroidal anti-inflammatory drugs on endogenous gastrointestinal
     prostalglandins and therapeutic strategies for prevention and treatment of non-steroidal
     anti-inflammatory drug-induced damage. Arch Intern Med 152:1145-55, 1992.
13.McCarthy DM: Nonsteroidal anti-inflammatory drug induced ulcers: management by traditional
     therapies. Gastroenterology 96:662-74,1989.
14.Soll AH: UCLA Conference - Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann
     Intern Med 114:307-319, 1991.
15.Hawkey CJ: Regular review - Nonsteroidal anti-inflammatory drugs and peptic ulcers. BMJ 300:
     278-84, 1990.
 

b. Refractory Ulcers.

1.  Tytgat GN: Lamers CB: Hameeteman W; Jansen JM; Wilson JA. Omeprazole in peptic ulcers
     resistant to histamine H2-receptor antagonist. Aliment Pharmacol Ther. Feb 1987 1[1] p31-8.
2.  Arakawa T; Kobayashi K: Dajani EZ. [United States] Refractory peptic ulcers. J Assoc Acad Minor
     Phys 1992 3 [3] p95-102.
3.  Guerreiro AS: Neves BC; Quina MG. Omeprazole in the treatment of peptic ulcers resistant to
     H2-receptor antagonists. Ailment Pharmacol Ther, June 1990 4 [3] p303-13.
4.  Clearfield HR, Challenges in acid / peptic disorders: a symposium overview. Aliment Pharmacol Ther
     1991 5 suppl [1] p1-4.
5.  Chelvam P; WongEC, Omeprazole in acute and long term treatment of Asian patients with peptic
     ulcer refractory to H2-antagonists. J Gastroenterol Hepatol 1989 4 suppl 2 p75-81.
6.  Welch JP. Hammond JG Jr: Nissen CW. Management of benign, giant gastric ulcers. Am Surg. May
     1992 58 [5] p300-4.
7.  Dammann GH. H2-blocker refractory ulcers; what can be done? J Gastroenterol [G] Apr 1992 30 [4]
     p268-71.
8.  Dobrilla G; Amplitz S. Powerful gastric acid inhibition: when is it justified? Ital J Gastroenterol 1990
     22 suppl [1] p13-7.
9.  Bardhan KD; Naesdal J: Bianchi Porro M; Petrillo M; Lazzaroni M; et al. Treatment of refractory ulcer
     with omeprazole or continued H2 receptor antagonists: a controlled clinical trial. GUT, 1991; 32:
     435-8.
10.Pulcini M: Riccardelli FVF; Castellari M: Metelli G; Angioni C. Long term treatment of refractory
     peptic ulcers. Omeprazole: current therapeutic possibilities. Gazz Med Ita Arch Sci Med, 1991; 150:
     511-6.
11.Di Mario F: Battagalia Gl Grassi SA; Vigneri S; et al. Different doses of omeprazole in the
     maintenance treatment of patients with peptic ulcers resistant to H2-blockers. Current Ther Res
     1994; 55: 1363-71.
12.Bardhan KD, Is there any acid peptic disease that is refractory to proton pump inhibitors? Aliment
     Pharmacol Ther, 1993; 7 [suppl1]: 13-24. Review.
13.Arakawa T, H2 receptor antagonists refractory ulcers, its pathophysiology and tole of proton pump
     antagonists. Nippon Rinsho. Jan 19992 50 [1] p122-30.
14.Takase S: Tadaka A, Endoscopic studies on refractory gastric ulcers, treated with proton pump
     inhibitors. Nippon 1, Jan 19992 50[1] 116-21.
 
c. Long Term Maintenance Therapy.

1.  Robinson M. Review of peptic ulcer maintenance trials. Am J Med 1984;77(58):23-9.
2.  Jan Deventer Gm. Approaches to the long term treatment of duodenal ulcer disease. Am J Med
     1984;77(58):15-22.
3.  Hui WM, Lam SK, Ng MMT, Lai CL, Lok ASF. Long term maintenance therapy for duodenal ulcer: a
     comparison of 8 forms of treatment. Gastroenterology 1989;96:A222.
4.  Jensen DM et al. A controlled study of ranitidine for the prevention of recurrent hemorrhage from
     duodenal ulcer. N Engl J Used 1994;330:382-6.
5.  Joelson S et al. Safety experience from long term treatment with omeprazole. Digestion
     1992;51(Suppl):93-101.
6.  Shreeve DR, Klas HJ, Joues PE. Comparison of cimetidine and tripotassium bicitrato bismuthate in
     healing and relapse of duodenal ulcer. Digestion 1983;28:96-101.
7.  Forbes FM et al. Duodenal ulcer treated with Helicobacter pylori eradication; seven years follow-up.
     Lancet 1994;343:258-60.
 
d. Stress Ulcers.

1.  Palmer ED: Upper gastrointestinal haemorrhage. Springfield: Charles C. Thomas 1970.
2.  Curling TB: On acute ulceration of duodenum, in cases of burns. Medico-Chir Trans (London)
     1842;25:260-81.
3.  Selye H: Gastrointestinal system. In: The Physiology and Pathology of Exposure to Stress: A
     Treatise Based on the Concepts of the General Adaptation Syndrome and the Diseases of
     Adaptation. Montreal, ACTA, 1950, pp 688-707.
4.  Lucas CE, Sugawa C, Riddle J et al: Natural history and surgical dilemma of "stress" gastric
     bleeding. Arch Surg 1971;102:226-273.
5.  Skillman J, Suchnell LS, Goldman H et al: Respiratory failure, hypotension, sepsis and jaundice. A
     clinical syndrome associated with lethal haemorrhage for acute stress ulceration of the stomach.
     Am J Surg 1969;117:523-530.
6.  Fusamoto H, Hagiwara H, Meren H, Ksahara A, Hayashi N, Kawano S, Sugimoto T, Kamada T. A
     clinical study of acute gastrointestinal haemorrhage associated with various shock states. Am J
     Gastroenterol 1991;86:429-433.
7.  Harjola P, Sivula A: Gastric ulceration following experimentally induced hypoxia and haemorrhaghic
     shock: In vivo study of pathogenesis in rabbits. Ann Surg 1966, 163:21-8.
8.  Mersereau WA. Hinchey EJ: Effect of gastric acidity on gastric ulceration induced by haemorrhage
     in the rat, utilising a gastric chamber technique. Gastroenterology 1973:64:1130-5.
9.  Moody FG, Aldrete JS: Hydrogen permeability of canine gastric secretory epithelium during
     formation of acute superficial erosions. Surgery 1971,70:154-60.
10.Poleski MH, Spanier AH: Cimetidine vs antacids in the prevention of stress erosions in critically ill
     patients. Am J Gastroenterol 1986;81:107-11.
11.Hillman K: Acute stress ulceration. Anaes & Inten Care 1985;13:230-240.
12.Layne EA, Mellow MH, Lipman TO: Insensivity of guiaic slide tests for detection of blood in gastric
     juice. Ann Intern Med 1981;13:230-40.
13.Hastings PR. Skillmann JJ, Bushnell LS et al: Antacid titration in the prevention of acute
     gastrointestinal bleeding; A controlled randomised trial in 100 critically ill patients NEJM
     1978;298:1041-5.
14.Zinner MJ, Zuidena GD, Smith PL et al: The prevention of upper gastrointestinal bleeding in
     patients  in an ICU. Surg Gynaecol Obstet 1981; 153:214-20.
15.Cook DJ, Pearl RG, Cook R et al: Incidence of clinically important bleeding in mechanically
     ventilated patients. J Int Care Med 1991;6:167-174.
16.Hase T, Anderson PR, Mehlmann P. Significance of gastric secretory changes in pathogenesis of
     stress ulcers. Dig Dis 1975;20:443-449.
17.Fiddian-Green RG, McGough E, Pittenger G, Rothman E (1983): Predictive value of intramural pH
     and  other risk factors for massive bleeding from stress ulceration. Gastroenterology 1983;85:613.
18.Lucas CE. Stress ulceration: the clinical problem. World J Surg 1981;5:139-151.
19.Stannard VA, Hutchison A, Morris DL, Byrne A. Gastric exocrine "failure" in critically ill patients:
     incidence and associated features. BMJ 1988;296:155-6.
20.Urakawa T, Nagahata Y, Azumi Y, Sano I, Takeda K, Hashimoto Y, Ichihara T, Morimoto H, Saitoh
     Y. The mechanism of acute gastric ulceration after induced haemorrhaghic shock. Scand J of
     Gastroenterology 1989;24:193-201.
21.Kamada T, Sato N, Kawano S, Fusamoto H, Abe H. Gastric mucosal haemodynamics after thermal
     or head injury. Gastroenterology 1982;83;535-40.
22.Fridovich I. The binding of oxygen radicals. Science 1978;201:875.
23.Del Maestro RF, Thaw NH, Bjork J, Plankers M, Arfers KE. Free radicals as mediators of tissue
     injury. Acta Physiol Scand (suppl) 1980;492:43-47.
24.James Valentine, William Turner, Kareen Borman. Does nasoenteral feeding afford adequate
     gastroduodenal stress prophylaxis? Critical Care Medicine; July 1986; 599-601.
25.Susan Pingleton, Stephen Hadzima. Enteral alimentation and gastrointestinal bleeding in
     mechanically ventilated patients. Critical Care Medicine 1983; Vol 11; 13-16.
26.Salim AS. Protection against stress induced acute gastric mucosal injury by free radical scavengers.
     Inten Care Med 1991;17:455-460.
27.Crowen DE, Kunches LM, Kilinsky C, Lichtenberg DA, Make BJ, McCabe WR: Risk factors for
     pneumonia and fatality in patients receiving controlled mechanical ventilation. Am Rev Respir Dis
     1986 133:792-96.
28.Tryba. Side effects of stress bleeding prophylaxis. Am J of Med 1989;86:85-93.
29.Samloff IM, Odell C. Inhibition of peptic activity by sucralfate. Am J Med 1985:79(2C):15-8.
30.Hollander D, Tarnawski A, Krause WK et al: Protective effect of sucralfate against alcohol induced
     gastric mucosal injury in the rat: Macroscopic, histologic, ultrastructural and functional time
     sequence analysis. Gastroenterology 1985:88:366-74.
31.Crampton JR, Gibbons LC, Rees W: Effect of sucralfate on gastroduodenal bicarbonate secretion
     and prostaglandin E2 metabolism. Am J Med 1987; 83(3B):14-8.
32.Cook DJ, Reeve BK, Guyatt GH, Tryba M: Replicate variability in meta-analysis: Stress ulcer
     prophylaxis. In press 1993.
33.Cook DJ, Witt LJ, Cook RJ, Guyatt GH. Stress ulcer prophylaxis in the critically ill: a meta-analysis.
     AM J Med 1991;91:519-27.
34.Lacroix J, Infante-Rivard C, Jenicek M, Gauthier M. Prophylaxis of upper gastrointestinal bleed in
     ICUs: a meta-analysis; CCM 1989;17:862-69.
35.Schuster DP, Rowley H, Feinstein S, McGue MK, Zuckerman GS. Prospective evaluation of the risk
     of upper gastrointestinal bleed after admission to a medical ICU; Am J Med 1984;76:623-30.
36.Zandstra, Stoutenbeck. The virtual absence of stress ulcer related bleed in ICU patients receiving
     prolonged mechanical ventilation without any prophylaxis. Inten Care Med 1984;20:335-340.
 
3. Role of Endoscopy in Peptic Ulcer Disease

1.  Deneshmend TK et al. Omeprazole versus placebo for acute gastrointestinal bleeding: randomised
     double blind controlled trial. BMJ 1984;288:1277-80.
2.  Walt RP et al. Continuous intravenous Famotidine for haemorrhage from peptic ulcer. Lancet
     1992;340:1058-62.
3.  C Villanueva et al. Omeprazole vs Ranitidine as adjunct therapy to endoscopic injection in actively
     bleeding ulcers: a prospective and randomised study. Endoscopy 1995;27:308-12.
4.  Ponsky JL et al. Saline irrigation in gastric haemorrhage: the effect of temperature. J Surg Res
     1980;28:204-5.
5.  Magnusson J et al. Randomised double blind trial of Somatostatin in the treatment of massive upper
     gastrointestinal haemorrhage . Gut 1985;26:221-6.
6.  Henry DA. Effects of fibrinolytic inhibitors on mortality from upper gastrointestinal haemorrhage. BMJ
    1989;298:1142-6.
7.  Chung SCS et al. Natural history of the sentinel clot: an endoscopic study. Gastroenterology
     1990;98:Suppl A31, Abstract.
8.  Emmanuel A et al. Prognostic importance of visible vessel in haemorrhage of peptic ulcers.
     Gastrointest Endoscopy 1985;31-52.
9.  Laine L et al. Prospective evaluation of immediate vs delayed refeeding and prognostic value of
     endoscopy in patients with upper gastrointestinal haemorrhage. Gastroenterology 1992;102:314-6.
10.Hui WM et al. Can bleeding ulcer patients without stigmata of recent haemorrhage be discharged on
     the same day? A retrospective and prospective study. Gastroenterology 1992;102:Suppl:A85,
     abstract.
11.Panes J et al. Controlled trial of injection sclerosis in bleeding peptic ulcers. Lancet 1987;2:1292-4.
12.Chung SCS et al. Endoscopic injection of Adrenaline for actively bleeding ulcers: a randomised trial.
     BMJ 1988;296:1631-3.
13.Laine L et al. Multipolar electrocoagulation vs injection therapy in the treatment of bleeding peptic
     ulcers: a prospective, randomised trial. Gastroenterology 1990;99:1303-6.
14.Chung SCS et al. Injection or heat probe for bleeding peptic ulcers. Gastroenterology 1991;100:33-7.
15.Loizou LA et al. Endoscopic treatment for bleeding peptic ulcers: randomised comparison of
     Adrenaline and Adranaline injection + Nd:Yag laser photocoagulation. Gut 1991;32:1100-3.
16.Binmoeller KL et al. Endoscopic haemoclip treatment for gastrointestinal bleeding. Endoscopy
     1993;25:167-70.
17.Benjamin SB. Advances in the treatment of pyloric stenosis. ASGE Course 1992; stomach and
     doudenum - complications of peptic ulcer disease.
18.Michaeletz-Onody PA. The rebleeding peptic ulcer: should I treat the ulcer again? ASGE Course
     1995;32-36.
 

4. Role of Surgery in Peptic Ulcer Disease

1.  Johnston G.W. et al. Proximal gastric vagotomy: follow-up at 10-20 years. Br. J. Surg. 1991, Vol. 78.
     January 20-23.
2.  Wilkinson J. M. et al. Long-term results of highly selective vagotomy: a prospective study with
     implications for future laparoscopic surgery. Br. J. Surg. 1994. 81. 1469-1471.
3.  Taylor T.V. Patietal cell vagotomy: long term follow up studies Br. J.Surg 1987. Vol. 74, November,
     971-972.
4.  Johnson A.G. Management of peptic ulcer. Br J. Surg. 1994, 81. 161-163.
5.  Hunt P.S. et al. Choice of emergency operative procedure for bleeding duodenal ulcer. Br. J. Surg,
     1990. Vol 77. September, 1004-1006.
6.  Bender J. et al. Bleeding Gastroduodenal Ulcers; Improved Outcome from a Unified Surgical
     Approach. Am J Surg May 1994. 313-315.
7.  Branicki J.F. Minimal Access Gastroduodenal Surgery.Aust. N.Z.J. Surg. (1994) 64, 589-598.
8.  Lawa H.L. et al. Endoscopic Management of Peptic Ulcer Disease.Annals of Surg. May 1993. Vol.
     217, No. 5, 548-556.


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